This monocentric cross-sectional study was conducted at the University Medical Center Hamburg-Eppendorf between 11 February 2022 and 11 April 2022. We employed questionnaires addressing self-reported somatic symptom burden  and neuropsychiatric symptoms including mood , anxiety , attention  and fatigue  in a cohort of hospital workers. Scores were compared between 175 individuals less than 4 weeks after positive testing for severe acute respiratory syndrome coronavirus 2, 88 individuals more than 4 weeks after positive testing and 87 severe acute respiratory syndrome coronavirus 2 uninfected controls. The majority  of included individuals were vaccinated at least three times. After recovery from infection, no significant differences in scores assessing neuropsychiatric and somatic symptoms were detected between the three groups  independent of age, sex, preconditions and vaccination status. In addition, self-reported symptom burden did not significantly correlate with the number of vaccinations against severe acute respiratory syndrome coronavirus 2, time from recovery or the number of infections. Notably, in all three groups, the mean scores for each item of our questionnaire lay below the pathological threshold. Our data show that persistent neuropsychiatric and somatic symptoms after recovery from severe acute respiratory syndrome coronavirus 2 infection in fully vaccinated hospital workers do not occur more frequently than that in uninfected individuals. This will guide healthcare professionals in the clinical management of patients after recovery from breakthrough infections with severe acute respiratory syndrome coronavirus 2.Persistent somatic and neuropsychiatric symptoms have been frequently described in patients after infection with severe acute respiratory syndrome coronavirus 2 even after a benign clinical course of the acute infection during the early phases of the coronavirus severe acute respiratory syndrome coronavirus 2 pandemic and are part of Long COVID. The Omicron variant emerged in November 2021 and has rapidly become predominant due to its high infectivity and suboptimal vaccine cross-protection. The frequency of neuropsychiatric post-acute sequelae after infection with the severe acute respiratory syndrome coronavirus 2 Omicron and adequate vaccination status is not known. Here, we aimed to characterize post-acute symptoms in individuals with asymptomatic or mildly symptomatic breakthrough infection with severe acute respiratory syndrome coronavirus 2. These individuals had either proven infection with the Omicron variant ( et al. investigated self-reported somatic and neuropsychiatric symptoms in a cross-sectional study of a closely monitored cohort of hospital workers after infection with the severe acute respiratory syndrome coronavirus 2 Omicron variant in comparison with uninfected individuals. No differences were detected between groups adjusted for age, sex, pre-existing conditions and vaccination status.Woo and Mayer   Most commonly, the term Long COVID is used when symptoms persist for more than 4 weeks after the infection and cannot be explained by other causes.6 During the first wave of the coronavirus SARS-CoV-2 (COVID-19) pandemic, when vaccines were not yet available, it has been estimated that 31–69% of patients suffered from post-acute sequelae.7-9 Certain risk factors have been identified during the acute disease in recent observational and retrospective cohort studies that might predict the development of Long COVID. These include type 2 diabetes, SARS-CoV-2 RNAemia, Epstein–Barr virus viraemia and specific autoantibodies.11 Furthermore, female sex, high body mass index (BMI), social deprivation, advanced age, the presence of multiple comorbidities, a severe disease course and being unvaccinated predisposed to Long COVID.12 Neurological deficits during acute COVID-19 range from unspecific dizziness, headache and nausea to acute encephalitis and cerebral ischaemia.13-15 Neuropsychiatric symptoms of Long COVID remain ill-defined due to unspecific clinical presentation and diagnostic findings. For individuals infected during the first waves of COVID-19 in 2020 and 2021, persistent neuropsychiatric deficits were associated with severe acute disease and pre-existing mental health conditions.17 However, several studies also described prolonged neuropsychiatric deficits after mild SARS-CoV-2 infection in previously healthy individuals.19Long COVID has been used as an umbrella term to describe the multitude of persistent symptoms attributed to long-term effects of a SARS-CoV-2 infection. These symptoms can affect nearly every organ system and include symptoms such as fatigue, headaches, shortness of breath, fever or cognitive impairment.20 However, vaccination only conferred partial protection since the incidence of post-acute sequelae was still elevated in comparison with healthy control groups.20 This is supported by other studies21 that observed only partial protection of vaccination against persistent symptoms. However, these studies did not stratify for different SARS-CoV-2 variants and were performed before emergence of the Omicron variant and before vaccination was available. This is particularly important for patients at risk for breakthrough infections such as individuals with a compromised immune system22-24 and individuals who are frequently exposed to infection such as hospital workers.Due to the availability of vaccination, an increasing number of SARS-CoV-2 infections occur in vaccinated individuals and are referred to as breakthrough infections. The frequency and severity of post-COVID-19 symptoms in these breakthrough infections are still unclear. A recent study that utilized the US Department of Veterans Affairs national healthcare databases and compared the medical health records of more than 33 000 breakthrough infections with more than 6 million controls showed that vaccinations reduce the risk of post-acute death and Long COVID.Here, we surveyed neuropsychiatric symptoms after recovery from breakthrough infections with the SARS-CoV-2 Omicron variant. In a large cohort of otherwise healthy hospital workers, we assessed post-acute sequelae after SARS-CoV-2 Omicron infection by self-reported scores for fatigue, attention, mood, anxiety and somatic symptoms and found no significant differences in every scoring system in comparison with individuals without SARS-CoV-2 infection. These findings were independent of age, sex, preconditions, number of vaccinations and infections and did not correlate with time after recovery.25 between February 11 2022 and 11 April 2022. In total, 1575 eligible individuals with polymerase chain reaction (PCR)-confirmed infections were contacted via email by the department of infection prevention and asked to participate in an anonymized survey after recovering from acute SARS-CoV-2 infection. We received fully completed responses from 293 individuals. Of these, we excluded individuals who reported a PCR-confirmed infection with a SARS-CoV-2 variant other than the Omicron variant (n = 22), those who did not state the virus variant they were infected with and were infected before January 2022 where Omicron was not yet the predominant variant (n = 3) and those who were hospitalized during infection (n = 5). Subvariants of Omicron were not reported. We included 22 patients who were infected twice with SARS-CoV-2 of which at least one infection was with the Omicron variant. In total, 263 individuals were included after recovery from acute infection (175 less than 4 weeks after positive testing and 88 more than 4 weeks after positive testing). As a control group, we included 87 randomly selected hospital workers who did not have positive SARS-CoV-2 PCR results in their medical history and reported not having been infected before. In total, we included 350 individuals  for the final analysis.This monocentric cross-sectional analysis was performed on a longitudinally monitored cohort of hospital workers at the University Medical Center Hamburg-Eppendorf (UKE) in Germanylimesurvey.org. The Fatigue Assessment Scale (FAS) score is a 10-item self-reported questionnaire.27 It measures fatigue independent of depression and was validated multiple times in the general population, the working population and patients with chronic inflammatory diseases27 as well as cancer.28 A cut-off score above 21 points indicates fatigue. The Mindful Attention Awareness Scale (MAAS) was used to assess attention in our study cohort.29 It is a 15-item questionnaire that measures the frequency of mindful states in day-to-day life, using both general and situation-specific statements. Higher scores in the MAAS indicate higher attention.30 The Patient Health Questionnaire 2 (PHQ-2) addresses the two core criteria of depressive disorders: the loss of interest and feeling depressed. The PHQ-2 has been reported to have a high sensitivity for depressive disorders and detects changes with a performance like other longer depression scales.31 The Generalized Anxiety Disorder 7 (GAD-7) is a well-established 7-item questionnaire to screen for anxiety severity. The score has been validated for the four most common anxiety disorders in clinical practice: generalized anxiety, panic, social anxiety and post-traumatic stress disorder. Sum scores range from 0 to 21, and a score above 10 is an indicator of the presence of an anxiety disorder.33 For the self-reported burden of somatic symptoms, we applied the Somatic Symptom Scale 8 (SSS-8), which addresses somatic symptoms falling into one of the four following groups: cardiopulmonary, gastrointestinal, pain and general.34 According to the score reached in the SSS-8, individuals can be categorized into five groups of somatic symptom burden: no to minimal (0–3 points), low (4–7 points), medium (8–11 points), high (12–15 points) and very high (16–32 points). The questionnaires are provided in the The online questionnaires were distributed with the openly available tool All employees of the UKE, a tertiary care centre, were screened twice weekly for SARS-CoV-2 infection by reverse transcription PCR (RT-PCR) of nasopharyngeal swabs or gargle samples throughout the COVID-19 pandemic to prevent nosocomial transmission to coworkers and vulnerable patients. Thus, also asymptomatic and oligosymptomatic infections were detected with high sensitivity. Only study participants who reported a SARS-CoV-2 infection diagnosed by RT-PCR were included in the study.All statistical analyses were performed using the R environment (version 4.0.3). Difference in age and sex distribution as well as number of pre-existing conditions and vaccination status between groups were calculated by chi-square test. To assess the impact of Omicron infection less and more than 4 weeks after positive PCR on self-reported somatic and neuropsychiatric symptoms, we fitted a linear regression model with the sum score as dependent and recovery from Omicron infection (less versus more than 4 weeks) as independent variables. We controlled for sex , age groups , vaccination status and the number of pre-existing conditions as independent variables. To test the interaction of independent variables with recovery from Omicron SARS-CoV-2, we performed one-way ANCOVA. We corrected for multiple comparisons by false discovery rate (FDR) adjustment. Correlation analysis between time from recovery and number of vaccinations with the sums of each score were performed using Pearson’s correlation. To analyse the minimum mean difference between groups that could have been missed by each questionnaire, we calculated the effect size using a power of 0.8, a significance level of 0.05 and the respective group sizes and multiplied it with the pooled standard deviation.The study was approved by the ‘Ärztekammer Hamburg’ with the registration number 2022-300157-WF.All individuals gave consent for participation, data analysis and publication.1 To do so, we conducted a monocentric study and made use of a representative cohort of hospital workers with predominantly up-to-date vaccination status after proven infection that mainly occurred as breakthrough infection. All participants underwent regular PCR testing for SARS-CoV-2 that ensured also the detection of asymptomatically infected individuals.35-37 The algorithm of inclusion and exclusion criteria is depicted in www.rki.de). Thus, they were assumed to be infected with the Omicron variant. In addition, we randomly recruited 87 hospital workers as controls who have not been infected with SARS-CoV-2.We aimed to survey neuropsychiatric and somatic disease burden in an unbiased and self-reported fashion after infection with the SARS-CoV-2 Omicron variant in a cohort of highly exposed individuals who are critical to the healthcare system.n = 126; male, n = 49; 72% female; mean duration after infection = 25.6 ± 10.6 days), participants in the post-acute phase over 4 weeks after positive testing for SARS-CoV-2  and uninfected participants . In all groups, female participation was higher than male participation. All three groups had a similar age distribution , sex distribution χ2 = 0.04, P = 0.98) and number of pre-existing conditions  and were mostly vaccinated three times χ2 = 0.09, P = 1). Characteristics of included participants are summarized in For further analysis, we stratified participants into three groups: individuals with recovery from acute infection who were included less than 4 weeks after positive PCR testing  and participants more than 4 weeks after recovery as well as in comparison with uninfected controls , we observed no significant differences between uninfected controls and individuals that recovered from infection with the SARS-CoV-2 Omicron variant that was also independent of time after infection . Of note, the mean FAS score for all groups was below 21 points, which is commonly used as a threshold for the diagnosis of fatigue . Last, we compared patients with one infection (n = 241) and re-infection (n = 22) and identified no significant differences in remaining somatic  or neuropsychiatric symptoms  underlining the absence of post-acute neuropsychiatric deficits in individuals with up-to-date vaccination status after recovery from Omicron infection.Since we observed significant differences in some of the scores between different age groups , we perfIn this cross-sectional single-centre study, we investigated self-reported neuropsychiatric and somatic symptoms in individuals who experienced a mild breakthrough infection with the SARS-CoV-2 variant Omicron as compared with uninfected controls in a cohort of German hospital workers mostly having an up-to-date vaccination status. We used a comprehensive online questionnaire, addressing common neuropsychiatric symptoms including fatigue, attention deficits, depression and anxiety as well as the self-reported burden of somatic symptoms. For these symptoms, we did not detect any significant differences between individuals less and more than 4 weeks after infection with SARS-CoV-2 and uninfected controls after adjustment for sex, age, number of preconditions and vaccination against SARS-CoV-2.40 Recent meta-analyses and systematic reviews revealed that more than half of individuals experienced at least one symptom after recovery from SARS-CoV-2 infection that persisted for more than 6 months with mobility impairment, pulmonary abnormalities and mental health disorders being the most common.40 Furthermore, several publications showed that neuropsychiatric deficits occur independently of the severity of the initial infection.40 However, these studies were conducted at a time when mainly the Wild-Type, Alpha, Beta and Delta variants of SARS-CoV-2 were prevalent, vaccination was not available, and Omicron had not yet emerged. In contrast, cross-sectional studies that correlated cerebral imaging with neuropsychological deficits reported no differences associated with the Wild-Type variant during the first wave.41 Clinical characterization of individuals after recovery from infection with Omicron is of utmost importance since it became the predominant variant worldwide due to high infectivity and poor cross-reactivity of available vaccinations.43 It is unclear, whether the Omicron variant leads to persistent or novel neuropsychiatric and somatic symptoms after recovery from acute infection. Here, we demonstrate that vaccinated hospital workers after recovery from mild infection with Omicron do not have a higher burden of symptoms than hospital workers who never experienced SARS-CoV-2 infection. This is further supported by a recent study that analysed data from the COVID Symptoms Study app in the UK and showed that the risk of developing Long COVID was significantly lower in individuals who were infected with the Omicron variant compared with those infected with the Delta variant.44Our results are in contrast to previous studies that report frequent and severe post-acute sequelae of COVID-19 during the first phases of the pandemic.45 and on the other hand by direct invasion of the central nervous system (CNS).47 Although in vitro studies suggested neuronal tropism of SARS-CoV-2, post-mortem analyses of large cohorts could only identify SARS-CoV-2 by PCR or immunohistochemical staining of its capsid protein in the blood vessels and endothelial cells in the CNS,49 together with bystander immune cell activation51 but without parenchymal infiltration or neuronal infection. Additionally, there is no evidence of long-lasting persistence of SARS-CoV-2 in the CNS. On a systems level, elevated concentrations of the cytokine CCL11 were detected in individuals suffering from Long COVID as compared with those who experienced no symptoms following infection. Subsequent studies in mice suggest that CCL11 leads to white matter enriched microglial reactivity followed by a dysregulation of the oligodendroglial lineage and myelin loss.19 Other hypotheses include microclot formation in the blood52 and immunological dysfunctions following infection with a lack of naïve B and T cells as well as elevated expression of type I and III interferons.53 However, these studies did not analyse infection with the Omicron variant and lack specificity for SARS-CoV-2 since individuals after recovery from infection with other common viruses such as influenza virus were not investigated. Furthermore, we consider it important to include individuals who have not been infected as controls since the neuropsychiatric and somatic symptoms that are associated with Long COVID are unspecific, highly prevalent in the general population and could be exacerbated by the pandemic itself with its fundamental impact on daily living.54 Furthermore, Long COVID is currently a constant topic in the media that could contribute to overestimation of its prevalence and foster heightened attention in infected individuals.55 Studies as ours might therefore help mitigate negative expectations in susceptible individuals.The mechanistic underpinnings of Long COVID after infection with the Wild-Type, Alpha, Beta and Delta variants remain unclear. Neuropsychiatric deficits during the acute infection might be on the one hand explained by SARS-CoV-2–induced dysregulation of multiple organ systems56 In our study, we did not discriminate between Omicron subvariants. This should be systematically investigated by future studies due to the high escape of especially the BA.5 subvariant against neutralizing antibodies57 that might result in higher acute and persistent disease burden. Our cross-sectional study was restricted to hospital workers, and we cannot exclude a population bias. Nonetheless, our findings are supported by other studies that compared self-reported symptoms after infection with the Omicron and Delta variants and reported fewer individuals with long-lasting symptoms after Omicron infection.44 Furthermore, we did not have serological data for our control group available, and they were included due to self-reportedly denying past infection and the absence of positive SARS-CoV-2 PCRs in their medical history. The close monitoring of SARS-CoV-2 positivity by PCR in our cohort enabled us to sensitively identify individuals with mild disease or asymptomatic infection.Our study is limited by its cross-sectional monocentric design without longitudinal follow-up and limited sample size. We therefore calculated the difference in means for each questionnaire that could have been undetected using our sample size. However, we included a healthy control group without SARS-CoV-2 infection and did not identify differences in comparison with individuals after recovery from infection. Our study focused on hospital workers, potentially leading to selection bias since this cohort might be specifically vulnerable to develop persistent symptoms of SARS-CoV-2 infection due to the heightened workload and pressure of medical staff resulting from the pandemic and increased attention to symptoms. However, both infected and uninfected individuals reached scores mostly within the physiological range for all questionnaires. One possible explanation is the inclusion of asymptomatic infections and the better position of hospital workers to mitigate symptoms. Furthermore, we analysed self-reported symptoms, which were not affirmed through clinical examination or diagnostic tools by healthcare professionals and are potentially prone to selection bias. However, one advantage of this approach is that it facilitates the investigation of symptoms and disease burden in a large number of individuals in an unbiased and cost-effective manner. Thus, this approach has the potential to perform population-based screens to assess prevalence of post-acute sequelae. For the future, standardized questionnaires to quantify persistent neuropsychiatric symptoms after infection with SARS-CoV-2 would be desirable. Since most of the participants were vaccinated at the time of the survey, it is difficult to discriminate whether the absence of self-reported post-acute neuropsychiatric and somatic symptoms is due to vaccination or if the Omicron variant of SARS-CoV-2 is less likely to cause these symptoms. The latter is supported by a large cohort study where vaccination showed no effect on post-COVID fatigue, cognitive symptoms or affective disorders before the emergence of the Omicron variant.In summary, our data allow us to conclude that vaccinated hospital workers after recovery from mild infection with the Omicron variant of SARS-CoV-2 do not suffer from persistent somatic and neuropsychiatric symptoms in our study cohort. These findings have wide clinical implications and will guide occupational health specialists and other public health specialists in the management of potential Long COVID patients after recovery from Omicron infection.


Thus, these aberrant splicing events make promising novel therapeutic targets to restore functional gene expression. Moreover, presence of these cryptic exons is highly specific to patients and areas of the brain affected by TDP-43 proteinopathy, offering the potential to develop biomarkers for early detection and stratification of patients. In summary, the discovery of cryptic exons gives hope for novel diagnostics and therapeutics on the horizon for TDP-43 proteinopathies.TDP-43 is an RNA-binding protein with a crucial nuclear role in splicing, and mislocalises from the nucleus to the cytoplasm in a range of neurodegenerative disorders. TDP-43 proteinopathy spans a spectrum of incurable, heterogeneous, and increasingly prevalent neurodegenerative diseases, including the amyotrophic lateral sclerosis and frontotemporal dementia disease spectrum and a significant fraction of Alzheimer’s disease. There are currently no directed disease-modifying therapies for TDP-43 proteinopathies, and no way to distinguish who is affected before death. It is now clear that TDP-43 proteinopathy leads to a number of molecular changes, including the de-repression and inclusion of cryptic exons. Importantly, some of these cryptic exons lead to the loss of crucial neuronal proteins and have been shown to be key pathogenic players in disease pathogenesis (e.g. TDP-43 proteinopathy encompasses a wide spectrum of progressive neurodegenerative diseases and phenotypes. It is a key feature in ~ 97% of people with amyotrophic lateral sclerosis (ALS) and ~ 45% of people with frontotemporal dementia (FTD), a seminal discovery made in 2006 , 2. SubsTARDBP, the gene which encodes TDP-43, are rare, occurring in < 1% of ALS cases, but underscore TDP-43’s central role in disease pathogenesis [Common to TDP-43 proteinopathies is a lack of directed disease-modifying therapies, and an inability to confirm and stratify individuals that have TDP-43 pathology ante-mortem. The disease that is most frequently characterised by TDP-43 mislocalisation is ALS, which is a rapidly progressive paralysing illness with eventual death on average 3 years from symptom onset . Up to 1ogenesis –14. AlteIn this review, we will focus on a key ‘on-off’ consequence of nuclear TDP-43 loss of function, which has emerged over recent years – the occurrence of splicing defects leading to the erroneous inclusion of intronic sequences into mature mRNA, forming so-called ‘cryptic exons’ . With a CFTR gene, first realising TDP-43’s role as an RNA-binding protein and regulator of alternative splicing [POLDIP3, SORT1, and PFKP have all been used as reliable readouts for nuclear TDP-43 function in models with TDP-43 knockout, overexpression, and for studying TDP-43 ALS-causing mutations [TDP-43 was identified in 1995 as a suppressor of HIV gene expression. It was later discovered that TDP-43 expression promotes skipping of exon 9 in the splicing . Since tutations –27.TDP-43’s consensus binding motif comprises “UG”-rich dinucleotide repeats. High-throughput sequencing, combined with cross-linking immunoprecipitation experiments to discover direct TDP-43 mRNA targets, revealed that the majority of TDP-43’s binding sites in pre-RNAs were in introns , 27. A nWhat are the possible consequences that result from the insertion of novel non-conserved sequences in mRNA Fig. ? Most crSTMN2 gene [. This gene encodes for stathmin-2, a microtubule-associated protein needed for axonal growth and repair in neurons. Occurring after exon 1 and containing a stop codon and polyadenylation site, the cryptic exon leads to premature transcript termination and predicted formation of a truncated non-functional protein. Using in vitro neuronal models of TDP-43 depletion via knockdown, induction of TDP-43 mislocalisation, and pathological loss of function TDP-43 mutations known to cause ALS, the research groups demonstrated a resultant dramatic reduction in levels of mature STMN2 mRNA and functional protein. Crucially, the STMN2 cryptic exon was confirmed to be detectable also in ALS-FTD brains and spinal cords where TDP-43 pathology is present and specifically in patient post-mortem neurons with TDP-43 pathology isolated by laser capture or nuclear sorting [In 2019, a breakthrough discovery from two independent groups found that TDP-43 loss of function leads to the inclusion of a cryptic exon within the MN2 gene , 30. Thi sorting , 37. WitUNC13A is one of the top genetic risk factors for ALS, first reported in a genome-wide association study in 2009 [Munc13–1 in mice) have synaptic impairments and die soon after birth [UNC13A result in fatal microcephaly, cortical hyperexcitability, and myasthenia [UNC13A have been shown to increase risk of ALS and also shorten survival in patients. However, the underlying mechanism by which these UNC13A variants increase ALS risk was not known until earlier this year when, along with the Gitler and Petrucelli groups, we independently found that TDP-43 depletion resulted in inclusion of a cryptic exon between exons 20 and 21 of UNC13A, leading to reduced expression. Similarly to the STMN2 cryptic exon, this event can also be detected in post-mortem brain and spinal cord tissue from patients with ALS-FTD, exclusively where TDP-43 pathology is present, but not in healthy controls. in 2009 . UNC13A er birth . In humaasthenia . Single UNC13A SNPs, rs12608932 (A > C) and rs12973192 (C > G), were found to be located within the intron containing the cryptic exon, with the former SNP being located within the cryptic exon region itself. Especially given the large size of the UNC13A gene (~ 87 kb), the proximity of the SNPs to the cryptic exon led us to hypothesise a direct link between the SNPs and UNC13A cryptic splicing. Given that the cryptic exon is not present in RNA-sequencing data from healthy controls, even when homozygous for the risk SNPs (approximately 10% of Caucasians are homozygous for both risk SNPs), they seem not to be sufficient to cause cryptic exon inclusion on their own. Thus, it was hypothesised that rather than increasing ALS or FTD risk directly, the SNPs act by potentiating the expression of a cryptic exon which is dependent on TDP-43 depletion.Intriguingly, two of the associated UNC13A cryptic exon-containing transcripts in a dose-responsive manner compared to heterozygotes and non-carriers. This discovery provides a biological explanation for how presence of the UNC13A risk SNPs in ALS-FTD patients with TDP-43 pathology modifies disease outcomes, negatively affecting survival from symptom onset [Indeed, the risk SNPs enhance cryptic splicing and alter direct TDP-43 binding, thereby reducing its ability to physiologically repress cryptic exon inclusion. In keeping with this, patients homozygous for either SNP had more om onset , 41–47. ECD [Biomarkers for early diagnosis, disease stratification of subtypes and clinical stages, prognostication, and monitoring treatment response are vitally important, both for clinical trials and patient care. Fluid biomarkers of general neurodegeneration exist, most notably serum neurofilament light chain, cerebrospinal fluid (CSF) phosphorylated neurofilament heavy chain, and urinary p75ECD –50. HoweSTMN2 cryptic exon in post-mortem frontal cortex samples, in which its presence was able to discriminate between patients with FTD-TDP, progressive supranuclear palsy, and healthy control participants [Unlike canonical TDP-43 regulated splicing, the ‘on-off’ expression of cryptic exons only under TDP-43 nuclear loss of function makes them potential potent biomarker candidates for TDP-43 pathology. This proof of concept was first shown with the icipants .A key future direction will be to exploit this characteristic to develop methods that detect TDP-43 pathology ante-mortem in patient biofluids, such as in blood, CSF, urine, or tissue. Assays could involve either direct RNA detection of the cryptic exon itself, or detection of novel cryptic peptides for transcripts that escape NMD. An ideal biomarker would have a reproducibly high and linear correlation with disease activity, high sensitivity and specificity, stability throughout the day, and easy access to obtain a sample .UNC13A, undergo NMD and are therefore not stable. Moreover, if transcripts are at low levels, highly sensitive tools would be required. Detection of a panel of relevant cryptic exons deemed to be pathogenic players could theoretically increase sensitivity.With regards to biomarker detection of RNA, methods have been developed that can sensitively detect circulating RNA in the blood of individuals with Alzheimer’s disease that reflect disease-specific neural transcriptome changes . HoweverSTMN2, even though the cryptic-containing transcript is highly expressed and escapes NMD, attempts to detect the putative 16 amino acid cryptic peptide have not yet been successful. However, antibody generation to specifically detect pathological proteins is evolving, including in the field of ALS-FTD, with antibodies now available to detect dipeptide repeats that occur in the C9orf72 subtype of ALS-FTD. These have not only furthered our understanding of disease mechanisms, but are also being utilised to assess therapies [For cryptic exons that produce cryptic peptides, specific antibodies could be designed to detect these via immunohistochemistry, or ELISA and SIMOA-based assays. This has its own challenges, whether it be due to NMD of cryptic-containing transcripts, low expression, or instability of the peptides. For herapies –56.HDGFL2, detects the cryptic peptide in C9orf72-associated ALS. Strikingly, this includes pre-symptomatic mutation carriers [Excitingly, two new pre-print publications this year have independently reported the detection of cryptic peptides in the CSF of patients with ALS , 58. Irwcarriers . In SeddNeurofascin in these cells, highlighting how, if certain TDP-43 cryptic exons are expressed only by given cells, they could allow tracing of TDP-43 proteinopathy. Furthermore, recent work showing that pTDP-43 and loss of nuclear TDP-43 can be detected years before ALS disease presentation in central nervous system and non-central nervous system tissue suggests that detection of TDP-43 cryptic exons could possibly pre-date disease onset [Given the cell-type specificity of TDP-43 controlled cryptic exons, it is also possible that biomarkers towards cryptic exons could be designed to assess the flow of TDP-43 proteinopathy across the nervous tissue , 59, 60.se onset , 65.Another interesting avenue is the use of model systems to determine the timing of the emergence of cryptic exon inclusion events. For instance, studies assessing the presence of cryptic exons at different levels of TDP-43 knockdown in vitro, or in patients with or post-mortem tissue from varying clinical stages of ALS-FTD, could allow curation of a database reflecting which cryptic exons appear early and late in disease. Further analysis of this could provide a greater mechanistic understanding of cryptic exon biology and what factors make certain genes more sensitive and susceptible to the inclusion of cryptic exons with TDP-43 loss. Such a stratification may also have implications for biomarker studies and early diagnosis and stratification of people with ALS-FTD.Further work is necessary to utilise the specificity of cryptic exons to develop appropriate biomarkers, which could be transformative to the field of ALS-FTD and other TDP-43 proteinopathies. Particularly with new therapies on the horizon for neurodegenerative diseases, early diagnosis of individuals who are or will become affected and a readout for treatment response will be critical in halting the disease process at an early enough stage to pre-empt the point of no return in the ALS disease cascade .The discovery that certain cryptic exons, and potentially more that remain to be explored, underpin the disease process in ALS – either by impairing neuronal health, increasing ALS risk, or worsening disease progression – makes them exciting novel therapeutic targets. If early diagnosis can be achieved, the hope would be to restore expression of critical proteins to normal functional levels, or use splicing therapies to modulate and prevent aberrant splicing from occurring altogether in TDP-43 proteinopathies.STMN2 cryptic exon leads to a reduction in STMN2 expression. Thus, one strategy would be to restore normal STMN2 levels using a viral vector containing the correct DNA sequence, such as via adeno-associated viral (AAV) or lentiviral delivery. This proof of concept was shown when transduction of TDP-43 depleted iPSC-derived motor neurons with lentivirus carrying STMN2 restored STMN2 levels and also, importantly, restored axonal regeneration after axotomy [Stmn2 (Stmn2−/−) that the introduction of the human STMN2 gene was able to rescue motor deficits [SMN overexpression [UNC13A would be too large to be introduced via this methodology, as opposed to STMN2, which would theoretically be more amenable.The  axotomy . It was deficits . Howeverpression . Moreovepression . AnotherSOD1 and C9orf72 have been tested in ALS clinical trials . The former showed very encouraging results, but failed to reach significance in achieving primary clinical endpoints in a phase 3 trial, and the latter phase 1 trial showed no difference from placebo for clinical endpoints and in fact trended towards greater decline at the higher dose. These results highlight some of the caveats of ASO therapies [Other important gene-therapy strategies involve the prevention of erroneous RNA splicing. Compared to the above described gene delivery methods, these approaches aim to correct endogenous splicing and therefore avoid problems deriving from overexpression and toxicity. One method is via antisense oligonucleotide therapies (ASOs), which are short synthetic DNA sequences that are designed to selectively bind to pre-mRNA in cells. ASOs have come to the forefront as a new tool for numerous neurodegenerative diseases, including toxic gain of function gene-specific ALS subtypes, where they have been used to degrade mutant transcripts. ASOs designed to reduce protein produced from mutant herapies , 71. ASOherapies . One draRuminococcus flavefaciens), and using modified uridine-rich small nuclear RNA (snRNA) gene therapy, such as via U7 snRNA delivery, which has shown promise in DMD, and has entered its first clinical trial [Other effective splice switching strategies include systems that target pre-mRNA, but are stably expressed in the long-term, thereby preventing the need for repeated dosages, whilst also aiming to circumvent the above concerns regarding overexpression. These include CRISPR-Cas ribonuclease programming, such as via RfxCas13d (also named CasRx, from al trial –78. In aFinally, small molecule delivery has been developed as a further tool to alter splicing. A clear benefit of this therapeutic platform is the ability to deliver the treatment to patients orally. The first small molecule splicing modifier to be approved was Risdiplam for oral delivery in SMA. It was shown to increase SMN protein in the central nervous system and peripheral tissues in mice, and to restore functional SMN protein in patients with SMA –82.STMN2 and UNC13A that have been reported in humans are not present in mice. In fact, and interestingly, different UNC13A cryptic exons are present in mice [Homing in on correcting cryptic exon-related mis-splicing, a phase I clinical trial is planned to assess an ASO designed to restore STMN2 levels . Commonl in mice . Therefo in mice , 85. Ano in mice , 35. WhiWhilst blocking TDP-43 cryptic exons to restore gene expression appears to have a relatively clear mechanistic benefit, it remains to be seen how many and which cryptic exons need to be targeted for an effective therapy. Future experiments may seek to determine which cryptic exon inclusion events are pathologically relevant, impacting on a biological pathway that contributes to disease, as this may impact the development of therapies and potential ways to restore the expression of multiple mRNA targets, as opposed to one at a time.The past decade has seen leaps forward for people with gene-specific ALS-FTD, now with gene-based therapies coming into play. However, these would not benefit people with sporadic disease, making up the majority of patients with ALS-FTD, or those that have different pathogenic genes that are not amenable to treatment with available gene-based therapies. Given that almost all patients with ALS have TDP-43 pathology, the recent breakthroughs revealing that TDP-43 dependent mis-splicing of mRNA plays a major role in disease pathogenesis provides a fresh injection of hope into the field, not only for the ability to better understand molecular mechanisms, but also for the transformative potential with regard to biomarker development and therapeutics, desperately needed for patients living with this fatal disease. Important focuses going forward will be to establish which other cryptic exons, if any, are pathogenic players, and for the knowledge gained about cryptic exons to be transferred to and explored in other TDP-43 proteinopathies.


In November 2021, seven western lowland gorillas and four Asiatic lions were diagnosed with COVID-19 at Rotterdam Zoo. An outbreak investigation was undertaken to determine the source and extent of the outbreak and to identify possible transmission routes. Interviews were conducted with staff to identify human and animal contacts and cases, compliance with personal protective equipment (PPE) and potential transmission routes. Human and animal contacts and other animal species suspected to be susceptible to SARS-CoV-2 were tested for SARS-CoV-2 RNA. Positive samples were subjected to sequencing. All the gorillas and lions that could be tested  were RT-PCR positive between 12 November and 10 December 2021. No other animal species were SARS-CoV-2 RNA positive. Forty direct and indirect human contacts were identified. Two direct contacts tested RT-PCR positive 10 days after the first COVID-19 symptoms in animals. The zookeepers’ viral genome sequences clustered with those of gorillas and lions. Personal protective equipment compliance was suboptimal at instances. Findings confirm transmission of SARS-CoV-2 among animals and between humans and animals but source and directionality could not be established. Zookeepers were the most likely source and should have periodic PPE training. Sick animals should promptly be tested and isolated/quarantined. What did you want to address in this study?In Rotterdam Zoo, in late 2021, two animal species (gorillas and lions) were simultaneously infected with SARS-CoV-2, despite the use of personal protective equipment (PPE) by their zookeepers. We aimed to identify all possible transmission routes and provide recommendations to optimise the protection of animals and zookeepers from infection.What have we learnt from this study?We found several possible transmission paths and SARS-CoV-2 positive zookeepers were the most likely source of the outbreak. The genomic data of SARS-CoV-2 supported transmission of SARS-CoV-2 among animals and between humans and animals. It was beneficial to work with several specialists in animal and human health, virology, occupational medicine, public health and zoo management during the outbreak investigation. What are the implications of your findings for public health?This outbreak affecting multiple species showed challenges in preventing interspecies SARS-CoV-2 transmission. To prevent respiratory zoonotic diseases, it is necessary to adopt stringent prevention and control strategies in zoos. Working with animals may make adhering to PPE guidelines challenging. Zookeepers should be supported in using PPE correctly, by providing repeated training and by provision of PPE that fits optimally.To date March 2023), the COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in more than 600 million cases and 6.5 million human deaths worldwide 023, the . Severe In several zoos, SARS-CoV-2 has caused infections among captive animals such as felines and non-human primates, likely caused by human-to-animal transmission -13. To pIn November 2021, within 6 days, multiple western lowland gorillas and Asiatic lions experienced fever, coughing and lethargy in Rotterdam Zoo, the Netherlands. An outbreak was confirmed when both animal species were diagnosed with COVID-19 by means of positive SARS-CoV-2 real-time polymerase quantitative chain reaction (RT-qPCR) tests. The risk of further transmission among animals, staff and visitors were reasons to conduct an extensive outbreak investigation.In this report we describe the findings of investigating the source, possible transmission routes and the extent of the outbreak.The Rotterdam Zoo welcomed 1.5 million visitors per year before the pandemic . The zooSupplementary Figure S1). The outside enclosure of the gorillas is surrounded by a few metres of bushes. At some spots where the public can come closer, the gorillas are separated from the public by means of a ditch and a glass wall. Gorillas hardly use their outdoor enclosure during autumn and winter. The indoor gorilla enclosures have a separate airflow and the enclosure is separated by a wall and glass window from the visitors. There is an open connection between the indoor gorilla enclosures and the staff work- and breakrooms (via an open roof construction of the gorilla enclosure and an air vent and possible open windows of the breakroom of the staff). In the lion indoor enclosure, air from the visitors’ area flows through a high-efficiency particulate air (HEPA) filter through the indoor enclosures of the animals to outside. The lions’ and gorillas’ food was prepared in different kitchens.The lions and gorillas each have indoor facilities and adjacent outdoor enclosures, their enclosures are ca 200 m apart  protocol . PersonaVisitors were obliged to show a COVID-19 admission ticket i.e. a proof in the form of a QR code that they had been (i) fully vaccinated either with two doses of Comirnaty, Spikevax or Vaxzevria, Moderna Vaccine or one dose of Jcovden, (ii) recovered from COVID-19, or (iii) recently tested negative for SARS-CoV-2. Moreover, a one-way walking route for visitors was set up in the zoo. It was possible for visitors to throw food, although not allowed, to the outdoor animal enclosures.An outbreak team was convened with the zoo head veterinarian, public health and communication experts of the Public Health Service (PHS) and virologists specialised in One Health.Direct contact was defined as contact of > 15 min at < 1.5 m with persons or animals who tested SARS-CoV-2 positive. Indirect contact was defined as having entered the gorilla or lion enclosures or being involved with animal food preparation or having come into contact with animal faeces, all regardless of the use of PPE. Clinical and epidemiological data were collected on the identified human and animal cases. A case was defined as RT-qPCR-confirmed SARS-CoV-2 infection in either animals or staff between 2 weeks before and 4 weeks after the first occurrence of symptoms compatible with a COVID-19 infection of an animal. A line-listing of all identified cases was compiled and summarised according to time, place and person.Specimen collection and diagnosticsNose and throat specimens were collected from identified contacts, including all zookeepers (n = 19) of the gorillas and lions and facility staff members (n = 21) at 3 and 5 days after the confirmation of SARS-CoV-2 in those animals respectively. The samples were then analysed for SARS-CoV-2 in regional laboratories.Supplementary Table S1) [Samples were taken from lions and gorillas, where possible, after the first clinical signs of disease. After confirmation of SARS-CoV-2 infection, all animals of the taxonomic (sub)orders of Primates and Carnivora were sampled between 19 November and 8 December 2021. Following novel reports on SARS-CoV-2 infections in white-tailed deer and hippopotamuses, faeces of related animal species were also tested for SARS-CoV-2 if possible (able S1) ,17. SampRodents that were caught in regular pest control between 15 November and 8 December 2021 were also tested. Specimens were pooled per animal species and throat swabs, rectal swabs and lung tissue of all rodents were tested for SARS-CoV-2 RNA . Lung tiTo study the extent of the SARS-CoV-2 outbreak, available sera (blood drawn for other purposes) collected between October 2021 and March 2022 were tested for IgG antibodies for SARS-CoV-2. We did not subject the animals to blood sampling for outbreak research. The procedure for the direct enzyme-linked immunosorbent assays (ELISA) is as previously described  but withSevere acute respiratory syndrome coronavirus 2-positive specimens with sufficient viral loads were sequenced using an amplicon-based Nanopore sequencing approach, using ARTIC V3 primers . LibrariAll available genomes from the Netherlands in the period February 2020 to September 2021 were downloaded from GISAID and down sampled based on 10 nucleotides (nt) differences . All avaTo investigate other routes of transmission, an extensive environmental investigation was initiated. The zoo veterinarian was interviewed concerning the functioning of the sewage system, the food handling, possibilities of (in)direct contact between visitors and animals, pests and the occurrence of incidents that may have enabled transmission between humans and animals. Public Health Service infectious disease specialists visited the zoo to assess compliance to hygiene measures, PPE use in practice  and the Supplementary Table S2). In addition, faecal samples deriving from multiple gorillas or lions (group samples) also tested positive. The animals tested negative for influenza, parainfluenza and rhinovirus and Toxocara.On 11 November 2021, zookeepers noticed that some of the gorillas were coughing. In the next 2 days, all seven gorillas living in the same enclosure displayed coughing and a decreased food intake and three of the seven gorillas also showed sweating and lethargy . An eighThe data are graphically illustrated in an epidemiological curve incorporated in a timeline, in which the events are described chronologically . One weeThe gorillas and lions were managed under two different animal departments and were taken care of by separate groups of zookeepers. Both groups used the same changing rooms. Nineteen staff were identified as direct contacts: two veterinarians, a trainee veterinarian, eight gorilla zookeepers, six lion zookeepers and two zoo laboratory staff. Twenty-one facility staff were identified as indirect contacts e.g. through food handling and cleaning of the animal housing.Seven gorillas in one enclosure and a solitary gorilla in a different enclosure were identified as direct contacts of each other and/or their zookeepers. Four lions lived with each other, and another adult female was housed separately from the group, however, they shared the same enclosure using a rotating system. Consequently, the lion group and the single female were indirect contacts via secretions of each other. Three mangabeys living in the outside gorilla enclosure were considered direct contacts of the gorillas.Supplementary Table S1).To identify the possible source of infection in the animals, direct human contacts were RT-qPCR tested on 21 November 2021. Two of 19 were confirmed SARS-CoV-2 positive: one zookeeper of the gorillas (Z1) and one of the lions (Z2). Since the zookeepers had high viral loads (quantification cycle (Cq) Z1: 19.5, Cq Z2: 22.5) and one had symptom onset after the start of illness among the animals, the source of the outbreak remained uncertain. Therefore, we decided to test all but one (one staff member declined) indirect contacts (n = 20) on 24 November 2021, all of whom tested negative. The solitary living gorilla and mangabeys also tested negative. All faecal samples of all other animals that are part of the orders Carnivora (n = 17), Primates (n = 70), Macroscelides (n = 1) and Ungulates (n = 5) tested negative (Supplementary Table S3). None of the sera was positive. There was no serum available for animals who tested RT-qPCR positive after November 2021. The serum sample collected on 9 March 2022 belonged to the gorilla who lived in the separate enclosure.Seventy-one serum samples of 13 different species belonging to the orders Carnivora, Primates and Ungulates  were screened for IgG antibodies for SARS-CoV-2 between October 2021 and March 2022  . Whole gSupplementary Table S4). Zookeeper Z2 taking care of lions, remained asymptomatic, and tested positive on 21 November.Ultimately, three zookeepers were confirmed SARS-CoV-2 positive. Zookeeper Z1 who was taking care of gorillas, had symptom onset on 18 November 2021. This zookeeper had contact with zookeeper Z3 on 16 November, who tested positive on 18 November. Zookeeper Z3 had not been in contact with the gorillas, the lions or with zookeeper Z2 . The hygiene protocol was extended to the use of changing overalls and splash goggles.We describe the results of an extensive investigation of a SARS-CoV-2 outbreak in a zoo among lions and gorillas. It is most probable that the animals were infected through their zookeepers, although we could not determine the transmission routes with certainty. In this outbreak, two animal species, which were housed ca 200 m apart from each other and cared for by two different zookeeper groups, plus two direct human contacts (zookeepers), were infected, despite PPE use and the implemented preventive measures of the zoo. Listing all hypothetical transmission routes, we considered one or multiple asymptomatic infectious zookeepers, who may have had contact with each other in private settings or in the changing rooms, as the most likely outbreak source. Subsequent animal-to-animal transmission is likely given the high attack rate among the animals and the consistent PPE use of the zookeepers. Moreover, the genomic data of the two zookeepers and the lions and gorillas clustered, which may indicate transmission between the animals and their zookeepers. However, similar Delta variant SARS-CoV-2 circulated predominantly in the Rotterdam population during the same time. Therefore, it is impossible to make definitive statements on the outbreak source, based on the generated sequence data. Previous SARS-CoV-2 infections in zoo-managed animals also pointed to zookeepers as the most probable source of infection -13,24. TOther possible outbreak routes are airborne or indirect transmission (e.g. fomites or food-borne) to the animals by infectious visitors. However, this is unlikely since the distance between visitors and animals outside is at least 1 m and evolving evidence about SARS-CoV-2 transmission suggests that the share of SARS-CoV-2 transmission via fomites is small . In a reIn a zoo, the number of captive animals living in proximity to each other is relatively small, which makes the chance of developing a new variant of SARS-CoV-2 in an animal reservoir small. However, knowledge on transmission and identifying potential reservoirs is important for monitoring and surveillance purposes.Before this outbreak, no animals had been confirmed to be SARS-CoV-2 infected in our zoo. The absence of positive serologic findings supports the absence of previous SARS-CoV-2 infections. A systematic review showed that after vaccination, neutralising antibodies are detectable after 1 week in primates . This maThe two identified SARS-CoV-2 infected staff displayed symptoms and tested positive 7 days after the disease onset of their animals. They were also found to have high viral loads, indicating a recent infection. Therefore, we considered them an unlikely source of the SARS-CoV-2 infection of the animals. Although human-to-human transmission is the most probable explanation, we cannot rule out animal-to-human transmission. The zookeepers may have (self) contaminated through touching their facemasks because of discomfort  and their reported re-use of facemasks. Besides that, both zookeepers had close contact with the sick animals.Working with animals may make adhering to PPE guidelines challenging. Challenges with PPE, such as uncomfortable facemasks during physically tough work in warm circumstances or inadequate doffing and donning, which is also seen with healthcare professionals, may play a role in several outbreaks that have been reported among captive animals and their human contacts worldwide -13,28-30Based on our experience and the literature on the topic, we propose five actions to limit the risk of SARS-CoV-2 transmissions in zoos. Firstly, all animals in zoos showing clinical COVID-19-like signs should be promptly tested for respiratory pathogens . SecondlWe described an outbreak of COVID-19 among two animal species in separate locations within a single zoo, in which positive zookeepers were the most probable source of the outbreak despite PPE use by them. We identified several potential transmission paths. It is crucial to adopt stringent prevention and control strategies to avoid introduction of respiratory pathogens in animal populations. One Health collaboration remains important to contribute to the reduction of known and potential public health risks and occupational hazards for zoo staff.


Electronic health records (EHRs) have yet to fully capture social determinants of health (SDOH) due to challenges such as nonexistent or inconsistent data capture tools across clinics, lack of time, and the burden of extra steps for the clinician. However, patient clinical notes (unstructured data) may be a better source of patient-related SDOH information.It is unclear how accurately EHR data reflect patients’ lived experience of SDOH. The manual process of retrieving SDOH information from clinical notes is time-consuming and not feasible. We leveraged two high-throughput tools to identify SDOH mappings to structured and unstructured patient data: PatientExploreR and Electronic Medical Record Search Engine (EMERSE).We included adult patients (≥18 years of age) receiving primary care for their diabetes at the University of California, San Francisco (UCSF), from January 1, 2018, to December 31, 2019. We used expert raters to develop a corpus using SDOH in the compendium as a knowledge base as targets for the natural language processing (NLP) text string mapping to find string stems, roots, and syntactic similarities in the clinical notes of patients with diabetes. We applied advanced built-in EMERSE NLP query parsers implemented with JavaCC.We included 4283 adult patients receiving primary care for diabetes at UCSF. Our study revealed that SDOH may be more significant in the lives of patients with diabetes than is evident from structured data recorded on EHRs. With the application of EMERSE NLP rules, we uncovered additional information from patient clinical notes on problems related to social connectionsisolation, employment, financial insecurity, housing insecurity, food insecurity, education, and stress.We discovered more patient information related to SDOH in unstructured data than in structured data. The application of this technique and further investment in similar user-friendly tools and infrastructure to extract SDOH information from unstructured data may help to identify the range of social conditions that influence patients’ disease experiences and inform clinical decision-making. There is growing recognition that addressing social determinants of health (SDOH)—the conditions in which people are born, grow, work, live, and age—in patient care is necessary for achieving optimal and equitable diabetes outcomes ,2. PriorInternational Classification of Diseases (ICD) codes have become more widespread, these are often not used by clinicians , and Current Procedural Terminology) [In 2018, researchers from the University of California, San Francisco (UCSF) created the Compendium of Medical Terminology Codes for Social Risk Factors that maps SDOH to existing ICD codes   and unstructured  patient data: PatientExploreR and Electronic Medical Record Search Engine (EMERSE) . We usedUCSF EHR data were extracted using the SQL-based deidentified Clinical Data Warehouse (De-ID CDW) and PatientExploreR. The De-ID CDW is a deidentified database copy of high-value UCSF EHR data . De-ID CThe De-ID CDW includes data from UCSF’s Epic-based EHR tool and historical EHR data prior to Epic adoption. The De-ID CDW includes the following data elements from the Epic EHR at UCSF Health: patient demographic and geographic information, allergies, billing, coverage, diagnoses, encounters, immunizations, lab, medication orders, procedure orders, providers, clinical notes, and vitals.PatientExploreR is a user-friendly R Shiny application that enables rule-based mining of structured, clinical, patient-level interactive dynamic reports using Boolean operators and provides auto-generated visualization of clinical data. PatientExploreR’s data pipeline comes from the De-ID CDW, and exploration of the EHR data requires no advanced programming skills, as PatientExploreR data can be queried and extracted in a web-based format.ICD-10-CM: E10, E11) [For this study, we queried PatientExploreR to identify all adult patients (≥18 years of age) receiving primary care services for diabetes between January 1, 2018, to December 31, 2019. Primary care patients were defined as those who had completed two office visits with a primary care department on different dates of service and who had a documented encounter diagnosis of diabetes  . We excl10, E11) .EMERSE clinical notes are deidentified through automated machine redaction using a protected health information filter  Figure . A visuaFor the same cohort of patients with diabetes identified within PatientExploreR, we then conducted a second exploration of SDOH documentation within the unstructured clinical notes . We linkTo compare the SDOH ICD Compendium codes from the structured EHR data to the unstructured clinical notes, we first transformed the Compendium into a set of textual search terms and concepts that would emerge within the free-text sections of the physician’s note. We used expert raters to develop a corpus using SDOH in the Compendium as a knowledge base as targets for the NLP text string mapping to find string stems, roots, and syntactic similarities in the clinical notes of patients with diabetes. To reduce false positives, we applied Boolean logic and proximity searches to create an exclusion term list within the NLP rule . We deteTwo independent reviewers (SM and JA) manually assessed the clinical notes for each SDOH domain to validate the classification performance of the NLP rule. One reviewer (SM) manually reviewed 100% of the clinical notes from each SDOH domain to validate the NLP rule’s classification performance. Reviewers tagged the clinical note as a true positive if the narrative had at least one mention of the social risk factor associated with the respective SDOH domain .A second reviewer (JA) conducted a 2-step validation process. First, all the patients with clinical notes tagged “positive” for SDOH social risk factors by SM were reviewed by JA to ascertain the observed proportional agreement. Second, we randomly sampled 10% of clinical notes from each SDOH domain to ascertain the interrater agreement between SM and JA.ICD-10 Z code groupings to calculate the prevalence of patients with SDOH documented within their structured data [We use the Center for Medicaid Services red data . Our firThe institutional review board at the University of California San Francisco approved this study (IRB number: 18-25696).ICD-10-CM: E10, E11) at UCSF from January 1, 2018, to December 31, 2019. In the structured data, 16 (0.38%) patients had ICD-10 Z60 codes for social connectionsisolation, 14 (0.33%) patients for stress, 4 (0.09%) patients for employment insecurity, 26 (0.61%) patients for housing insecurity, 39 (0.91%) patients for food insecurity, 4 (0.09%) patients for problems related to education, and 4 (0.09%) patients for financial insecurity (We identified 4283 adult (≥18 years of age) patients with 30,288 clinical notes receiving primary care for their diabetes  was defined as a lack of social connections or feelings of isolation or loneliness [ICD-10-CM Z60 groupings diagnosis within their structured data, and 298 patients did not. A manual review of the clinical notes confirmed social connections/isolation problems for 197 (62.9%) of the 313 patients  was defined as problems related to employment, unemployment, job loss, and work-related stressors [ICD-10-CM Z56 diagnosis and 355 patients did not. One patient did not have any clinical notes registered in the EMERSE system. Among 358 patients identified by the NLP rule, a manual review of the clinical notes confirmed problems related to employment for 197 (55%) patients , and unstable housing using the roupings . The EMEICD-10-CM Z59.4) was defined as a lack of adequate food or intermittent access to food [ICD-10-CM Z59.4 or ICD-10-CM Z59.41 diagnosis code in their structured data and 118 patients did not. Among 118 patients identified by the NLP rule, a manual review of the clinical notes confirmed food insecurity for 102 (65%) patients  patients  was defined as patients reporting financial burdens, low income, poverty, or no income [ICD-10 Z59.5, ICD-10 Z59.6, or ICD-10 Z59.7 diagnosis code in their structured data and 207 did not. Among the 211 patients identified by the NLP rule, a manual review of the clinical notes confirmed financial insecurity for 113 (53.6%) patients  patients  patients for housing insecurity compared to 197 (62.9%) patients for social connections/isolation. The findings highlight that future descriptive research should combine the usage of structured and unstructured data.ICD-10-CM diagnosis codes for SDOH [Our study findings are consistent with prior studies that found that EHR structured data underestimates SDOH. These studies found that less than 1% of cohorts had respective for SDOH -21 documfor SDOH . HoweverTo our knowledge, this is the first study to use PatientExploreR and EMERSE, two high-throughput tools, to identify SDOH mapping in structured and unstructured data for a population of patients with a specific chronic health condition. Neither tool requires users to have prior expertise in programming skills, which makes it accessible to a wider audience of clinicians and researchers. We used the compendium of medical terminology codes for social risk factors as a new data source to generate a corpus. The wider application of this adaptable technique may help to more robustly identify social factors that influence disease management and outcomes for a range of diseases and conditions and inform clinical decision-making.There are several limitations of this study. This study was conducted using patient-level data from the UCSF medical system, which may limit external validity to the general population of patients with diabetes . HoweverDespite these limitations, this method has proven useful for clinicians and researchers interested in high-throughput ways to capture additional SDOH information related to patients to inform clinical decision-making. The ability to identify patients who are at risk via a streamlined high-throughput method can prevent downstream health burdens of social risk factors. Future work could focus on developing a rule-based machine learning algorithm to create and refine NLP rules associated with the other SDOH domains . Additionally, it is important for future work to understand the semantic variations that are used to characterize SDOH in clinical notes. Future research in this area to understand whether the performance of the NLP rule differed by certain patient characteristics  would be valuable.Using unstructured data of patients with diabetes via EMERSE, we discovered more patient information related to a set of SDOH than we identified using structured data alone. Application of this technique, and future investments in similar user-friendly tools and infrastructure for capturing information from unstructured EHR data, may help to identify the range of social conditions that influence patients’ disease experience and inform clinical decision-making. If these data lead to improvements in clinical care and connections to social services, they are likely to result in improved patient health outcomes and, ideally, contribute to reducing health disparities.


To deliver the most wide-ranging set of antimicrobial resistance (AMR) burden estimates for Croatia to date.A complex modeling approach with five broad modeling components was used to estimate the disease burden for 12 main infectious syndromes and one residual group, 23 pathogenic bacteria, and 88 bug–drug combinations. This was represented by two relevant counterfactual scenarios: deaths/disability-adjusted life years (DALYs) that are attributable to AMR considering a situation where drug-resistant infections are substituted with sensitive ones, and deaths/DALYs associated with AMR considering a scenario where people with drug-resistant infections would instead present without any infection. The 95% uncertainty intervals (UI) were based on 1000 posterior draws in each modeling step, reported at the 2.5% and 97.5% of the draws’ distribution, while out-of-sample predictive validation was pursued for all the models.Escherichia coli, Staphylococcus aureus, Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa (ordered by the number of deaths). Trimethoprim/sulfamethoxazole-resistant E coli and methicillin-resistant S. aureus were dominant pathogen-drug combinations in regard to mortality associated with and attributable to AMR, respectively.The total burden associated with AMR in Croatia was 2546 (95% UI 1558–3803) deaths and 46 958  DALYs, while the attributable burden was 614 (365–943) deaths and 11 321  DALYs. The highest number of deaths was established for bloodstream infections, followed by peritoneal and intra-abdominal infections and infections of the urinary tract. Five leading pathogenic bacterial agents were responsible for 1808 deaths associated with resistance: We showed that AMR represented a substantial public health concern in Croatia, which reflects global trends; hence, our detailed country-level findings may fast-track the implementation of multipronged strategies tailored in accordance with leading pathogens and pathogen-drug combinations. Antimicrobial resistance (AMR) belongs to the most pressing public health hazards worldwide and demands the commitment of all countries in determining priorities and framing adequate policies . The mosCroatia has been aware of the importance of this hazard for several decades. AMR surveillance in this country was inaugurated in 1996 with the establishment of the Croatian Committee for Antibiotic Resistance Surveillance at the Croatian Academy of Medical Sciences . This stHowever, previous ECDC reports focused on prevalence surveillance of resistant invasive strains  and covered only eight bacterial species that were deemed of public health significance in Europe ,9, an efNotwithstanding such an established history in resistance tracking and participation in the burden of AMR assessment, there is also an issue of whether the publication and dissemination of these results actually informed health care providers and influenced prescription patterns in Croatia. Croatia is placed among European countries that have a rather high total consumption of antimicrobial agents , which, consequently, translates to high resistance rates of many pathogenic species . In CroaAccordingly, there is a need for even better indicators of country-level AMR burden that would offer precise insights to health care professionals, the scientific community, and the general public to inform policy decisions. In this study, we aimed to present the most complete and wide-ranging country-level estimates of the bacterial AMR burden in 2019 for Croatia to date, showing the proportion of deaths and DALYs caused by antibiotic-resistant microorganisms across different infectious syndromes, and covering a comprehensive set of bacterial agents and pathogen-drug combinations with the use of two innovative counterfactual scenarios.This study used the methodological approach and robust estimation process of overall and age-specific deaths/DALYs from the global burden of AMR framework  to provihttps://ghdx.healthdata.org/record/ihme-data/global-bacterial-antimicrobial-resistance-burden-estimates-2019).More specifically, the majority of microbial data came from the SENTRY Antimicrobial Surveillance Program, Pfizer ATLAS Programme, European Antimicrobial Resistance Surveillance Network, Study for Monitoring Antimicrobial Resistance Trends, Global Antimicrobial Resistance Surveillance System by the World Health Organization (WHO), and specific country-level resistance data for tuberculosis and the Gonococcal Antimicrobial Surveillance Programme. More details on the data sources and systematic reviews that were used for the estimation process can be found in the Appendix of the article by Murray et al on the global burden of AMR , and datWe estimated the AMR disease burden for 12 main infectious syndromes and one residual group, 23 pathogenic bacteria, and 88 bug–drug combinations. Our overall approach consisted of five components: 1) mortality count where infection was implicated, 2) infectious deaths (proportion) that are attributable to a specific infectious syndrome, 3) infectious syndrome deaths (proportion) attributable to a specific pathogen, 4) pathogens that are resistant to an antimicrobial drug of interest in percentage terms, and 5) the excess death or infection duration risk associated with this resistance. These components enabled us to estimate disease burden based on two plausible counterfactual scenarios : deaths that are attributable to AMR considering an alternative scenario where drug-resistant infections are substituted with sensitive ones, and deaths that are associated with AMR considering an alternative scenario where individuals with drug-resistant infections would instead be without any infection.Across these five modeling components, there were ten broad estimation steps. Estimation steps 1-2 defined the death counts where infection was implicated by referring to the Global Burden of Disease (GBD) 2019 cause of death estimates , taking Advanced statistical techniques including the Bayesian meta-regression tool MR-BRT, a network analysis using multinomial estimation with partial and composite observations , a two-stage spatiotemporal modeling framework , and spatiotemporal Gaussian process regression were used in the process. More details on our modeling approach and major methodological innovations can be found in the AMR global burden  and the In Croatia in 2019 there were 5333 deaths (95% UI 3378–8010) associated with one of 11 infectious syndromes  as an underlying or an intermediate cause of death. Bacterial pathogens of interest  caused 4160 (2582–6237) of such deaths. The burden of associated and attributable mortality due to bacterial AMR was 2546 (1558–3803) and 614 (365–943) deaths, respectively. Among the estimated syndromes, bloodstream infections had the highest total burden with 1067 (529–1804) deaths associated with and 264 (132–460) deaths attributable to any resistant pathogen-drug combination, followed by peritoneal/intra-abdominal infections, infections of the urinary tract, and lower respiratory infections (by order of number of deaths). These four syndromes were behind more than 90% of fatal outcomes associated with and attributable to AMR in Croatia in 2019. A complete breakdown by infectious syndrome for deaths and DALYs is shown in Escherichia coli (694 [443–1017] deaths), Staphylococcus aureus (335 [198–522] deaths), Acinetobacter baumannii (288 [142–510] deaths), Klebsiella pneumoniae (281 [174–420] deaths), and Pseudomonas aeruginosa (210 [130–322] deaths)  were 59.9 (95% UI 36.7–89.5) and 28.9 (17.4–43.6) per 100 000 people, respectively, while the overall crude and age-standardized associated DALY rates were 1105.4 (659.9–1686.2) and 629.7 (369.4–971.9) per 100 000 people, respectively. The burden of AMR among children younger than 5 years of age was low, accounting for only 0.34% and 1.67% of total infectious deaths and DALYs associated with bacterial resistance, respectively. Five pathogens dominated the landscape of mortality associated with AMR:  deaths) . Each ofths each .S. aureus was the leading combination for the overall mortality attributable to AMR , while E coli resistant to trimethoprim/sulfamethoxazole (co-trimoxazole) was responsible for most deaths associated with AMR  (S. aureus and co-trimoxazole-resistant E coli were responsible for 1092 (421–2046) and 10 273  DALYs, respectively  . These tectively . When coA. baumannii, fluoroquinolone-resistant E coli, and fluoroquinolone-resistant E. faecium  were among the top pathogen-drug combinations by attributable AMR burden for each infectious syndrome. In addition to co-trimoxazole-resistant E coli, there were three more pathogen-drug combinations among the leading combinations of associated AMR burden (both deaths and DALYs) that included E coli: those resistant to aminopenicillin, beta-lactam/beta-lactamase-inhibitor (co-amoxiclav), and fluoroquinolones. Interestingly, these three specific pathogen-drug combinations had comparatively different fatal and nonfatal burdens when assessed across infectious syndromes, as the highest number of deaths (jointly) was estimated for bloodstream infections , whereas the highest number of DALYs (jointly) was estimated for peritoneal and intra-abdominal infections .In addition to these two pathogen-drug combinations, carbapenem-resistant To our knowledge, this is the most detailed study thus far that reports the burden of mortality and DALYs due to AMR for Croatia, and the first one to use two measures – burden attributable to and associated with AMR – for a wide-ranging list of pathogens and pathogen-drug combinations. We demonstrated that bacterial resistance played a considerable role in excess mortality in 2019, as more than 2500 deaths could have been fended off if all resistant infections had been substituted by no infection, whereas more than 600 lives could have been saved if all drug-resistant infections had been substituted by drug-sensitive ones. These exhaustive, country-level estimates are novel and, thus, hold immense value for progress in this field.E coli, P. aeruginosa, or A. baumannii as a result of data scarcity regarding colistin resistance , while multidrug resistance (MDR) estimation in P. aeruginosa or A. baumannii was not assessed due to our approach to MDR infections , particularly in bloodstream infections, where this pathogen-drug combination was responsible for 28 (10–61) and 109 (53–190) deaths in 2019 attributable to and associated with AMR, respectively. After 2008, MRSA rates decreased, with resistance rates falling to 12% by 2014; however, since 2015 MRSA rates started to increase again and reached 16% in 2019  may be explained by the use of the higher-valent pneumococcal vaccines, which substantially reduced the prevalence of multidrug-resistant strains, and in turn the rate of invasive pneumococcal disease  and 0.19 (0.09–0.36), respectively, and those associated with AMR were 73 (42–117) and 0.84 (0.48-1.37), respectively. However, these metrics were much higher for E. faecium resistant to fluoroquinolones, with 35 (10–68) deaths and 0.40 (0.11-0.79) ASMR attributable to AMR, as well as 191 (113–290) deaths and 2.21 (1.28-3.4) ASMR associated with AMR.Gram-negative bacteria dominated the resistance burden in Croatia; however, andscape . A recenandscape  showed aThis is another warning signal about the importance of adequately addressing fluroquinolone prescription habits in Croatia. A recent survey involving 12 urology departments in Croatia showed that fluoroquinolones were by far the most commonly prescribed class of antibiotics (accounting for 84% of prescriptions), and the authors have emphasized how the lack of uniform guidelines contributes to varying protocols, ultimately leading to a concerning escalation in antibiotic resistance .We would like to state several limitations of this study, primarily a relatively low number of microbiological data points linked to clinical outcomes; this can be viewed as a general problem that will have to be addressed by improving and expanding systematic data collection approaches . AdditioIn conclusion, we showed that the burden of AMR in Croatia was considerable, which means there is a need for a rigorous systems approach that will address the complexities and nuance surrounding AMR as a public health threat. Although Croatia is committed to meticulous resistance tracking, tireless monitoring is of utmost importance  in order to close the gap between research and policy. National data serve as the foundation for monitoring trends, evaluating interventions, and guiding decision-making to effectively address the challenges posed by AMR. Without consistent and accurate data, the pursuit of research endeavors in this critical field would be hindered. This makes it crucial for countries like Croatia to prioritize and invest in enhancing their data-collection capabilities. We believe that our estimates represent an important step toward that goal.


Immune-mediated inflammatory diseases (IMIDs) are a highly heterogeneous group of diseases that share a common etiology of immune dysregulation, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis, among others. It is estimated that the prevalence of IMIDs ranges between 5% and 7% in developed countries. As current management of IMIDs includes the use of immunomodulatory medications, the resulting weakened immune response can increase the risk of infection, including with SARS-CoV-2 (the causative agent of COVID-19) and reduce response to vaccination, placing these individuals at continued risk of severe outcomes from COVID-19. In this article, we summarize the current literature related to COVID-19 outcomes and the immunogenicity and reactogenicity of COVID-19 mRNA vaccination among patients with rheumatologically dominated IMIDs, as well as the effect of immunomodulatory therapies on these outcomes. We conclude by providing current COVID-19 vaccination recommendations for individuals with IMID. Immune-mediated inflammatory diseases (IMIDs) are a highly heterogeneous group of diseases that share a common etiology of immune dysregulation , 2. IMIDThe weakened immune response caused by immunomodulatory medications in patients with IMIDs can increase the risk of infection, including with SARS-CoV-2, the causative agent of COVID-19 , 7. VaccWhile COVID-19 mitigation strategies for the IMID population include prioritization for vaccination against COVID-19, the complexity of treatment in this patient population and suboptimal immune responses following vaccination remain a challenge for healthcare professionals. Notably, as the COVID-19 pandemic continues and potentially moves into a more endemic state, a thorough understanding of vaccine responses among people with IMIDs, including those treated with immunosuppressive therapy, is crucial to inform clinical practice. In this article, we summarize the current literature related to COVID-19 outcomes and the immunogenicity and reactogenicity of COVID-19 mRNA vaccination among patients with IMIDs, as well as the effect of immunosuppressive therapies on these outcomes. We primarily focus on findings from patients with rheumatologically dominated IMIDs.Higher rates of SARS-CoV-2 infection and COVID-19–related hospitalization and death have been reported among patients with IMIDs, especially before the widespread availability of COVID-19 vaccines . A retroIn addition to the increased susceptibility to and severity of COVID-19 among patients with IMIDs, studies have shown that COVID-19 symptoms may persist for longer in comparison with the general population. Prolonged COVID-19 symptom duration has been reported in a global survey of patients with IMIDs conducted between April 2 and October 15, 2021 (following COVID-19 vaccine availability in some geographic regions) . Among tThe immunosuppressive medications taken by patients with IMIDs, rather than the disease itself, may be the primary contributor to poor outcomes following COVID-19 in this population . SpecifiPatients with IMIDs are concerned about flares of their underlying disease after acute COVID-19. However, in certain cases the IMID flaring may be caused by immunosuppressive medication disruption rather than by COVID-19 itself. A prospective study in the United States examined 174 patients with IMIDs who survived COVID-19 between March 1, 2020 and November 3, 2021 (a minority [9%] of patients were vaccinated before infection), and found that 41% experienced an IMID flare after COVID-19 . The timTherefore, the prescribed use of immunomodulatory therapy, as well as the altered use of medication during an episode of COVID-19, rather than the disease itself, may be the primary contributor to poor outcomes following COVID-19. It is important to understand how the disease and disease therapy may impact responses to COVID-19 vaccination or underlying disease flaring in this population to better guide vaccination schedules.It is well established that IMID populations respond less favorably to vaccination than healthy adults , 17. AltAdditional prospective or longitudinal observational studies have examined the immune response to a 2-dose primary series of COVID-19 mRNA vaccination among populations with IMIDs. These studies also found reduced seroconversion rates among the IMID populations  compared with healthy controls  , 23, 24.P = .002) among 1647 patients with IMIDs in a large prospective observational study ., 38.5, 3Patients with IMIDs are at higher risk for severe outcomes from COVID-19 compared with the general population; this risk may be caused by their IMID therapies rather than the IMID itself. Patients with IMIDs receive a wide range of immunomodulatory treatments, which can weaken their immune responses to infections. Patients with IMIDs who are receiving systemic immunomodulatory therapies are expected to have a blunted immunologic response to mRNA vaccination in terms of both magnitude and duration compared with the general population . Even th


To evaluate breastfeeding intent, rates at discharge, and continued breastfeeding at follow-up in patients managed in a comprehensive cardio-obstetrics program stratified by severity of maternal cardiac disease.Retrospective cohort of patients managed by a comprehensive cardio-obstetrics program at the University of Alabama at Birmingham (UAB). Patients were included if they had ≥1 prenatal visit with the Cardio-Obstetrics team and delivered at UAB. The primary outcome was the breastfeeding rate on discharge from the delivery-associated hospitalization. Secondary outcomes included intent to breastfeed on admission and breastfeeding at the postpartum visit. Baseline characteristics and rates were compared between patients with less severe (mWHO I – II/III) vs. more severe (mWHO III – IV) maternal cardiac disease.p = 0.027), lower gestational age at delivery , and higher rates of NICU admission . There were no significant differences between mWHO class I-II vs. mWHO class III-IV in intent to breastfeed upon admission to the delivery-associated hospitalization , breastfeeding rates upon discharge from the delivery-associated hospitalization , or breastfeeding rates at the postpartum visit .147 patients were included: 85 (57.8%) mWHO class I – II and 62 (42.2%) mWHO class III–IV. Patients with more severe maternal cardiac disease had higher rates of chronic hypertension (22.6% vs. 9.4%; Despite potential barriers in this high-risk population, over 85% of patients breastfed upon discharge from the delivery-associated hospitalization. However, breastfeeding rates dropped by 40% at the postpartum visit. Strategies to support breastfeeding in the post-partum period in patients with maternal cardiac disease are imperative. Breastfeeding confers many physiologic benefits for both the mother and neonate . One sysTherefore, our objective is to evaluate breastfeeding practices defined by breastfeeding intent, prevalence of breastfeeding at discharge from delivery-associated hospitalization, and continued breastfeeding at follow-up in patients managed in a comprehensive cardio-obstetrics program stratified by severity of maternal cardiac disease. We hypothesized that despite no difference in breastfeeding intent, women with severe heart disease (defined as mWHO Class III/IV) would be less likely to breastfeed than women with less severe heart disease (defined as mWHO Class I - II/III) both at discharge from the delivery-associated hospitalization as well as at the postpartum visit.We performed a single-center retrospective cohort study of women with cardiac disease managed by the University of Alabama at Birmingham (UAB) Cardio-Obstetrics Program. The program is a collaboration between the Division of Maternal-Fetal Medicine and the Division of Cardiovascular Medicine at UAB to provide comprehensive, multidisciplinary prenatal care to pregnant individuals with congenital and acquired heart disease. Approval for the study was obtained through the UAB Institutional Review Board (IRB-300002012). Informed consent was waived given the retrospective nature of the study. Patients were identified from the cardio-obstetrics database and included if they had ≥1 prenatal visit with the program and delivered at UAB between 03/01/2015 and 6/30/19; intrauterine fetal demise or death of the neonate prior to postpartum visit were considered exclusion criteria.Baseline demographics were collected from the medical record . Patientvia either direct feeding or pumping, at discharge from the delivery-associated hospitalization. Secondary outcomes included self-reported intent to breastfeed at admission for the delivery-associated hospitalization and self-reported breastfeeding at the postpartum visit between 4–8 weeks postpartum. Outcomes were abstracted by our team  from the admission History and Physical, hospital progress notes, and postpartum clinic notes.The primary outcome was breastfeeding, defined as an expression of maternal human milk and administered to the neonate t tests and Wilcoxon rank sum tests for continuous variables, while categorical variables were assessed, as applicable, using χ2 and Fisher’s exact tests. All analyses were performed using SAS version 9.4  and assessed at a significance level of p < 0.05.Differences between groups were compared using Student n = 9 were excluded due to lack of mWHO classification. Patients with mWHO class III – IV heart disease had higher rates of chronic hypertension , lower gestational age at delivery , and higher rates of NICU admission . They were also less likely to be married/living with a partner . Remaining baseline characteristics were not different between groups (One hundred forty-seven patients managed by the Cardio-Obstetric Program at UAB were included: 85 (57.8%) mWHO class I-II/III and 62 (42.2%) mWHO class III-IV. While 156 patients were identified in the database, n groups .p = 0.67), breastfeeding rates at time of discharge from delivery-associated hospitalization , or breastfeeding rates at the post-partum visit . Attendance of the postpartum visit in patients with less severe cardiac disease was 76.5% while in the more severe cardiac disease group it was 64.5% (p = 0.11). In both groups, there was a decrease in breastfeeding between hospital discharge and the postpartum visit. Breastfeeding rates decreased by 36.5% and 38.6% in patients with less and more severe cardiac disease, respectively (There were no significant differences between groups with less severe (mWHO class I-II/III) and more severe (mWHO class III/IV) disease, respectively, in intent to breastfeed (84.7% vs. 82.3%; ectively .via the widespread utilization of lactation consultants. We acknowledge that the sample size could be underpowered to detect a difference and that these data do not provide granul-specific cardiac-specific lesions, for example, decompensated heart failure.Despite potential breastfeeding barriers among patients with maternal cardiac disease, the severity of cardiac disease had no significant impact on breastfeeding practices in patients managed by UAB’s Cardio-Obstetrics Program. These results differ from the aforementioned studies, which demonstrate differences in breastfeeding practices based on the presence and/or severity of chronic disease ,6. RatesImportantly, there was a significant decrease in breastfeeding rates at the post-partum visit in our population. These results, while limited by potential selection bias due to loss of follow-up, signify the need for better interventions to support mothers who desire to breastfeed immediately after discharge. The literature has demonstrated an improved cardiovascular risk profile associated with women who breastfeed ,4. GivenThis study represents a well-characterized cohort of patients and data derived from the UAB Cardio-Obstetrics Program and provides insight into an increasingly prevalent subset of cardio-obstetrics patients in which breastfeeding rates have not been well-characterized. While the severity of heart disease did not significantly affect breastfeeding practices in our population of women with maternal cardiac disease, a decrease in rates of breastfeeding at the post-partum visit identifies important opportunities for future research and interventions. Strategies to support breastfeeding following hospital discharge in this population are imperative.Supplementary Material