Background: Specific microRNAs (miRs) have been implicated in the pathophysiology of atherosclerosis and may represent interesting diagnostic and therapeutic targets in carotid stenosis. We hypothesized that the levels of specific circulating miRs are altered in patients with symptomatic carotid stenosis (sCS) in comparison to those in patients with asymptomatic carotid stenosis (aCS) planned to undergo carotid endarterectomy (CEA). We also studied whether miR levels are associated with plaque vulnerability and stability over time after CEA.Methods: Circulating levels of vascular-enriched miR-92a, miR-126, miR-143, miR-145, miR-155, miR-210, miR-221, miR-222, and miR-342-3p were determined in 21 patients with sCS and 23 patients with aCS before CEA and at a 90-day follow-up. Transcranial Doppler ultrasound for detection of microembolic signals (MES) in the ipsilateral middle cerebral artery was performed prior to CEA. Carotid plaques were histologically analyzed.Results: Mean levels of miRs were not considerably different between groups and were only marginally higher in sCS than aCS concerning miR-92a, miR-210, miR-145, and miR-143 with the best evidence concerning miR-92a. After adjustment for vascular risk factors and statin pre-treatment, the effect sizes remained essentially unchanged. At follow-up, however, these modest differences remained uncorroborated. There were no relevant associations between miR-levels and MES or histological plaque vulnerability features.Conclusions: This study does not provide evidence for strong associations between specific circulating miRs and symptomatic state in a collective of comprehensively characterized patients with carotid stenosis. Further work is needed to elucidate the role of circulating miRs as targets in advanced carotid atherosclerosis. Carotid stenosis is the cause of ischemic stroke or transient ischemic attack (TIA) in about 10–15% of all cases  1β . MoreoveMeanwhile, there are various experimental and clinical studies that shed light on expression levels of tissue- and blood-based miRs in patients with and without atherosclerotic disease , and a rOf note, most of the studies investigating circulating miRs in human vascular diseases made use of a control group consisting of non-diseased individuals. This study aimed to investigate the levels of distinct circulating miRs implicated in atherosclerosis and platelet activation in patients with advanced atherosclerotic disease, i.e., in sCS vs. aCS. We hypothesized the following: (1) The levels of distinct circulating miRs are higher in patients with sCS than in those with aCS. (2) The levels of circulating miRs are stable over time and still different between sCS and aCS 90 days after enrollment. (3) Circulating miRs are associated with features of plaque vulnerability. Based on the pathophysiology of carotid stenosis, we focused primarily on miRs associated with atherosclerotic disease and, in particular, with inflammation, endothelial, and smooth muscle cell pathology, as well as with platelet activation.In this prospective case-control study, we considered patients with sCS or aCS who have been previously described in a previous work from our group investigating distinct plasma cytokine patterns . The stuAll patients provided written informed consent. The study was approved by the ethics committee at Hannover Medical School (Ethics vote no. 7484-2017) and was conducted according to the ethical principles of the Declaration of Helsinki.We conducted a standardized interview to collect demographical and clinical data as well as current medication. The vascular risk factors were subsumed using the Essen Stroke Risk Score (ESRS). The degree of carotid stenosis was defined according the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria and categorized into moderate (50–69%), severe (70–90%), or highly severe (>90%). Long-term clinical outcome was assessed at 3 months after surgery in a follow-up including collection of the NIHSS and the modified Rankin scale (mRS).In patients with sufficient transtemporal window, we performed a standardized transcranial Doppler (TCD) monitoring of the middle cerebral artery (MCA) on the side of carotid stenosis before surgery. The MCA was insonated in 45–55 mm depth using a 2-MHz transducer and monitoring was recorded for up to 1 h. Microembolic signals (MES) were quantified visually and audibly by an investigator blinded to the clinical data. The detection of MES was performed according to the criteria of the “Consensus on Microembolus Detection” .In the course of CEA, carotid plaques from all patients were obtained and were fixed in 4% buffered formalin immediately after removal. Specimens were embedded in paraffin and 2-μm-thick sections were cut followed by histological staining using Hematoxylin and Eosin, Elastica van Gieson (EvG), and Periodic Acid Schiff (PAS). Histological analysis was done blinded to the clinical characteristics and biomarker results at the Institute of Pathology at Hannover Medical School. Representative sections with maximal atherosclerosis were chosen. Histological examination and staging were performed. The examination included intima fibrosis (divided in stages I–III), lipid core (stages 0–II), calcification (stages 0–III), media degradation (stages 0–III), acute and chronic inflammation (stages 0–III), cholesterol crystals (present/not present), neovascularization (present/not present), intra-plaque hemorrhage (present/not present), fibrous cap rupture (present/not present), and prevalence of an adherent thrombus (present/not present). An amount of points was given for each criterion and summarized to a final score .8 copies/μl) was spiked-in due to normalization in ensuing analysis. To avoid interferences from heparin traces with qPCR reactions, the isolated RNA was treated with heparinase in order to exclude contamination in patients who have been treated with heparin in the hospital  according to the instructions of the manufacturer. This process synthetic cel-miR-39-3p . Afterwards, the miR expression data were log2 transformed.Relative miR expression levels were calculated and normalized to Cel-miR-39 with the 2t-test for normally distributed data or the Mann–Whitney U-test for ordinal or non-normally distributed data. Categorical data were analyzed using the chi-square test or Fisher's exact test. Correlations of biomarkers with the ESRS were calculated using Spearman's correlation. Binary logistic regression analysis was done by estimating the association of miRs with the study group adjusting for ESRS and statin pre-treatment, as these were relevant confounders.As appropriate, group differences of continuous data were analyzed using the two-sided Student's Group differences were visualized using the Gardner-Altman estimation plots.Statistical analyses were conducted using the IBM SPSS Statistics 26  and the SAS Enterprise Guide 7.1 . Figures were created using the GraphPad Prism 9.0.1 .Out of 50 patients originally included in the study, four patients were excluded . In two additional cases, miR levels could not be validly measured at baseline for technical reasons, leaving 21 patients with sCS and 23 patients with aCS. See In patients with sCS, the time from symptom onset to blood collection was calculated as 7 days in median. Of note, vascular risk factors were more frequent in the aCS than in sCS group.p = 0.766] nor the histological sum score  differed between the patients with sCS and aCS  vs. median = 0 (IQR: 1);  and aCS .The mean differences of miRs between groups were overall marginal at baseline, with the relatively largest effects observed for miR-92a, miR-210, miR-145, and miR-143, with best evidence for a difference concerning miR-92a. See At 90-day follow-up, the mean differences, if present, again were modest. Now, miR-342-3p, miR-222, miR-155, and miR-145 were measured with somewhat higher levels in the sCS than in the aCS group see .p = 0.041; No relevant correlations between baseline miR levels and the ESRS were found within the whole study population or within asymptomatic patients. However, in sCS, there was a positive correlation of miR-143 with the ESRS  (GMG and AAD) and by a German Research Foundation grant to DDJ and LN .TT is founder and shareholder of Cardior Pharmaceuticals GmbH and has filed and licensed patents about non-coding RNAs (outside of this study). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Objective: To report the case of a 35-year-old woman with treatment-resistant aquaporin-4 (AQP-4) immunoglobulin G (IgG) seronegative neuromyelitis optica spectrum disorder (NMOSD) successfully treated with eculizumab .Methods: The investigational procedures and treatment regimens the patient received were documented over 8 years [2012 (first presentation) to 2020].Results: The patient presented with subacute onset of lower-limb weakness and numbness, gait imbalance, and urinary incontinence. Magnetic resonance imaging (MRI) showed abnormalities in the thoracic spine from T7 to T10, but brain and cervical spine scans, visual evoked potential latencies, and IgG index were normal; cerebrospinal fluid pleocytosis and oligoclonal bands were both present. After treatment with intravenous methylprednisolone 1 g/day for 5 days, the patient was discharged without medication to acute rehabilitation but experienced relapses from 2012 to 2014. She was treated with oral prednisone  and mycophenolate mofetil (MMF) 1 g twice daily (from June 2015), but between 2014 and 2019 experienced 4–5 relapses/year, requiring treatment with intravenous methylprednisolone, with added maintenance plasma exchange from 2018 onwards. Although the patient tested negative for antibodies to AQP-4 and myelin oligodendrocyte glycoprotein, she was diagnosed with NMOSD in February 2017, based on recurrent episodes of longitudinal extensive transverse myelitis, MRI changes, and area postrema syndrome. By 2018 the patient needed a cane to walk. Prednisone and MMF were discontinued mid-2018, and rituximab was prescribed from July 2018 (maintenance regimen two 1 g doses 2 weeks apart every 6 months) but discontinued in July 2019 owing to lack of significant improvement. From July 2019 eculizumab was prescribed for 6 months . The patient had no relapses or adverse events during and after eculizumab treatment (as of August 2020) and was able to walk unaided; her Expanded Disability Status Scale score improved from 4–5 during 2015–2018 to 2 in 2020 following eculizumab treatment.Conclusion: Eculizumab shows promise as a treatment for AQP-4 IgG-seronegative NMOSD and further studies are warranted. Neuromyelitis optica (NMO)/NMO spectrum disorder (NMOSD) is a rare disease characterized by autoimmune demyelination and axonal damage predominantly affecting the spinal cord [longitudinal extensive transverse myelitis (LETM)] and optic nerve (optic neuritis) . It is pNMOSD is characterized by unpredictable recurrent episodes of optic neuritis and myelitis. Partial recovery occurs between attacks, but neurologic disability accumulates, including blindness and paralysis . The conEculizumab is a recombinant humanized monoclonal antibody that binds to complement component C5 and prevents its conversion to C5a and C5b . The preWe describe the case of a 35-year-old white woman. She initially presented in July 2012 at the age of 27 years, when she was working as a nurse. She reported subacute onset of lower limb weakness , lower limb numbness, gait imbalance, and urinary incontinence. Magnetic resonance imaging (MRI) of the thoracic spine, with and without contrast, demonstrated signal abnormality from T7 to T10 associated with post-contrast enhancement. MRI of the brain and cervical spine, with and without contrast, was normal. Visual evoked potential (pattern VEP) showed normal P100 latencies. A lumbar puncture showed cerebrospinal fluid pleocytosis , normal IgG index, and oligoclonal bands.A summary of treatment regimens and timelines is shown in In 2015, testing for anti-AQP-4 antibodies by fluorescence-activated cell sorting (FACS) proved negative. In March of that year, the patient's oral prednisone dose was reduced to 20 mg/day because of weight gain. In June 2015, the patient was initiated on mycophenolate mofetil 1 g twice daily.In 2016 and 2017, testing for MOG IgG (FACS assay) was negative; tests for antinuclear antibody panel, urine heavy metal screen, and paraneoplastic panel were also negative. In February 2017, following episodes of intractable nausea and vomiting with associated area postrema changes on MRI, the patient received a diagnosis of seronegative NMOSD from a National Multiple Sclerosis Society Center of Excellence, based on recurrent episodes of LETM, MRI changes, area postrema syndrome, and lack of anti-AQP-4 antibodies. The patient continued to experience relapses between 2014 and 2019, with 4–5 relapses per year , charact2 was administered intravenously every week for 4 weeks, then as two 1 g doses, 2 weeks apart every 6 months. Rituximab has not been approved for treatment of NMOSD; this regimen is the same as that used in a Phase 3 trial in patients with NMOSD . Eculizumab infusion was initiated on July 30, 2019, with the approval of the patient's insurance provider following a peer-to-peer review by one of her physicians (RG) and the provider. Two weeks before eculizumab initiation, the patient was vaccinated against Neisseria meningitidis with meningitis ACWY and B vaccines, according to the recommendations of the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices , another water channel in CNS astrocytes, has been suggested to be associated with the development of NMOSD , 21. OthIt follows that inhibition of complement activation should reduce damage to astrocytes in patients with AQP-4-IgG-positive NMOSD. Eculizumab prevents the cleavage of C5 to C5a and C5b, and significantly reduced the relapse risk in patients with AQP-4-IgG-positive NMOSD compared with placebo in a large Phase 3 trial, leading to its approval for this condition .Eculizumab is not approved for seronegative NMOSD. Given the pathological similarities between seropositive and seronegative NMOSD, we decided to try eculizumab in our patient. A distinct improvement was seen during the 6 months of eculizumab treatment. The last dose of rituximab was given 22 days before eculizumab initiation. Although there may have been some overlap in activity between the two drugs, we believe the subsequent improvement in the patient's condition to have been associated with eculizumab treatment, given that the patient experienced three relapses while receiving rituximab. Before eculizumab initiation, the patient's EDSS score was 4–5, but it reduced to 3 during eculizumab therapy, at which point the patient was also relapse-free . There iAlthough the repeated testing suggests that this patient did not have anti-AQP-4 or anti-MOG antibodies, it is possible that she harbored a low titer that may have been detectable with a more sensitive assay. Alternatively, she might have complement-activating antibodies to AQP-1 or a currently unidentified target. Outside of the research setting it may be difficult to conclusively identify the pathology; however, our experience suggests that a trial of eculizumab may be warranted in patients with AQP-4 IgG-seronegative NMOSD.Eculizumab shows promise as a treatment for AQP-4/MOG IgG-seronegative NMOSD, and further studies are warranted to explore the possibility of using this treatment in patients with treatment-resistant seronegative NMOSD. The mechanism of action of eculizumab in seronegative NMOSD remains to be elucidated.Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease that affects the spinal cord and optic nerve, causing severe disability. Despite standard treatment, including off-label oral and intravenous corticosteroids and immunosuppressants, patients often continue to have recurrent attacks. Eculizumab has been approved for patients with NMOSD who have autoantibodies to the protein aquaporin-4 (AQP-4); eculizumab blocks the damage to nervous-system cells triggered by these antibodies. The patient described in this case report belongs to a minority of patients with NMOSD who are seronegative for anti-AQP-4 antibodies and for antibodies to another protein implicated in NMOSD—myelin oligodendrocyte glycoprotein (MOG). The woman presented in 2012 (then aged 27 years) and was diagnosed with AQP-4 IgG-seronegative NMOSD in 2017. She experienced frequent relapses between 2012 and 2019, despite receiving courses of standard treatment and rituximab, and eventually needed a cane to walk. After receiving eculizumab for 6 months in 2019, the patient experienced improvements in her level of disability and no longer experienced relapses. At follow-ups after treatment discontinuation, the patient continued to be relapse-free and could walk unaided. These findings suggest that eculizumab may be a useful addition to treatment options in the subgroup of patients with AQP-4-antibody seronegative NMOSD.The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided her written informed consent to participate in this study. Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.All authors: conception, organization, execution of the research described in the manuscript, review, and critique of the manuscript.RG has served on advisory committees for Alexion Pharmaceuticals, argenx, and Catalyst Pharmaceuticals, and is a member of the speakers' bureaux for Alexion Pharmaceuticals and Catalyst Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This cross-sectional study evaluates neighborhood-level data in the 9 largest US cities to identify inequities in COVID-19 vaccination rates. This study used only deidentified, publicly available data and was therefore exempt from institutional review board approval and informed consent in accordance with the Common Rule and Columbia University policy. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.The following 9 largest US cities , representing 40.8 million people, reported neighborhood-level vaccination rates from the beginning of vaccinations through April 13, 2021: New York, New York; Los Angeles, California; Chicago; Houston, Texas; Phoenix, Arizona; Philadelphia, Pennsylvania; San Antonio, Texas; San Diego, California; and Dallas, Texas. In this cross-sectional study, we obtained data on COVID-19 vaccination and death rates for these cites from health authority websites and sociodemographic information from the American Community Survey.4We defined neighborhoods using zip codes. In Los Angeles we used communities, a similar level of aggregation. Within each city, we divided neighborhoods into quartiles according to vaccination rate (adults with at least 1 dose) and calculated the mean sociodemographic characteristics and COVID-19 death rates in each quartile. To measure vaccination rates relative to historical disease burden (defined as the cumulative death rate from COVID-19), we tested the association between COVID-19 death rates and vaccination rates within cities using linear regression and conducted a concentration analysis assessing the share of vaccinations administered in neighborhoods with the highest death rates.P < .05 from 2-sided tests to be statistically significant. Analyses were performed using Stata/MP, version 16.0 .We considered We analyzed 1127 neighborhoods with a mean (SD) COVID-19 vaccination rate of 42.3% (13.4 percentage points). Neighborhoods in the lowest quartile had less than half the vaccination rate of those in the highest quartile  were lowest in neighborhoods with the highest vaccination rates, even though these neighborhoods had more older adults. A 10-percentage-point increase in the vaccination rate was associated with 25 fewer historical COVID-19 deaths per 100 000 population (2 as well as county-level analyses of early vaccination efforts that found comparatively small differences in vaccination rates by county social vulnerability index.5 Using more granular neighborhood-level data, we documented substantial inequities in vaccination rates in the first 5 months of vaccine distribution.In the 9 largest US cities, COVID-19 vaccination rates were disproportionately high in communities with lower burdens of this disease. This study builds on reports of inequitable COVID-19 vaccination rates by race and ethnicity that were frequently based on incomplete demographic data from statesLimitations of this study include potential inaccuracies in vaccination and death reporting, the inability to distinguish the role of supply- and demand-side factors, and limits on the generalizability of the results beyond the included cities. We were also unable to assess the role of vaccine supply and eligibility policies in creating or mitigating disparities. However, given that all US adults have been eligible to receive the vaccine since April 2021 and there is current excess supply, other policies are now more actionable targets to improve vaccination equity.6 The findings of the present study emphasize the opportunity and need for cities to address vaccination inequities in marginalized communities.Inequities in vaccination rates across neighborhoods likely reflect several root causes, including systematic underinvestment in public health in segregated communities, unequal access to health care information and services, and medical racism that drives legitimate mistrust among members of marginalized groups.


Previous studies have suggested that some individuals experience neuropsychiatric symptoms following coronavirus disease 2019 (COVID-19) infection. We describe a case of new-onset psychosis following COVID-19 infection in a 55-year-old female with no prior psychiatric history. The patient started exhibiting symptoms of COVID-19 infection three weeks prior and was treated in the hospital with 4 L oxygen, dexamethasone 6 mg, and remdesivir therapy for seven days. Throughout her hospital stay, the patient had no neuropsychiatric symptoms. During her last week of stay, she was solely getting oxygen at home before presenting to the emergency department (ED) with severe psychosis. Her COVID-19 test in ED presentation was negative, and all potential etiologies for psychosis were ruled out. She was effectively treated for two weeks with 10 mg haloperidol and 1000 mg sodium valproate daily, followed by outpatient care. While variables such as a family history of bipolar disorder, psychosocial stressors, and steroid medication may have contributed to the patient's presentation, these circumstances alone did not result in neuropsychiatric symptoms in the past. COVID-19 infection may enhance the likelihood of developing neuropsychiatric problems on its own or amplify the effects of risk factors associated with an increased risk of psychosis. Neuropsychiatric consequences of COVID-19 infection may be under- or over-reported in individuals treated with steroids. Further research is necessary to identify individuals at risk of experiencing neuropsychiatric issues owing to COVID-19 infection and the prognosis. Virus-borne infections are associated with neuropsychiatric complications. HIV infection, for example, may result in depression, manic episodes, psychosis, and anxiety . AdditioThis article was previously presented as a meeting abstract at the 39th Annual AAPI Convention and Science Assembly on July 2-5, 2021.3. She had non-command type auditory hallucinations and delusions of religious nature. She reported hearing God’s voice asking her to save the earth. COVID-19 was also the central theme of such hallucinations/delusions. She was agitated, screaming at staff members, and removing IV lines. She received diphenhydramine 25 mg, haloperidol 5 mg, and lorazepam 2 mg for acute management of symptoms. She was also started on metoprolol 25 mg for management of her hypertension. Infectious disease workup was negative. MRI and CT scans of the brain were unremarkable. The urine drug screen was negative for substances. All etiologies of such presentation were ruled out.A 55-year-old female with a past medical history of hypertension, type 2 diabetes, and obesity was brought to the emergency department by her family members for concerns regarding her behavior. The patient was discharged from another hospital a week ago, where she was treated for COVID-19 infection using oxygen therapy, steroids, and remdesivir. She received dexamethasone 6 mg IV for seven days. She was discharged with no psychotic symptoms during her hospital stay and continued to receive oxygen therapy at home after steroids and remdesivir were discontinued. The patient became symptomatic with COVID-19 three weeks before her current presentation, and she tested negative on the COVID-19 RNA test performed during the current ED visit. In ED, the patient had a blood pressure of 147/119 mmHg and tachycardia (130 bpm). Her SpO2 saturation was 97%. The patient was without any fever at the presentation. Her lactate dehydrogenase levels were 825 units/L, and her white blood cell count was 4500 cells/mmOn a follow-up visit the next day, the patient continued to have grandiose delusions, her speech was pressured. She was preoccupied with God, COVID-19, and the Devil. She reported seeing God and reported that God is talking with her during the interview. It was decided to admit the patient to the inpatient psychiatric ward. She was started on haloperidol 10 mg and sodium valproate 1000 mg for treatment. She continued to show improvement in her symptoms. Considering the better side effect profile of second-generation antipsychotics regarding extrapyramidal side effects, she was discharged from the hospital on aripiprazole 10 mg and sodium valproate 1000 mg daily after two weeks of inpatient stay to follow-up at the outpatient clinic.During her stay, we collected collateral information from multiple sources. The patient was never diagnosed with any psychiatric illness. She never visited a psychiatrist in her lifetime. Family history is positive for bipolar disorder type I in a distant cousin. Her family also has a history of developing psychiatric symptoms following steroid use. However, there is no history of her developing psychiatric symptoms following treatment with steroids in the past. The family members reported that they have never seen abnormal behavior in her before this instance.Although COVID-19 was previously thought to be a respiratory illness, new research indicates a multi-systemic vascular disease affecting several organs . This caSteroid treatment for COVID-19 pneumonia could potentially explain the patient’s new-onset psychosis. However, in our case, on ED presentation, the patient’s lab work did not show leukocytosis that would be expected for individuals currently using corticosteroids. She had high blood pressure, which could be attributable to steroid use, but collateral history confirmed that the patient was poorly compliant with her blood pressure medications. It is also unusual for a patient to not have psychiatric symptoms while receiving steroids for COVID-19 pneumonia and then present with psychosis seven days after cessation of steroid therapy. Although there is a family history of adverse psychiatric effects from steroid use in the patient’s brother, the patient herself did not have such a history of any acute or delayed onset psychiatric symptoms from past steroid use. According to research on SARS patients, the severity of the disease, the dose of steroids, and psychosocial variables led to an increased chance of developing mental symptoms . Thus, oA large retrospective cohort study using electronic health record data found that patients with no prior psychiatric history diagnosed with COVID-19 had a greater likelihood of receiving their first psychiatric diagnosis after 14-90 days . Thus, nAlthough COVID-19 is commonly linked with respiratory symptoms, some vulnerable individuals might develop new-onset neuropsychiatric symptoms without a prior history of psychiatric illness. This presentation may be acute throughout the course of the illness or may occur post-infection. While a family history of mental disease, steroid usage for COVID-19 pneumonia therapy, and psychological stresses associated with the COVID-19 pandemic may have had a role in our case. The patient acquired neuropsychiatric symptoms only after acquiring COVID-19 infection. It's possible that COVID-19 had a unique function, either by itself or by enhancing the impact of other neuropsychiatric symptoms-related variables. Our case also highlights the interplay between corticosteroids, COVID-19, and psychosis. Steroid use for the treatment of COVID-19 pneumonia could lead to under- or over-reporting COVID-19-related neuropsychiatric symptoms.Additional research must identify vulnerable individuals at an elevated risk of acquiring neuropsychiatric problems due to COVID-19 infection and the prognosis of such presentations.


Screening mammography is recommended for the early detection of breast cancer. The processes for ordering screening mammography often rely on a health care provider order and a scheduler to arrange the time and location of breast imaging. Self-scheduling after automated ordering of screening mammograms may offer a more efficient and convenient way to schedule screening mammograms.The aim of this study was to determine the use, outcomes, and efficiency of an automated mammogram ordering and invitation process paired with self-scheduling.We examined appointment data from 12 months of scheduled mammogram appointments, starting in September 2019 when a web and mobile app self-scheduling process for screening mammograms was made available for the Mayo Clinic primary care practice. Patients registered to the Mayo Clinic Patient Online Services could view the schedules and book their mammogram appointment via the web or a mobile app. Self-scheduling required no telephone calls or staff appointment schedulers. We examined uptake (count and percentage of patients utilizing self-scheduling), number of appointment actions taken by self-schedulers and by those using staff schedulers, no-show outcomes, scheduling efficiency, and weekend and after-hours use of self-scheduling.P<.001). The odds ratio of no-shows for self-scheduled mammograms to staff-scheduled mammograms decreased to 1.12  when adjusted for age, race, and ethnicity. On average, since there were only 0.197 staff-scheduler actions for each finalized self-scheduled appointment, staff schedulers were rarely used to redo or “clean up” self-scheduled appointments. Exclusively self-scheduled appointments were significantly more efficient than staff-scheduled appointments. Self-schedulers experienced a single appointment step process (one and done) for 93.5% (7553/8079) of their finalized appointments; only 74.5%  of staff-scheduled finalized appointments had a similar one-step appointment process (P<.001). For staff-scheduled appointments, 25.5%  of the finalized appointments took multiple appointment steps. For finalized appointments that were exclusively self-scheduled, only 6.5% (526/8079) took multiple appointment steps. The staff-scheduled to self-scheduled odds ratio of taking multiple steps for a finalized screening mammogram appointment was 4.9 .For patients who were registered to patient online services and had screening mammogram appointment activity, 15.3%  used the web or mobile app to do either some mammogram self-scheduling or self-cancelling appointment actions. Approximately 24.4%  of self-scheduling occurred after normal business hours/on weekends. Approximately 9.3%  of the patients used self-scheduling/cancelling exclusively. For self-scheduled mammograms, there were 5.7% (536/9433) no-shows compared to 4.6%  no-shows in staff-scheduled mammograms (unadjusted odds ratio 1.24, 95% CI 1.13-1.36; Screening mammograms can be efficiently self-scheduled but may be associated with a slight increase in no-shows. Self-scheduling can decrease staff scheduler work and can be convenient for patients who want to manage their appointment scheduling activity after business hours or on weekends. About 1 in 8 women in the United States will develop breast cancer during her life . DespiteAutomated ordering and self-scheduling of screening mammography with the assistance of the electronic health record (EHR) is an intervention that could help deliver the preventive service of early breast cancer detection in a primary care practice. Criteria for screening mammography can often be found within the EHR. For example, the American Cancer Society recommends mammograms up to every year for women aged 40-75 years depending on the life expectancy . DetermiThe screening mammogram appointment is also a visit type with its own unique set of rules that distinguish it from other visit types. The unique challenges for self-scheduling screening mammograms are (1) there are specific criteria for patient age, date of the last mammogram, and whether a screening mammogram is appropriate; (2) it is a radiologic procedure requiring an electronic order; (3) there are patient and provider requirements so that the assignment and communication of results is assured. In addition to examining the outcomes of self-scheduled mammograms, we show our automated processes for the self-scheduled screening mammogram visit that address the unique challenges of this visit type.The implementation of automated ordering paired with self-scheduling of mammograms took place at Mayo Clinic in 2019. Mayo Clinic is a multispecialty group practice with several locations in the United States and internationally. Our study focuses on the screening mammogram process of the primary care practices of Mayo Clinic for 12 consecutive months from September 2019 through August 2020. Mayo Clinic has primary care practices in the United States in Florida, Arizona, and many locations in the upper Midwest, primarily in the states of Minnesota, Wisconsin, and Iowa. All the primary care sites were included in this study. This study was limited to the bilateral breast screening mammogram examination, which is the recommended radiographic procedure for the early detection of breast cancer.At Mayo Clinic, screening mammography requires an order for the specific imaging examination. Patients are not allowed to self-order a mammogram. However, Mayo Clinic has developed a process with rules that automatically generates orders for screening mammograms, allowing one-click bulk ordering of hundreds of mammograms by a single provider. The top part of After the prerequisite EHR system configurations are completed, the mammogram ordering process starts by using EHR data to identify patients who are eligible and due for screening mammography. The appointment scheduling system is also queried for those who are due and have a mammogram ordered but not scheduled. For those who do not have an active mammogram order but are due for a mammogram, a mammogram order is created. Thus, all patients who are due for a mammogram either have a mammogram order generated automatically to enable scheduling or they are identified to enable scheduling if an active mammogram order is already in place but not yet scheduled. Staff schedulers are clinic staff employees who schedule or cancel appointments for patients. Until the self-scheduling process was implemented, staff employee appointment schedulers were responsible for working with patients and radiology schedules to schedule mammograms. Patients, whether patient online services–enabled or not, can schedule their mammograms by telephone or in person via staff appointment schedulers. Appointment scheduling via staff schedulers normally occurs during business hours of 7 AM to 5 PM on weekdays. Appointment schedulers have the ability to schedule mammograms more than 12 weeks into the future. Self-scheduling via patient online services can be done either via web or via mobile and is available 24/7. Patients can directly see the mammogram scheduling template for the days that they select and can click on the appointment time that they want. Self-schedulers are restricted to scheduling their mammogram in a 12-week rolling window from the day that they could schedule. Self-schedulers are also not allowed to double book.Self-schedulers or self-cancelers are the patients who used the Mayo software interface (web or mobile) to self-schedule or self-cancel the mammogram appointments. It should be noted that we focus on self-schedule actions in this study. There were some patients who never used the self-scheduling feature but self-cancelled the appointments made by the staff schedulers. To be considered self-scheduled, a patient had to have at least one appointment action of self-scheduling (booking an appointment with the self-schedule software). The few patients who self-cancelled their staff-scheduled appointment were classified as staff-scheduled.An appointment action is either a schedule or cancel event. With the self-scheduling process, appointment actions could be done either by the patient (self) or staff. An appointment path is the sequence of appointment actions leading to a finalized appointment or cancellation outcome . AppointFinalized appointments were those scheduled appointments that were left scheduled up to the appointment date and time (not cancelled before appointment time). Appointment outcomes are dichotomously categorized as finalized appointments or cancellations. Finalized appointments are further dichotomously categorized as completed or no-shows (never arrived at the scheduled appointment time). Our data source was EHR-generated scheduling and cancelling information on all bilateral screening mammogram appointments made for primary care patients for the 12 months from September 1, 2019 through August 31, 2020. Scheduled mammogram appointments were either cancelled or completed (patient arrived or no-show) by September 1, 2020 for our follow-up on finalized appointments and no-shows. Patients eligible for automated ordering and invitation to schedule a mammogram were primary care practice patients of Mayo Clinic in Arizona or Florida or in the Mayo Clinic Health System . Self-scheduling through web or mobile required patient online service registration; staff scheduling was available for all patients who had an active mammogram order, regardless of patient online service registration status.A finalized scheduled mammogram was the outcome of scheduling and cancelling actions as shown in Data were collected by the Epic EHR of Mayo Clinic. Patients who either staff-scheduled or self-scheduled were registered patients of Mayo Clinic. In addition, we limited this study to portal-registered patients who were established primary care patients; therefore, there were essentially complete demographic data available for each patient . Any uncategorized or missing information on race or ethnicity was placed in the other or unknown category. Appointment data were entered by the Epic scheduling software. Dates and times of self-scheduling and staff scheduling were automatically entered into the EHR software by patient record number and categorized on data entry as being sourced from self-scheduling (patient online services) or by the staff scheduler. Mammograms were not done unless the patient was checked in by radiology staff as “arrived.” If the patient did not arrive and the radiology staff overlooked listing the patient as a no-show, an EHR scheduling rule marked the visit as a no-show 72 hours after the scheduled appointment to ensure the capture of these overlooked no-shows.We categorized scheduling and cancelling actions according to whether they occurred outside of the usual business hours . The proportion of mammogram appointment lead times over 12 weeks was calculated for both staff-scheduled and self-scheduled appointments. As mentioned above, only those scheduled for mammography who were registered with patient online services were analyzed. Thus, portal registration status was not in our primary analysis. Those without portal registration were included in additional analysis as described below. Age is a known confounder for no-shows in radiology visits ; therefoWe used JMP 14.3 (SAS Institute Inc) for the statistical analysis. The chi-square test was used for categorical analysis. We used logistic regression analysis in a model to explain the differences in the no-shows adjusted by patient age to control for age as a known confounder in radiology no-shows . A logisThis was a retrospective study examining quality measures and uptake of a self-scheduling process. Self-scheduling was a voluntary additional option offered to all primary care patients with patient online services; all individuals could continue to schedule their mammograms with staff schedulers if that was their preference (see patient decision point in P=.90).As mentioned in Methods, before an appointment is finalized, it can be cancelled and rescheduled many times. Approximately 24.4%  of the mammogram self-scheduling activity was accomplished either on the weekend or on weekdays after usual staff scheduler hours . This afP<.001) for multiple steps in scheduling when comparing staff scheduling to self-scheduling.The average scheduling actions per finalized visit were similar between self-schedulers and staff schedulers . There was not a major increase in scheduler work owing to self-scheduling. In fact, staff schedulers averaged only 0.197 appointment actions per finalized visit that had any self-scheduling. Thus, staff rework for patients attempting self-scheduling did not appear to be a major issue. P<.001). Rosenbaum et al [P=.07). However, in a multivariable logistic regression model adjusting for race and ethnicity as well as age, we found a significant no-show odds ratio of self-scheduled to staff-scheduled of 1.12 .For the 12 months studied, there were bilateral screening mammograms scheduled for 93,901unique patients with patient online service access. Of the 131,110 mammograms scheduled, there were 44,146 cancellations, leaving 86,964 scheduled mammograms that were expected to be completed on the scheduled date. Of those appointments expecting to be completed, 95.3%  arrived for the visit for an overall no-show rate of 4.7%  for those with patient online service access. um et al  found thSelf-scheduled patients were unable to make their mammogram appointment more than 12 weeks in advance. We found that 4.9%  of staff-scheduled appointments were scheduled out further than 12 weeks.The percentage of self-scheduled appointment actions is sensitive to the denominator used. Since self-scheduling requires patient online services, we used patients with patient online services as the denominator for our analysis. Portal engagement is not static in many practices. Mayo Clinic patient online services engagement increased from 33% to 62% during 2013 to 2018 , and 83.By 11 months, 21.1% (1991/9442) of the patients with self-scheduling access were engaged in self-scheduling their screening mammogram and 24.4%  of the self-scheduling actions were outside of normal business hours for appointment scheduling. For 93.5% (7553/8079) of those who exclusively self-scheduled their screening mammograms, only 1 appointment step was used—that of a single step of choosing the date and time of the mammogram.Patients performed a large number of scheduling actions, which otherwise would have been done by staff schedulers. There was very little staff-scheduler activity required for each finalized appointment in the self-scheduled group. Thus, there was not an unintended consequence of extra staff-scheduler work required to redo or “clean up” a self-scheduled appointment. We showed that the average self-scheduled finalized appointment involved only 0.197 staff actions compared to 2.04 staff actions on average required for a staff-scheduled finalized appointment. We did not measure the actual staff labor cost for each finalized appointment associated with self-scheduling and staff scheduling. However, with the average self-scheduled finalized visit using only 9.7% (0.197/2.04) of the staff appointment actions compared to a staff-scheduled appointment, there is likely a significant savings. Our findings suggest that the mammogram order generation and self-scheduling features will fit into the cost-effective multicomponent intervention framework for cancer screening identified by Mohan et al .We did not identify major unintended consequences to the practice. No-shows were significantly greater for those in the self-scheduled group but were reduced to an odds ratio of 1.12 when adjusted for the patient age, race, and ethnicity differences noted in Patient self-scheduling is likely a benefit for many patients. We showed that many patients took advantage of the ability to self-schedule 24/7. With 24.5%  of the self-scheduling occurring after business hours or on weekends and 24.5%  of the self-scheduling occurring via mobile app, patients were using the anytime and anywhere capability of self-scheduling. Those who self-scheduled also were extremely efficient at doing so, with 93.5% (7553/8079) of their finalized appointments occurring after just 1 scheduling step. Mathioudakis et al  noted thThere appear to be few comparable studies for self-scheduled imaging. A review of web-based appointment scheduling by Zhao et al  focused The outcomes for self-scheduled mammograms show some interesting contrasts and similarities to outcomes for Mayo Clinic’s self-scheduled well-child visits . DespitePatients self-scheduling mammograms were 93.7%  White, and 83.6%  of all patients scheduling mammograms were registered with patient online services. Other populations could have different results. Even with our comparison limited to the 83.6%  of patients who had patient online service access, there were still significant differences in the ages of patients self-scheduling versus those using staff schedulers. The COVID-19 pandemic occurring in the last 6 months of this study limits some of our findings. However, our subgroup analysis into pre- and post-COVID time frames shows that the extra staff scheduler cancellations due to COVID was associated with only a small increase in average staff-scheduling activity in the self-scheduled group. No-show outcomes in imaging examinations are known to be influenced by a number of factors that we did not take into consideration. For example, in their review of over 3 million outpatient radiology visits, Mieloszyk et al  found siWe limited the mammogram self-scheduling feature to a 12-week window as mentioned above. This limits the conclusions about some of the scheduling efficiency. It is possible that the 12-week appointment window resulted in patients having more clarity on their future availability and some reschedules were avoided. Further, the inability to self-schedule more than 12 weeks in the future likely had an impact on the uptake of this feature. Since 4.9%  of the staff-scheduled appointments were scheduled greater than 12 weeks out, there are likely patients who may have self-scheduled had they had the opportunity to schedule past the 12-week limit. We only examined mammograms that were scheduled. We did not look at the potential issues involved in the identification of individuals who met the criteria for generating a mammogram order. For example, if a mammogram had been recently done elsewhere, the patient might have been misidentified as being due for a mammogram. Further, patients who had changed their email or postal address and had not changed their address in their EHR might not have received their invitation for ordering a mammogram that was due. Our data only reflected those who had acted on screening mammogram orders. In this study, we did not evaluate the accuracy of the mammogram orders or if the patients had received their invitations.Additional research will be needed to evaluate whether web and mobile mammogram self-scheduling will lead to a higher percentage of women receiving timely screening mammograms. A study by Gann et al  had an uA large number of patients successfully self-scheduled their screening mammogram by using the web or mobile without staff-scheduler assistance. Self-scheduling actions were accomplished outside of normal staff-scheduling hours in 24.4%  of the cases, and 93.5% (7553/8079) of exclusive self-scheduled mammogram appointments were done with just 1 appointment step (one and done). Self-scheduled screening mammograms were associated with more no-shows than staff-scheduled mammograms, with a small but significant odds ratio of 1.12 in a model adjusted for age, race, and ethnicity. There was no unintended consequence of an increase in staff-scheduler work because, on average, each finalized self-scheduled mammogram used less than one-tenth the staff-scheduler appointment actions compared to those completely staff-scheduled.


This study aimed to assess the survival of direct composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities.α = 5%).Survival of composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities was retrospectively analyzed. Failure was defined as the need for replacement of at least one surface of the original restoration or extraction of the tooth. Individual-, tooth-, and restoration-related factors were obtained from dental records. Five-year mean annual failure rate (mAFR) and median survival time were calculated (Kaplan-Meier statistics). The effect of potential risk factors on failure was tested using univariate log-rank tests and multivariate Cox-regression analysis (p = 0.001) and combined intellectual/physical disability  compared with intellectual disability only, presence of a removable partial denture , and restorations in incisors  or molars  compared with premolars to increase the risk for failure.A total of 728 restorations in 101 patients were included in the analysis. The survival after 5 years amounted to 67.7% (5-year mAFR: 7.5%) and median survival time to 7.9 years. Results of the multivariate Cox-regression analysis revealed physical disability (HR: 50.932, Composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities showed a reasonable longevity as 67.7% survived at least 5 years.Survival of composite restorations depends on risk factors that need to be considered when planning restorative treatment in patients with intellectual and/or physical disabilities. NCT04407520 Dental composites have been becoming the materials of choice for direct restorations in permanent teeth, especially when considering the phase down of amalgam. Recent systematic reviews and meta-analyses reported mean annual failure rates of 0 to 4% for anterior  and 0.6 Patients with special needs, such as elderly people or persons with intellectual and/or physical disability, often belong to the group of patients with high caries risk. Interestingly, only few data on the performance of direct restorations in this specific group of patients have been published. In elderly and geriatric patients, median survival of composite restorations ranged from 5.5 to 9.9 years . Tong etAs data on the survival of composite restorations in adult patients with intellectual and/or physical disabilities are very limited, this retrospective study aimed to assess the survival of direct composite restorations of adult patients with intellectual and/or physical disabilities placed under general anesthesia. Additionally, we evaluated individual-, tooth-, and restoration-related risk factors on restorations’ longevity.ClinicalTrials.gov (NCT04407520). Data were collected from digital and paper-based dental records of adult patients with intellectual and/or physical disabilities that were treated under general anesthesia in the Department of Preventive Dentistry, Periodontology and Cariology. The following inclusion criteria were defined: direct anterior and/or posterior composite restoration placed in general anesthesia in permanent teeth of adult patients with intellectual and/or physical disability, general anesthesia performed between January 2011 and December 2019, restoration made from a nano-hybrid composite placed in etch&rinse technique without rubber dam. Patients aged below 18 years, restorations on root canal-treated teeth, and restorations without a minimum follow-up of 14 days were excluded from the analysis.This study was approved by the ethics committee of the University Medical Center Göttingen (no. 15/1/18) and registered on One investigator (M.M.) reviewed all records and obtained the following data: date of the placement of the original anterior and/or posterior composite restoration and date of first re-intervention  or date of the last checkup of the patient. Further individual and tooth-/restoration-related variables were assessed: type of disability , living situation (care facility/private setting), oral hygiene , nutrition (without restrictions/pureed or liquid food/feeding tube), presence of a removable partial denture (yes/no), postoperative checkup within 3 months (yes/no), tooth location (upper/lower jaw), tooth type (anterior/premolar/molar), load-bearing restoration (yes/no), number of surfaces (1/2/≥ 3), gender, age, average number of follow-up visits per year, number of decayed teeth, number of missing teeth, number of filled teeth, and DMFT score.For all variables except follow-up visits per year, the status prior to the treatment session of initial restoration was evaluated. Restorations including the occlusal or incisal surface were defined as “load-bearing”. The average number of follow-up visits per year was only calculated for follow-up intervals > 6 months to exclude unreliable results in case of short follow-up intervals.All restorations without any further interventions until the date of last checkup were considered as survived. Composite restorations were rated as failed if at least one of the involved surfaces was re-restored or the tooth was extracted. If in case of re-intervention, restorations were regarded as failed at the date of intervention. Censoring at the time of intervention was performed if endodontic treatments on the original restored tooth became necessary. Censoring was also performed in case a mesial-occlusal (mo) or distal-occlusal (od) restoration was placed during follow-up of an initial od or mo restoration, respectively, as a clear distinction between two separate restorations or a combined restoration was not possible.For calculating the time-until-event or time-until-censoring (years) of direct composite restorations, Microsoft Excel for Mac (version 16.33) was used.www.r-project.org) and the packages “survminer” (version 0.4.6), “survival” (version 3-1.11), and “dplyr” (version 0.8.5). The level of significance was set at α = 0.05. Longevity of restorations was assessed up to 8 years by Kaplan-Meier statistics. Mean annual failure rate (mAFR) at 5 years was calculated by the following formula [Statistical analysis was performed using the software R  and Cox regression (continuous variables) were used to assess the univariate effect of both individual-, tooth-, and restoration-related variables. Subsequently, variables with a significant effect were used in a multi-variate Cox regression model with shared frailty of correlated observations (restorations within the same patient). Hazard ratios (HR) and their respective 95% confidence intervals were calculated for factors associated with failure.n = 6) or follow-up of less than 14 days (n = 541). Thus, 728 restorations in 101 patients (mean age: 37.3 ± 13.1) were included in the analysis.A total of 1275 direct composite restorations were placed in 185 patients from January 2011 to December 2019. A total of 547 restorations had to be excluded due to previous root canal treatment . Longevity of restorations was assessed up to 8 years by Kaplan-Meier statistics. The survival after 5 years amounted to 67.7% (5-year mAFR: 7.5%) and median survival time to 7.9 years , 116 restorations failed  or molars  were at higher risk for failure compared with premolars  was performed by the same operator. Physically disabled patients showed a higher risk for failure than patients with intellectual or both intellectual/physical disabilities. This result has to be interpreted with great caution, as comparatively few patients were affected from physical disability only Table . HoweverCaries experience (DMFT) of our patients was distinctly higher compared with adult athletes with intellectual disabilities , 16 and Finally, the tooth type had a significant effect on restoration failure, as premolars showed a significantly lower risk than molars and incisors. This result is in line with previous studies on composite longevity in patients without disability , 19. In Other restoration-related parameters, such as load-bearing restoration and number of involved surfaces, were significant only in the univariate model, but not in the multivariate analysis; probably, these parameters do not precisely account for restoration size and depth.Due to the retrospective design, this study presents some methodological limitations: data were extracted from digital and paper-based records, so that only variables that were consistently documented could be obtained. Potentially, restorations might have been repaired or replaced outside our department and without our knowledge. However, this is overall unlikely, as our department is the only clinic in the near surrounding offering dental treatment  for patients with severe disabilities.Despite a large number of restorations was included in the statistical analysis, the overall number of patients was limited. However, statistical analysis controlled for multiple restorations of the same patient. Unfortunately, a high number of restorations (541 out of 1275) had to be excluded from the analysis as no follow-up was available. As in other retrospective studies dealing with restoration survival in special needs patients [Due to the severe impairment, patients were often unable to attend the postoperative check-up or routine dental recall appointments after treatment in general anesthesia. For these patients, survival of restorations might be reduced as they are missing preventive treatment, like oral hygiene instruction or fluoridation, reducing the risk for (secondary) caries.For patients included in the analysis, restoration survival was affected by the attendance of the postoperative check-up. Notably, these patients did not attend recall appointments on a regular basis so that the number or frequency of recall appointments could not be considered in the statistical analysis. Alternatively, the postoperative check-up was considered as variable. Nonetheless, the average number of patients attending the postoperative check-up was low, probably also due to the effect that dental visits are often difficult for patients with severe disabilities.In conclusion, composite restorations placed under general anesthesia in adult patients with intellectual and/or physical disabilities showed reasonable survival of at least 67.7% after 5 years. Further studies are needed comparing composite restorations to other direct fillings.


This is a case report describing delayed complications of COVID-19 pneumonia, which evolved into the vascular-ischemic complications leading to quadrantanopia and MRI findings consistent with recent ischemic event in the occipital pole of the brain.We report a case of a 46-year-old woman with quadrantanopia due to stroke confirmed with brain MRI, secondary to COVID-19 infection with chronically elevated D-dimers and treated with anticoagulation/antithrombotic modalities. Quadrantanopia was the only symptom recognized by the patient of a stroke localized in the occipital pole of the brain.The patient was diagnosed with quadrantanopia due to stroke confirmed with brain MRI, secondary to COVID-19 infection.Patient underwent ophthalmological examination and MRI.A thrombotic or ischemic risks in the chronic recovery from COVID-19 should be considered in patients with elevated D-dimers.An MRI should be considered as a long term follow up for post-COVID-19 patients reporting ophthalmic or neurologic complains. SARS-CoV2 is known to initially bind to the angiotensinconverting enzyme 2 receptors of epithelial and endothelial cells where an immediate immunological activation occurs that can, in severe cases, eventually lead to hypercoagulability or thrombophilia and increased tendency of clots forming in the blood and potentially acute ischemic stroke (AIS). In addition, non-respiratory clinical manifestations of the CoV-related disease, mainly ophthalmological and neuro-ophthalmological were also reported but not fully described. For example conjunctivitis and keratoconjunctivitis as well as retinal alterations and diplopia and ophthalmoparesis have been described as case reports or case series. We believe that this was at least in part due to both technical and safety issues concerning the detailed ophthalmological examinations in CoV patients and the legitimate tendency to neglect eye complaints due to life-threatening manifestations taking priority over the secondary symptoms.In December 2019, a novel corona virus associated with a series of acute, atypical cluster of pneumonia cases and respiratory symptoms was first detected in Wuhan, a city in the Hubei Province of China. Since then, the virus now known as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread to over 200 countries and it continues to be recognized as a major world pandemic. Stroke is perhaps the most serious non-pulmonary complication of COVID-19.It is assumed, that about one-third of patients hospitalized due to severe COVID-19 develops macrovascular thrombotic complications, including venous thromboembolism, myocardial injury/infarction, and stroke.In some patients, COVID-19 infection can be severe, with hypercoagulation being a common finding, with a vascular endothelial damage and the consequent risk of venous and arterial thrombotic complications. Coagulopathy secondary to COVID-19 infection significantly worsens the prognosis and increases overall mortality. Anosmia and dysgeusia have been reported as common early symptoms of COVID-19 in absence of nasal congestion or discharge, but severe neurologic presentations are rather rare with the exception of encephalopathy secondary to hypoxemia in the course of SARS-CoV-2 acute respiratory syndrome. Vascular and infectious encephalopathy had been correlated with COVID-19 in critically ill patients. However, whether COVID-19 may be considered a risk factor for stroke is still not established. The aim of this study was to present a case of quadrantanopia as the only symptom of post-COVID stroke in the occipital pole.There are many publications regarding broad range of respiratory-related COVID-19 manifestations, but there are very limited sources of data related to neuro-ophthalmologic complications of COVID-19.22) and cardiovascular risk factors and no personal or family history of thromboembolic events reported fever, cough, and myalgia in January 2020 after returning from her trip to Andora. After computed tomography scan of the chest with extensive multifocal dense ground-glass opacities in the lungs she was diagnosed with pneumonia and was treated in the hospital with 3 antibiotics and antiviral medication. Her illness was lasting 4 weeks. She had no neurologic signs during infection. D-dimer levels were as follows: 882 ng/mL on February 3, 2020, 3412 ng/mL on February 8, 2020, and 421 ng/mL on February 13, 2020 and the anticoagulation treatment was reinitiated with Clexane (enoxaparin sodium) given subcutaneously. Her consecutive levels of D-dimers were not normalizing during the course of the illness regardless the continued treatment. Additional studies in the courses of the hospitalization included ultrasound of the abdomen, Doppler ultrasound of lower limbs’ venous system, Doppler ultrasound of cervical/carotid and vertebral arteries, and all showed no abnormalities. At that time, the patient did not undergo a polymerase chain reaction diagnostic test for SARS-CoV-2 due to the pre-pandemic onset of illness. The patient's daughter had developed similar symptoms and virus pneumonia after 2 weeks since the contact. According to the official data at that time there were no known cases of COVID-19 in Poland.A 46-year-old previously healthy woman without obesity . In September 2020 the D-dimers level was 600 ng/mL.In October 2020 the patient presented at the Department of General Ophthalmology in Lublin and the ophthalmological tests have been completed due to bilateral visual deterioration mentioned by the patient. Best-corrected visual acuity was 0.8 the right eye and 0.9 in the left eye. Anterior segment examination and intraocular pressure were not remarkable. Fundoscopic examination and photography was normal, optical coherence tomography of the macula and peripapillary retinal nerve fiber layer thickness – also normal Figs.  and 2. TThe patient was referred to neurologist for additional evaluation. The neurological evaluation revealed isolated right homonymous lower quadrantanopia, the National Institutes of Health Stroke Scale score was 1 point. Routine computed tomography scan of the head did not show any pathology.The MRI examination was conducted using Magnetom-Avanto 1.5 T scanner . Study protocol comprised turbo inversion recovery magnitude sequence, diffusion-weighted imaging, and apparent diffusion coefficient maps, T1- and T2-weighted sequences with and without gadolinium enhancement obtained in coronal, sagittal, and axial planes. Within the medial cortex of the left occipital lobe, a banded high-signal area in turbo inversion recovery magnitude and T1-weighted sequence with the presence of cortical laminar necrosis areas and a slight enhancement after intravenous gadolinium administration was visible. Diffusion-weighted imaging/apparent diffusion coefficient imaging did not show diffusion restriction. The image obtained in MRI examination corresponds to the chronic vascular ischemic areas .Patient was admitted to the stroke unit of the neurological department to perform additional investigations. Duplex Doppler ultrasound assessing the cerebral arteries in the intracranial segments showed an occlusion of the left posterior cerebral artery.In order to search for a cardioembolic origin of the embolus, additional cardiological diagnostic examinations were carried out. Echocardiography did not reveal any valvular defects or myocardial contractility disorders; 24-hour Holter ECG monitoring did not disclose significant arrhythmias or conduction disorders. Patient was monitored for blood pressure and blood sugar.To determine the etiology of cerebral stroke additional laboratory tests towards rare blood diseases of increased coagulability states were carried out but without findings .Considering the age of the patient and the absence of serious concomitant cardiovascular diseases SARS-CoV-2 infection was taken to be an independent cerebrovascular risk factor.As the patients arrived beyond the time of the therapeutic window for thrombolysis (4.5 hours) this intensive treatment of AIS was not taken. As the secondary prevention of stroke acetylsalicylic acid was given orally.The patient was regularly followed-up by ophthalmologist and neurologist, but the visual acuity and neurological state were both stable. Visual acuity was 0.9 in both eyes after 6 months, the quadrantanopia was still present.3,13To date, neurologic comorbidities and complications of COVID-19 infections were broadly described including dysosmia, dysgeusia, Guillain-Barre syndrome, anosmia, and AIS. Rarely, neuro-ophthalmology complications of COVID-19 have been reported. and focal lesions leading to quadrantanopia has not been described, yet. Reviews of COVID-19 publications, reported clinically and autopsy-determined rates of acute brain infarction range from 0.4% to 8.1% while rates of acute brain hemorrhage range from 0.13% to 9.5%. Based on large meta-analysis, 1.4% of patients with COVID-19 suffer from cerebrovascular disease.This is a case report describing complications of COVID-19 pneumonia, which evolved into the vascular-ischemic complications leading to quadrantanopia few months later and MRI findings consistent with recent ischemic or thrombotic event in the occipital pole of the brain. Neuroimaging abnormalities had been described in patients with COVID-19-related encephalopathy, stroke, encephalitis, and other complications. The incidence of ischemic stroke associated with COVID-19 in hospitalized patients has been under 3% and majority of post-COVID patients (87.4%) develop AIS rather than intracerebral hemorrhage (11.6%). Moreover, people with COVID-19 developing a stroke were older than infected patients without stroke. None of the studies reported visual field results in patients with stroke. In a study of Mao et al, visual symptoms, not specified, were found in 4 of 214 patients with neurological symptoms accompanying COVID-19 infection. In our case report of post-Covid stroke we have shown documentation with the peripheral visual field results and localization of ischemic area in the occipital pole of the brain.It has already been observed that patients with COVID-19 and stroke are younger than patients with stroke without infectionA recent vascular/thrombotic event on MRI in studied patient was consistent with AISs in patients with COVID-19 reported in several case series and several mechanisms for AIS in COVID-19 were proposed including hypercoagulability, vasculitis, new onset atrial fibrillation, and the infection by the SARS-CoV-2 itself. recommended that D-dimer, PT, aPTT, fibrinogen, and platelet count testing could be prognostic at admission. A coagulation panel is not typically ordered in ophthalmology services, but we are convinced now that the rising D-dimer and the rapid drop in fibrinogen and platelet count could be associated with neuro-ophthalmologic comorbidities leading to complications in vision impairment or loss. In COVID-19, D-dimer elevation appears to be an important prognostic marker and has been observed in initial COVID-19 stroke patients, as in our patient.Connors and Levy,The American Stroke Association has indicated that the risk of stroke doubles every 10 years after age 55, so far more elderly people are affected by stroke.Due to the increase in COVID-19 infections, the literature reports an increasing number of premature strokes also in the younger generation.Early reports from China described cerebrovascular disease in about 5% of patients with severe COVID-19 disease, with strokes occurring almost 2 weeks after initial diagnosis. In our study, the stroke occurred probably few weeks after COVID-19 infection, the precise moment is not known, as the neurological signs were limited to quadrantanopia. and not described in details, only as accompanying neurological disturbances.Reports on visual disturbances during or post-COVID infection are scarceRecently developed treatments, such as intravenous thrombolysis and mechanical thrombectomy, can significantly improve the outcomes of AIS. However, the effects of these treatments are highly time-dependent. After the end of a therapeutic time window (4.5 hours) according to recommendations we can use antiplatelet drugs, hypotensive drugs and statins. In our case it is not possible to determine precisely when the thromboembolic event occurred. The present case of stroke delayed after COVID-19-related pneumonia seems to confirm that COVID-19 is an independent risk factor for AIS.In addition to the potential ischemic event, we have considered thrombotic risks and we have used anticoagulating and antithrombotic therapy (low-molecular-weight-heparins) in responses to elevated D-dimers keeping in mind a prevention of the acute visual loss due to ophthalmic artery occlusion. Fortunately, it was a low risk patient since the carotid and intracerebral circulation was normal based on the U/S and CTA, respectively.Nevertheless, the optimal treatment to prevent ischemic event (ischemic stroke) or vascular thrombosis in presence of D-dimer elevation in COVID-19 neuro-ophthalmic complications continue to be unclear and require attention to multimodalities in diagnostic evaluations and multispecialty team's collaboration in diagnostic evaluations of such patients.Conceptualization: Mario Damiano Toro.Funding acquisition: Robert Rejdak.Methodology: Maksymilian Onyszkiewicz.Resources: Anna Pankowska, Radoslaw Pietura.Visualization: Agata Szpringer, Aleksandra Czarnek-Chudzik.Writing – original draft: Katarzyna Baltaziak.Writing – review & editing: Katarzyna Nowomiejska.


Autoimmune cytopenias (AICs) have been reported as a common complication in chronic lymphocytic leukemia (CLL) with autoimmune hemolytic anemia (AIHA), accounting for most cases. According to iwCLL guidelines, AICs poorly responsive to corticosteroids are considered indication for CLL-directed treatment. Chemo-immunotherapy has classically been employed, with variable results, and little data are available on novel agents, the current backbone of CLL therapy. The use of idelalisib in the setting of AICs is controversial and recent recommendations suggest avoiding idelalisib in this setting. Ibrutinib, through ITK-driven Th1 polarization of cell-mediated immune response, is known to produce an immunological rebalancing in CLL, which stands as a fascinating rationale for its use to treat autoimmunity. Although treatment-emergent AIHA has rarely been reported, ibrutinib has shown rapid and durable responses when used to treat AIHA arising in CLL. There is poor evidence regarding the role of BCL-2 inhibitors in CLL-associated AICs and the use of venetoclax in such cases is debated. Furthermore, their frequent use in combination with anti-CD20 agents might represent a confounding factor in evaluating their efficacy. In conclusions, because of their ability to mitigate an immunological dysregulation that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice when treatment of autoimmune cytopenias is required. Chronic lymphocytic leukemia (CLL), the most common leukemia in western countries, is characterized by a marked clinical heterogeneity, ranging from years of stable disease to a rapidly progressive clinical course . Due to According to 2018 iwCLL guidelines  autoimmuThe diagnosis of AIHA (in CLL patients) usually requires the presence of the following criteria ,6: hemogSimilarly to primary cases, CLL-associated AIHA is generally categorized into two major entities: a warm type (wAIHA), characterized by a DAT positive to IgG or IgG + C3d and negative agglutination at 20 °C, and a cold type , with agglutination at 20 °C and a DAT positive for C3d. When available, a peripheral blood smear can sometimes be helpful as spherocytes are usually present in wAIHA, while red blood cell agglutination is a frequent feature of CAD.Autoantibodies are usually polyclonal high-affinity IgGs produced by non-malignant self-reactive B-cells (90% of cases), while CLL cells may sometimes produce autoantibodies (mainly IgM) in <10% of cases .Although it is usually possible to distinguish between the two forms, in some cases, a mixed DAT can be present, characterized by a DAT positive for IgG and C3, coexisting with high titre (>40) cold agglutinins .Moreover, rare cases of DAT-negative AIHA in CLL patients have been described, possibly due to the low affinity or to the very small number of autoantibodies, and, on the other hand, DAT positivity is sometimes present in CLL patients without evidence of active hemolysis .For cases arising in CLL, diagnosis can sometimes be challenging since some markers might be influenced by the underlying disease: LDH may be increased in progressive disease and haptoglobin might be only slightly reduced or normal when inflammatory/infective conditions are present; otherwise reticulocytosis might be impaired by bone marrow infiltration.It is important to underline that no prospective clinical trial has ever been conducted in the setting of CLL-associated AIHA, as patients with uncontrolled AICs are typically excluded from trials. Current strategies for first-line treatment are based on the approach used in primary AIHA.When considering treatment, the acuteness of onset, the severity of anemia and the degree of hemolysis must be taken into account, together with patient’s symptoms, age and comorbidities. Blood transfusions are usually indicated with Hb < 6 g/dL or higher in elderly comorbid patients. Over-transfusion should be avoided since it carries a high risk of allo-immunization .The management of CLL-associated wAIHA must take into account the stage of CLL: since isolated AIHA is not a criterion to treat CLL, patients in A stage should not receive CLL directed treatment. For warm AIHA occurring in patients with stage A CLL or in whom AIHA is the predominant feature, prednisone at 1 mg/kg/day for 3–4 weeks, followed by a slow tapering over several weeks (no less than 12 weeks) is considered the standard first line . MethylpA retrospective study evaluating obinutuzumab in a small cohort of CLL patients showed an overall response rate (ORR) of 87.5% (7/8) (complete response (CR) 50%) demonstrating that 2nd generation anti-CD20 agents may be an effective treatment for AIHA and ITP in patients with CLL/SLL .Some patients with CAD may have a milder clinical presentation with cold agglutinin associated symptoms  and not need immediate treatment. Therapy should be reserved for transfusion-dependent cases, active hemolysis, and significant CAD-related cAIHA symptoms. As corticosteroids result in remission in very few patients, rituximab should be considered as a first line. A standard dose of 375 mg/sm weekly for 4 weeks guarantees a response in up to 70–100% of patients ,14.Considering patients refractory to first-line treatment  current guidelines advise the introduction of a CLL-directed therapy that should be tailored to disease features and the patient’s comorbidities . Historically, in the setting of wAIHA related to B-lymphoproliferative malignancies, combination regimens such as rituximab, cyclophosphamide and dexamethasone (RCD) or rituximab, cyclophosphamide, vincristine and prednisolone (R-CVP) have shown satisfying ORR (>80%) with a response duration of approximately 22 months ,17. SubsNowadays, with the availability of novel agents, treatment selection should be accurately made keeping in mind their ability to control disease burden and, possibly, to modulate autoimmunity in CLL.With the increasing use of small molecule inhibitors in clinical practice, chemotherapy has a limited role in CLL treatment, but when it comes to addressing autoimmune complications, no extensive literature is available on their use for AIHA. While their anti-tumor effect is well known, not all novel agents have shown immunomodulating activities; such peculiar mechanisms may justify their use against autoimmune disorders.There is currently no consensus on which agent should be preferred for AICs in CLL and the choice is largely left to single-center policy. Though literature is scarce, several centers have reported their experiences with small molecules currently in use, with interesting results .Little data evaluating the efficacy of Phosphatidylinositol 3-kinase-δ (PI3K-δ) inhibitors in CLL-related AICs are available to date. In particular, idelalisib has demonstrated correlation to autoimmune clinical complications  which does not make this class of inhibitors an attractive option for the treatment of AIHA. Therefore, recent recommendations suggest avoiding idelalisib in the context of CLL-associated cytopenias . Limited clinical reports have shown some degree of efficacy of idelalisib in addressing this condition, although a confounding effect of rituximab should be considered.A multicentre French study enrolled 44 CLL patients with AICs, of whom 25 received ibrutinib monotherapy and 19 patients received the idelalisib-rituximab association (12 patients were treated for AIHA).Overall response rates in both groups were 95% and 92% respectively, regardless of AIC type. In the R-idelalisib group, the ORR was 92% for AIHA patients and 100% for patients with ITP or PRCA. Notably, therapy with kinase inhibitors (KIs) allowed discontinuation of corticosteroids in 86% of ibrutinib patients and in 67% in the R-idelalisib cohort. With a median follow-up of 26.8 months, treatment failed to control AIHA in one case in the idelalisib group. For responding patients, no AIHA relapse was described during idelalisib treatment, although five patients experienced relapse after idelalisib discontinuation .Feld J et al. reported a case of unprecedented concomitance of mixed AIHA and B-prolymphocytic leukemia (PLL) evolution in an elderly CLL patient treated with a combination of prednisone, idelalisib and rituximab, allowing normalization of Hb levels and white blood count within 2 months of therapy .Although these results seem to show CLL-related AIHA might be effectively treated by the use of idelalisib, we need to consider that the combination with rituximab and/or steroids makes it difficult to selectively evaluate its efficacy against autoimmune cytopenias.There is growing evidence suggesting that Bruton’s Tyrosine Kinase (BTK) inhibitors may soon play an important role in the treatment of refractory AIHA in clinical practice. Ibrutinib is a first-in-class inhibitor of BTK approved for the treatment of treatment-naive (TN) and relapsed/refractory (R/R) CLL patients. As we will further elaborate, the many off-target effects of this agent provide a rationale for its use in the setting of CLL-related AICs ,31. HoweA small case series of five patients with AIHA requiring therapy in previously treated CLL patients was reported by Garcia-Horton et al. All five patients showed a response to ibrutinib and AIHA was controlled within a median of 6.5 weeks, with discontinuation of steroids achieved in all patients at a median of 10 weeks; none of the five patients showed evidence of AIHA relapse at a median follow-up of 3 years .Other similar case reports/series have been published over the last 5 years, confirming ibrutinib’s efficacy in treating AIHA in patients affected by CLL ,25,32 anPerhaps the most extensive data so far available of CLL-related AIHA and ibrutinib are based on a sub-analysis of the phase III RESONATE trial (ibrutinib vs. ofatumumab in R/R CLL patients) evaluating the effects of this agent on patients with concomitant AIHA and/or ITP . Although uncontrolled AIHA/ITP patients were excluded, the presence of mild autoimmune hemolysis in patients who met other iwCLL treatment criteria was allowed. n = 21 ibrutinib; n = 9 ofatumumab) at study entry were evaluated. Early after treatment initiation median Hb levels started rising and were maintained throughout a median follow-up of 17.5 months. In this analysis no new onset AIHA occurred in the ibrutinib group compared to four patients on ofatumumab. This event has been only sporadically reported in few series of CLL patients [Therefore, patients with ongoing AIHA  patients were able to discontinue or de-escalate AIC treatment and no patients had worsening of their AIC after initiating ibrutinib; 11/193 patients (among whom were 5 cases of AIHA: 3 cases in patients with remote history of AIC and 2 cases in patients with no such history), however, experienced treatment-emergent AIC, leading to drug discontinuation in 36% of cases . NotablyTo date, little evidence is available regarding novel BTK-inhibitors, such as acalabrutinib, and their effect on autoimmune complications in CLL, but results of a phase II study evaluating acalabrutinib monotherapy in 134 R/R CLL showed only one recurrence of AIHA among 11 patients with history of AIC .All things considered, published data suggest BTK-inhibitors and particularly ibrutinib represent a safe and effective therapeutic strategy in patients with history of AIC.Venetoclax, a BCL-2 inhibitor, has demonstrated activity in R/R CLL patients regardless of TP53 disruption when used alone or associated with rituximab .There is poor evidence regarding the role of BCL-2 inhibitors in treating autoimmune events in CLL as there are no trials addressing this issue. Nonetheless, some cases of emerging AHIA/ITPs have occasionally been reported in clinical trials.In particular, in their trial evaluating single-agent venetoclax in untreated 17p-deleted patients, Stilgenbauer et al. observed 8/158 patients experiencing AHIA and 3/158 immune thrombocytopenia during treatment, although none needed dose interruptions . Notably, all patients enrolled in the study harbored high-risk cytogenetic aberrations that are known to be associated with a higher frequency and severity of autoimmune cytopenias .This event, however, was not observed in other trials where venetoclax was used in combination with anti-CD20 agents, possibly due to an additional immunosuppressive effect ,41. Though limited to single case reports, some authors have reported their experience of successfully treating AICs with venetoclax. In 2017 Lacerda et al. described the case of a R/R 17p-deleted patient treated with alemtuzumab for concomitant disease progression and AHIA, with disease control but persistence of transfusion-dependent anemia. After failure with rituximab and high-dose dexametasone he was started on compassionate-use venetoclax with a significant improvement in Hb levels after 3 months and no relapse of AHIA after 10 months of therapy .Gordon et al. reported 2 cases (one ITP and one Evans Syndrome) that received single-agent venetoclax after several relapses of isolated AICs with little disease burden: both patients had a normalized Hb and platelet count within 4 weeks of starting therapy .BCL-2 inhibitors might represent a potential option in patients with refractory CLL-associated AHIA. In the absence of data comparing different small molecules inhibitors, it is debated whether venetoclax may be considered a preferred choice in this setting. AIHA is the most common AIC in CLL patients, with a prevalence of approximately 2.9% in stable Binet stage A disease compared with 10.5% in stage B and C [When AIHA occurs in CLL patients, acquiring information on the type of AIHA , biological CLL features based on FISH and IGHV, and the presence of other iwCLL treatment criteria is considered an essential step.Considering the suboptimal response to chemo-immunotherapy (CIT) regimens in high risk CLL patients   togetherNowadays, data regarding the use of targeted agents derive from retrospective studies, and direct comparisons between different small molecule inhibitors in this group of patients are lacking. As a consequence, no guidelines are available to direct the choice of therapy in CLL-patients developing AIHA and not responding to steroids/rituximab and chemo-immunotherapy. Currently available data show that ibrutinib appears to cause an improvement in the majority of patients with pre-existing AIHA ,25,26,33In addition to its direct anti-tumor effect on BTK, ibrutinib irreversibly binds ITK (Interleukin-2 inducible kinase) and inhibits downstream activation of Th2 cells after TCR stimulation both in vitro and in vivo . As ITK Although concerns have been raised because of reports of new onset AIHA after ibrutinib start , currentMoreover, in most patients where ibrutinib is used for the treatment of AIHA, time to steroid interruption is generally shorter than usual practice (10–12 weeks). As tapering off corticosteroids can often requires up to 6 months, patients are prone to experience several well-known complications of this treatment . Therefore, especially in patients with coexisting conditions, shortening steroid exposure represents an attractive option in patients who would otherwise be subject to further therapy-induced complications.For these reasons, we tend to favor ibrutinib in our practice for the treatment of CLL-associated AIHA.Idelalisib is frequently responsible for triggering non-hematological autoimmune complications, whereas data on its use in the management of AICs are limited. Although idelalisib in association to rituximab has shown some degree of efficacy in the treatment of CLL-related AIHA ,21, the Furthermore, the beneficial effects of co-administering an anti-CD20 monoclonal antibody with a targeted drug to gain a better control of pre-existing AIHA still need to be clarified.Finally, with regard to the potential use of BCL-2 inhibitors, the role of venetoclax in the treatment of AIHA in CLL is yet to be defined.Small molecule inhibitors are able to exert excellent disease control in chronic lymphocytic leukemia as first-line options or in R/R cases. Such activity on disease burden is usually able to extinguish the autoimmune dysfunction that is responsible for AIHA and related immune cytopenias. However, the choice of the right agent seems important as, with very little literature available so far, not all new drugs are able to yield the same efficacy in repressing hemolysis. Because of their ability to produce a deep change in the cytokine asset that is (at least partly) responsible for autoimmunity in CLL, to date BTK-inhibitors stand out as the most suitable choice.In the near future, clinical studies employing BTK-inhibitors as treatments for CLL-related AICs will manage to cast new light on their potential role as an earlier therapy line for these conditions and phase II trials using these inhibitors (with or without rituximab) are currently ongoing in CLL-wAIHA (NCT03827603) and ITP (NCT03395210).