The immunopathology of COVID-19 placentitis: A multi-omic spatial approach

Problem: COVID-19 placentitis is a rare complication of maternal SARS-CoV-2 respiratory infection associated with serious adverse obstetric outcomes, including intra-uterine death. The precise role of SARS-CoV-2 in COVID-19 placentitis is uncertain, as trophoblast infection is only observed in around one-half of the affected placenta. Method of Study: Through multi-omic spatial profiling, including Nanostring GeoMX digital spatial profiling and Lunaphore COMET multiplex IHC, we provide a deep characterization of the immunopathology of placentitis from obstetrically complicated maternal COVID-19 infection. Result(s):We show that SARS-CoV-2 infection of placental trophoblasts is associated with a distinct innate and adaptive immune cell infiltrate, florid cytokine expression and upregulation of viral restriction factors. Quantitative spatial analyses reveal a unique microenvironment surrounding virus-infected trophoblasts characterizedd by multiple immune evasion mechanisms, including immune checkpoint expression, cytotoxic T-cell exclusion, and interferon blunting. Placental viral loads inversely correlated with the duration of maternal infection consistent with progressive virus clearance, potentially explaining the absence of virus in some cases. Conclusion(s): Our results demonstrate a central role for placental SARS-CoV-2 infection in driving the unique immunopathology of COVID-19 placentitis.

Use of daily home spirometry to predict clinical outcomes in persons with cystic fibrosis

Background: Use of home spirometry to monitor lung function has been increasing in popularity in persons with cystic fibrosis (PwCF) since the start of the COVID-19 pandemic. Although clinic spirometry is interpreted from validated standards, expected test-to-test variation of home spirometry and how variation during baseline health may relate to clinical changes are unknown. The aim of this study was to determine variation in baseline lung function during daily home spirometry and identify associations with clinical outcomes. Method(s): Subjectswere selected based on available spirometry data from a cohort of PwCF enrolled in a long-term airway microbiome study. Subjects were provided with a PiKo-6 hand-held spirometer (nSpire Health, Inc., Longmont, CO) and asked to perform spirometry maneuvers three times per. Validity of home spirometry (percentage predicted forced expiratory volume in 11 second (FEV1pp)) was compared with that clinic spirometry using Bland-Altman plots. Spirometry acceptability across multiple maneuvers in the same day was assessed using the American Thoracic Society (ATS) guidelines, with grade A or B (two or more maneuvers within 150 mL) considered acceptable. Variation in FEV1pp was assessed by calculating a mean FEV1pp and coefficient of variation (CoV). The association between CoV and pulmonary exacerbations (PEx) was tested using Cox proportional hazards regression models. Result(s): Thirteen subjects (62% female) with a mean age of 28.7 +/- 8.3 and mean FEV1pp of 59.9 +/- 8.2%were included. Median study durationwas 377 days (range, 33-730 days). Subjects used the home spirometer on average 51.2% of the study days (range 15-97%). On average, 58.9% of subjects (range 12-100%) used the home spirometer at least twice aweek, and 76.8% (range 65-100%) at least once aweek. To focus on periods of baseline health, days associated with PEx (spirometry performed 2 weeks before and during times of antibiotic therapy) were excluded. A median of 204 days (range 11-728 days) of baseline spirometry readings was available for further analysis. Comparing validity of home spirometry with that of clinic spirometry, Bland-Altman plots demonstrated overall good agreement with a slight bias (+0.042 L) toward higher readings for clinic FEV1pp (95% limits of agreement, -0.11-0.19 L). Spirometry quality was graded as acceptable on most study days (mean 90.6 +/- 4.6%) in which two or more maneuvers were recorded. Intra-individual variation in baseline FEV1pp was high, with a mean variation of 17.6 +/- 5.9% day to day and 15.2 +/- 6.2% week to week. Neither rates of acceptable spirometry grades nor CoV was associated with lung disease severity. Of the 13 subjects, 10 experienced one or more PEx, for a total of 32 PEx during the study. CoV was not associated with time to first PEx (hazard ratio [HR], 0.78;95% confidence interval [CI], 0.51-1.21;p = 0.24) or time to subsequent PEx (HR, 0.91;95% CI, 0.73-1.12;p = 0.28) during the study. Conclusion(s): Although home spirometry has generally good validity and acceptability, variation in lung function during baseline health is present and often exceeds expected variation in clinic spirometry per ATS standards. Variability may represent normal physiological variation or be related to the home spirometer itself or other factors but did not portend upcoming PEx. Recognition of variation during baseline health provides important context for interpretation of home spirometry.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

‘If lecturers are at home, they can't tell their kids to shut up': university student engagement with blended learning during Covid-19: a mixed methods study

Covid-19 had an unprecedented impact on daily living and resulted in many restrictions across all areas of life. Consequently, educational establishments in the UK adapted teaching delivery by moving to online or blended learning during the main ‘stay at home' phase and many remained online as ongoing restrictions were announced. Many changes made during this period such as a move to online learning are likely to remain, in some capacity, as we emerge from the pandemic. The aim of this study was to explore student engagement with online and blended learning in a Higher Education (HE) institution using a mixed methods approach. One hundred and eighty-two HE sport students completed an online survey and a total of twenty one HE students took part in a series of online focus groups to gain a unique insight into how the move to online learning affected engagement from the student perspective. The findings indicated that although most students engaged with the online materials, many had a perceived negative experience. Students in general would not recommend online delivery to others and an overwhelming majority felt disadvantaged in terms of motivation and lack of community by moving to online learning. There was some positive feedback around the use of some technological tools to facilitate answering questions as well as use of online lectures for delivering content driven sessions. Our results clearly demonstrate that that a one size fits all approach is not appropriate when it comes to online learning. © 2023 UCU.

Multi-System and Cavernous Sinus Inflammatory Syndrome Presenting with Evolving Multiple Cranial Neuropathies Following Zoledronate Infusion

Case report - Introduction: Bisphosphonates are known to rarely cause multi-system inflammation, including multiple cranial neuropathies. This is possibly via provoking transient cytokine storm. The literature reports bisphosphonate-associated orbital inflammatory syndrome, and one case of retrobulbar optic neuritis following zoledronate. Bisphosphonate manufacturers report conjunctivitis, blurred vision, scleritis, orbital inflammation, uveitis and episcleritis as ocular side effects. Separately, neurological sequalae, including cranial neuropathies, are reported following COVID-19 infection and vaccination. Here, we report the first case of cavernous sinus inflammation temporally related to both zoledronate infusion, and more remotely, to Pfizer- BioNTech COVID-19 vaccination. Case report - Case description: A 76-year-old white man developed fever, bony leg pain - which rendered him unable to walk - and frontal headache, within 8 hours of his first zoledronate infusion for osteoporosis. A few weeks earlier he received his first Pfizer-BioNTech COVID-19 vaccine. His General Practitioner commenced a short course of lowdose oral prednisolone for the episode. One week later, off prednisolone, the headache localised around the left eye. He developed horizontal diplopia associated with abduction deficit. He was diagnosed with left VIth nerve palsy. He was started on high-dose steroids and clopidogrel (with PPI) with neuroimaging to exclude stroke or venous sinus thrombosis. Two weeks later, the diplopia worsened over 4 days, with new left adduction deficit (-2 limitation), left ptosis 1-2mm and anisocoria 0.5-1mm R>L suggestive of partial third nerve palsy and early Horner's syndrome. Ocular and neurological examinations were otherwise normal. He wore varifocals and had migraines, osteoporosis, and asthma, for which he used inhalers. He worked in visual arts and was an ex-smoker (>50 years) with moderate alcohol intake. Blood results revealed CRP 38mg/L, but otherwise normal inflammation/ vasculitis/infection screen;anti-thyroglobulin antibodies were >4000 U/ml;GQ1P, Creatinine Kinase, anti-ganglioside, and Anti- AChR/MuSK antibodies were normal. CT head and Optical Coherence Tomography were unremarkable. An enhanced MRI of the brain and orbits revealed abnormal thickening and T2 hyper-intensity of the left oculomotor nerve, most notably involving the left canalicular portion. The left cavernous sinus also appeared asymmetrically bulky with a rind of abnormal enhancing soft tissue in the left cavernous sinus. Subtle STIR hyper-intensity was also observed in the ipsilateral CN IIIinnervated extra-ocular muscles. After a 6-week course of tapering prednisolone, the vertical diplopia and leg swelling persisted;the horizontal diplopia and headaches had resolved. By 3months, there was resolution with mild residual visual changes. Case report - Discussion: We report a constellation of symptoms relating to multi-system inflammatory syndrome involving the cavernous sinus. There is a lack of epidemiological data on the incidence of this rare presentation in the population. This case has close temporal association to bisphosphonate infusion (<12h) and weaker association to coronavirus vaccination (<3wk). It is difficult to determine whether this is a rare presentation of a known drug reaction, a more delayed presentation of a vaccine reaction or whether these events were coincidental. A further possibility in this case is a combined predisposition resulting from both vaccination and bisphosphonate infusion. This case highlights a wider issue relating to the challenging possibility of ascertainment bias and increased 'Yellow Card' reporting of rare presentations during this historic global coronavirus pandemic, which may or may not have any true causal association to vaccination. There is difficulty in disentangling a true vaccine reaction from an unrelated presentation of a rare condition with an unknown baseline incidence rate. This is especially topical given that the majority of the population are receiving the coronavirus ccination at this time. We also question what a plausible cut-off point would be to propose a temporal relationship for an adverse reaction;in the literature, adverse reactions have been postulated to develop beyond 1 month after the provoking agent. Case report - Key learning points: . This case highlights the need for urgent assessment, investigations including neurological imaging and consultant input in patients with evolving cranial neuropathy. The priority is to rule out thrombotic, compressive, inflammatory and infectious pathology in the cavernous sinus, venous sinus, orbit and orbital apex. . Pathology of the cavernous sinus presents with variable involvement of CN III, IV, V and VI and Horner's syndrome. A differential for this case would be superior orbital fissure syndrome, which also presents with multiple oculomotor cranial neuropathies;it involves these cranial nerves and the ophthalmic branch of CN V. Orbital apex syndrome is SOF with a loss of vision due to additional CNII involvement. . The neuro-radiology differential included inflammatory, infiltrative, granulomatous and neoplastic aetiologies and that there was sufficient existing evidence to exclude brainstem pathology. . Through communication between specialties, the temporal relationship was established, and clinical examination and extensive investigation further honed the differential to either inflammatory or vascular. Since it was temporally related to the zolendronate infusion, it seemed plausible it was related. We demonstrate the need for multi-disciplinary collaboration for these patients between rheumatology, ophthalmology and neuro-radiology.

Lessons from COVID-19, challenges of remote learning for childhood cancer survivors

Background: More than half of childhood cancer survivors (survivors) will have neurocognitive deficits that impact schooling, most commonly reflecting attention and executive dysfunction. Schools are legally bound (IDEA, 2004) to support eligible students with Individualized Education Program (IEP) informed instruction and related services (e.g. assistive technology, speechlanguage, physical, or occupational therapy) to foster academic success. However, these service provision were not designed under the constraints of remote learning. The COVID19 shift to remote learning is likely to extend beyond the pandemic especially for medically fragile students. This quality improvement project describes challenges for survivors during remote learning and recently developed related patient education materials. Methods: Interviews with families were used to identify themes around challenges during remote learning, which informed development of a 29-question survey disseminated via flyer in local oncology clinics and social media posts by local childhood cancer organizations in Fall 2020. Results: The survey was completed by 67 parents describing their affected child (mean age= 8.6 years;60% male;78% White, 12% Black, 95% non-Hispanic). Most children (74%) had completed therapy (43% for leukemia, 18% for brain tumor;39% other). The majority (86%) attended public school and 37% received special education or related services: speech-language (26%), occupational (23%), and physical (14%) therapies, and vision services (3%). Fully remote learning was reported for 73%, in-person 4%, and hybrid learning for 14%. The majority (57%) reported observing greater difficulty with attention and focus during RL, indicating difficulty occurred about half of the time during related services therapies, class and/or small group video instruction. Technologyrelated challenges included difficulty navigating online instruction/equipment (28%), reading difficulty (16%), and difficulty seeing materials/lack of vision supports (18%). Findings did not differ based on treatment or IEP status (p>0.50). Few (14%) reported their school team discussed assistive technology options for online learning. Parents indicated the most helpful supports for addressing challenges included speech-to-text tools, screen readers, and audio books. Parents reported their oncology team was helpful in making referrals to neuropsychology and therapies and completing documentation necessary to secure supports. Conclusions:Childhood cancer survivors, irrespective of diagnosis or IEP status, report challenges with remote learning. Families find a lack of information or special accommodations as roadblocks to success. Oncology providers were identified as valued resources, so educational materials (https://tinyurl.com/nxbhj5or) were developed for oncology teams to share with families.