Famotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with Coronavirus disease 2019 (COVID-19). The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19.Five databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome  and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated.Four studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 . Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death—HR 0.67  and OR 0.79 . Heterogeneity ranged from 83.69% to 88.07%.Based on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further randomized controlled trials (RCTs) may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease. Coronavirus disease 2019 (COVID-19) is predominantly a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) that first arose in December 2019 in Wuhan, China –10. Bamlet al. ..2 = 83.62 = 88.07%) and OR of 0.79   and OR of 0.37   . Again, 6, 0.86) . OverallWe conducted an updated systematic review and meta-analysis on the therapeutic impact of famotidine in treating hospitalized COVID-19 patients in accordance with methodological standards set by the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group for high-quality systematic review and meta-analysis . Our reset al. and Sun et al. for four main reasons: 1) to reduce discrepancies in patient characteristics, we did not include the studies by Cheung et al. and Zhou et al. as they included all patients with COVID-19 in Hong Kong, including outpatient, inpatient, and emergency settings as opposed to four other studies where only hospitalized patients were included [et el [Our current analysis is different from the two meta-analyses published by Kamal included ; 2) mored [et el ; 4) finad [et el . In factd [et el –17.et al. showed a HR of 0.43 (95% CI: 0.21–0.88) for the composite outcome of 30-day mortality or intubation when patients were given famotidine on day 1 of hospitalization [Among reports included in this meta-analysis, two earlier retrospective cohort studies reported that famotidine is associated with a decreased rate of mortality and/or composite outcome for patients with COVID-19 , 15. Forlization . Howeverlization , 17.et al. in this meta-analysis as the study included patients diagnosed with COVID-19 in the ambulatory and emergency settings, it is important to note that the study showed an increased composite outcome of intensive care unit admission, intubation, and all-cause mortality  for COVID-19 patients treated with famotidine [et al. also investigated the effect of another class of acid suppressor agents in proton pump inhibitors (PPIs), which block the hydrogen/potassium adenosine triphosphatase enzyme system as opposed to the H2 receptors in famotidine. They found that current or regular PPI users were more likely to have severe outcomes of COVID-19 compared to non-users [et al. showed that when compared to patients on H2 blockers, patients on PPIs have an increased risk of death [Although we did not include Zhou motidine . The stuon-users —findingson-users . The mecof death . Similarof death .Currently, there is very limited data on the efficacy of oral famotidine in treatment of COVID-19 patients with mild to moderate disease solely in the outpatient setting. A case series of 10 non-hospitalized COVID patients reported improved symptoms score after initiation of high dose famotidine . Howeveret al.. Furthermore, while we employed a random effects model for our analysis, the heterogeneity is high. Lastly, there are subtle yet meaningful differences in the definition of composite outcome across the four studies, thereby allowing for potential bias when calculating aggregate ORs/HRs. Given the paucity of data reported in the literature, the directionality of these results should only be used for hypothesis-generation rather than clinical decision making.There are several limitations to this study. First, the strength of our findings is limited by the quality of included studies as is the case for all systematic reviews and meta-analyses. To account for confounding, this meta-analysis contains only observational data that reported adjusted relative risks. Although all the included observational studies had some concern for risk of bias, they employed propensity score matching to minimize selection bias. Additionally, only one study explicitly included patients with COVID-19 treated with famotidine before and during hospitalization . Other sIn conclusion, this meta-analysis suggests that famotidine does not reduce the risk of mortality in individuals hospitalized with COVID-19. Similarly, there was a point estimate suggesting a decreased risk of the composite outcome of death, intubation, and/or use of intensive services among famotidine users, but this did not meet statistical significance. Further RCTs may help determine the efficacy and safety of famotidine in treating COVID-19 patients in various care settings.S1 Checklist(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


The authors evaluated a reformed psychiatry clerkship curriculum based on entrustable professional activities (EPAs).The authors conducted an exploratory pilot study of a reformed clerkship curriculum based on EPAs. A novel workplace-based assessment format including an entrustment-supervision scale and curricular adaptations were introduced. The Kirkpatrick model was used to evaluate outcomes of the reformed clerkship curriculum on three levels .n = 10) completed a questionnaire, 180 self-assessments (18 per student) on need for supervision, and 63 workplace-based assessments . Level 1: high overall satisfaction with the clerkship . Level 2: the overall significant decrease in self-assessed need for supervision before and after the clerkship was two supervision levels . The most frequently documented admissions included schizophrenic disorders , affective disorders , substance abuse disorders , and anxiety and stress-related disorders . Level 3: clinical supervisors used history taking, assessing the mental status, and documentation and presentation for workplace-based assessments. According to supervisors’ ratings, there was a decreasing need for supervision from the first to last week of the clerkship.The pilot student cohort (Students reacted positively to the reformed clerkship curriculum. The workplace-based assessments with entrustment ratings appeared to support achievement of competency-based learning objectives. Better understanding of how to cover assessment of all core EPAs in the psychiatry clerkship is needed. Competency-based national frameworks with entrustable professional activities (EPAs) have been introduced in the USA, Canada, and Switzerland for undergraduate medical education –3. EPAs The introduction of an EPA-based clinical curriculum typically involves informing students and staff about EPAs as learning goals, for implementation of new teaching activities, and in some cases for reforming workplace-based assessment instruments –12. ObseOur objective for this exploratory pilot study was to evaluate educational outcomes after introduction of EPAs, a novel assessment format and associated curricular adaptations to a psychiatry core clerkship curriculum. Therefore, we aimed to explore multiple data sources on the first three Kirkpatrick model levels  as one of the most widely used evaluation models in medical education . Within We conducted an exploratory pilot study of a competency-based clerkship curriculum reform and assessed the educational curriculum reform outcomes on levels 1–3 of the Kirkpatrick model for program evaluation . The eduMedical students at our institution have to complete five mandatory core clerkships during the fourth year of their 6-year medical curriculum (Bachelor and Masters of Medicine). Each year, our psychiatric teaching hospital provides treatment for approximately 3800 inpatients and over 10,000 outpatients. We train about 10 medical students per month, with each teaching ward taking on one or two medical students per month. Students spent 4 weeks on 10 different wards. The interprofessional staff of a ward typically consists of one attending physician and two residents, in addition to nurses, a psychologist, and a social worker, and takes care of 20–22 hospitalized patients. We do not use grades for clerkship rotations but students have to hand in several mandatory formative assessments: ≥4 workplace-based assessments (with at least one on EPA 1 and one on EPA 2); 4 documented patient admissions with active student participation; and 1 scientific paper or clinical case presentation, per student.On level 1 , we analyzed the student evaluation of the reformed clerkship curriculum and student in-between and end-of-clerkship feedback. The pilot clerkship rotation with the new curriculum and novel workplace-based assessment format was evaluated by all students with a five-point Likert scale.On level 2 , we analyzed the self-entrustment ratings of perceived need for supervision for each EPA before and after the clerkship rotation. To explore the patient-mix exposure as surrogate for learning outcomes , we collOn level 3 , we analyzed all of the supervisor-rated workplace-based assessments. These assessment and evaluation data were either collected through paper-based evaluation forms or electronically via ILIAS, throughout February 2019. We used the statistical software R to analyze the supervision scale ratings, with Wilcoxon signed-rank tests.Students were introduced to the clerkship structure in a reformed clerkship orientation seminar on the first day of their clerkship rotation. In addition to working on the wards and taking part in routine ward and department meetings, students were expected to participate in six didactic clerkship seminars , a scientific paper presentation exercise, and a scientific “journal club.” Furthermore, off-site visits to specialized services, such as addiction-treatment facilities and the child and adolescent psychiatric clinic were part of the curriculum, which also included a patients-as-teachers seminar. Clerkship learning material  and knowledge tests for self-regulated learning purposes were provided through a newly integrated online clerkship platform. The sample for this explorative pilot study consisted of 10 medical students with an average age of 22.5 years . Students were routinely assigned to our teaching hospital by the administrative staff of the medical school. Clerkship directors and supervising clinical staff were introduced to the new workplace-based assessment format with entrustment-supervision ratings in a workshop and via online instruction before implementing the curriculum reform. The new student assessment format included 15 to 20 min direct observation and documentation of the observed EPA, the entrustment rating, and providing narrative feedback.A clerkship syllabus with nested EPAs for psychiatry Table  was deveProgram evaluation data, workplace-based assessments, and self-entrusted need for supervision were collected from all of the medical students in February 2019. We used a published supervision scale for each core EPA  for selfLevel 1 (acceptance): Overall satisfaction indicated agreement with the statement: “I am very satisfied with the overall clerkship experience,” from disagree (1) to agree (5). The overall satisfaction average was 4.9 . Students felt well integrated into their ward teams , and they found the online learning platform helpful for their learning experience . They tended to agree with a statement whether the workplace-based assessments were helpful for their learning experience . Seminars and off-site visits were rated from bad (1) to excellent (5), and received an average of 3.5 . The positive aspects in the written evaluations by the students mentioned motivation of the attending physicians and residents, and structure and organization of the clerkship curriculum. The students emphasized the importance of structured bedside teaching in the first clerkship week and suggested better instruction of residents with regard to workplace-based assessments and avoidance of redundancy in some of the face-to-face seminars.p < 0.05, Wilcoxon signed-rank tests).Level 2 (learning): The changes in the self-assessed need for supervision differed both across the core EPAs and intra-individually Fig. . The aven = 40). Documented admissions included schizophrenic disorders , affective disorders , substance abuse disorders , anxiety and stress-related disorders , personality disorders , organic illness , and eating and impulse control disorders , while two admissions did not include any diagnosis (5%).Each student participated in and documented four patient admissions  of the EPA assessments were documented, in week #2, 41% (n = 26), in week #3, 17% (n = 11), and in week #4, 8% (n = 5); two assessments were not dated (3%). The average EPA supervision levels as evaluated by the clinical supervisors per week were: 2.5 (week #1), 2.6 (week #2), 2.5 (week #3), and 3.0 (week #4). Of all of the assessments, 38% (n = 24) addressed EPA 1, 43% (n = 27) addressed EPA 2, 3% (n = 2) addressed EPA 3, 1.5% (n = 1) addressed EPA 5, and 14% (n = 9) addressed EPA 8 (see Table Level 3 (change of behavior): Clinical supervisors completed 63 workplace-based assessments . In week #1, 30%  might be that structuring a clerkship curriculum around EPAs provides a learning scaffold that directly reflects the clinical working environment . To explWhile self-assessment of competence is challenging in terms of reliability and objectivity and also not specific in terms of learner needs , clinicaIn contrast, EPAs which were not formally observed showed very heterogenous or no changes in self-entrustment. The potential reasons behind these changes might include varying complexity levels of the clinical tasks , or inadBased on our observations, the deliberate use of formative workplace-based assessments  might be a potential driver to achieve learning objectives with regard to EPAs on Kirkpatrick level 3. Since most (71%) of the workplace-based assessments occurred in the first two weeks of a 4-week clerkship our results likely underestimate the students’ performance level at the end of the clerkship. Further research into strategies to effectively support students in mastering core EPAs is needed. Studies and educational reports from psychiatry and other specialties have revealed similar results concerning student satisfaction, improvements in self-confidence in patient care activities and challenges with sufficient workplace-based assessments in the context of EPA-based curricula in undergraduate medical education , 14, 15.The present pilot study is limited by the small sample size, and these preliminary results need to be confirmed. Further research is needed to better understand how and why or why not core EPAs are chosen by supervisors for workplace-based assessments in psychiatry. However, to our knowledge this is one of the first pilot studies that used a systematic evaluation strategy to explore an early EPA-based clerkship curriculum reform.In conclusion, EPAs as specific patient care responsibilities and the corresponding workplace-based assessments might be used to effectively guide clerkship curriculum design and support students’ attainment of competency-based learning objectives.


Peripartum severe mental disorders (PSMDs) encompass schizophrenia, affective psychosis, and psychotic and non-psychotic forms of bipolar disorders. PSMDs are well documented in high-income countries. However, much less is known about the prevalence of PSMDs in low- and middle-income countries (LMICs). The aim was to review the available literature systematically and estimate the prevalence of PSMDs among women in LMICs. We searched the Ovid MEDLINE, Embase, PsycINFO, CINAHL and Maternity and Infant Care databases systematically from the date of inception to Dec 31, 2020, for English-language publications with data on the prevalence of PSMDs among women in World Bank–defined LMICs. Selection of studies, extraction of data and assessment of study quality were each undertaken independently by at least two of the investigators. A total of five studies (completed in three countries spanning two continents) met the inclusion criteria. Five studies reported cumulative incidence of postpartum psychosis (ranging from 1.1 to 16.7 per 1000 births). We found no studies on the prevalence of severe mental disorder during pregnancy in these settings. Marked heterogeneity in methodology precluded meta-analysis. These findings indicate that PSMDs occur at a similar prevalence in low- and middle-income to high-income countries. However overall, there is a paucity of high-quality evidence from these settings. There is a need for rigorous studies with standardized methods to increase knowledge of the nature, prevalence, and determinants of PSMDs among women in resource-constrained LMICs to inform policies, service development, program planning and health professional training.The online version contains supplementary material available at 10.1007/s00737-021-01201-9. Mental health problems experienced by women who are pregnant or who have recently given birth (often referred to as the peripartum period) are common. These disorders contribute significantly to maternal morbidity and mortality, including obstetric complications, and adverse pregnancy outcomes and increase risk of self-harm and deaths by suicide  guidelines  and text words  for Evaluating Primary Research Papers from a Variety of Fields , Tanzania (n = 1) and India (n = 1). All were published since 2000. Most (n = 4) were conducted in tertiary hospital inpatient settings. Only one study  focussed on the postpartum period and reported cumulative incidence of new-onset PSMDs. There were variable definitions of the postpartum period, 28 days  included in this review (1.1 to 3.2 per 1000 births) is similar to the commonly reported population incidence (1–2/1000 births) . Psychosocial disadvantage and gender-related risk factors generally experienced by women in LMICs have a negative influence on help-seeking behaviours and reduce their access to treatment settings and resources. This potentially leads to amplified impact on the women, children and society in general with far more negative consequences compared to HIC settings. These factors make postpartum psychosis a public health priority, even in LMICs settings.We could find no specific peripartum mental health assessment and treatment guidelines in resource-constrained LMICs. Our findings, in combination with high prevalence of PCMDs Supplementary file2 (21.7 KB)Below is the link to the electronic supplementary material.


Although the original data on systemic oxidative stress in COVID-19 patients have recently started to emerge, we are still far from a complete profile of changes in patients’ redox homeostasis. We aimed to assess the extent of oxidative damage of proteins, lipids and DNA during the course of acute disease, as well as their association with CT pulmonary patterns. In order to obtain more insight into the origin of the systemic oxidative stress, the observed parameters were correlated with inflammatory biomarkers and biomarkers of multiorgan impairment. In this prospective study, we included 58 patients admitted between July and October 2020 with COVID-19 pneumonia. Significant changes in malondialdehyde, 8-hydroxy-2’-deoxyguanosine and advanced oxidation protein products levels exist during the course of COVID-19. Special emphasis should be placed on the fact that the pattern of changes differs between non-hospitalized and hospitalized individuals. Our results point to the time-dependent relation of oxidative stress parameters with inflammatory and multiorgan impairment biomarkers, as well as pulmonary patterns in COVID-19 pneumonia patients. Correlation between redox biomarkers and immunological or multiorgan impairment biomarkers, as well as pulmonary CT pattern, confirms the suggested involvement of neutrophils networks, IL-6 production, along with different organ/tissue involvement in systemic oxidative stress in COVID-19. Efforts to decipher the pathophysiology of acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) infection, from the very beginning of the COVID-19 pandemic challenge, have been pointing to the pleiotropic roles of free radicals, including the interaction of the virus with its receptor (i), viral replication (ii), interplay of cytokine storm and free radical storm in overactive immune response induced by virus (iii) and consequent end-organ damage (iv) ,4. AlthoStratification of COVID-19 disease severity, ranging from asymptomatic or mild to moderate, severe or critical, has been well established over the course of the pandemic. Thus, patients with mild disease symptoms exhibit rapid recovery, while those with moderate to severe disease exhibit high mortality and poor prognosis . It has Therefore, we hypothesized that in the acute course of the COVID-19 disease, redox biomarkers correlate with inflammatory and multiorgan impairment biomarkers and are associated with changes in the chest multidetector computed tomography (MDCT) findings in patients with COVID-19 pneumonia. In addition, we aimed to assess if the redox biomarker profile differs between hospitalized patients in comparison with outpatients.This prospective study included a total of 58 patients with COVID-19 pneumonia, admitted to one of the leading COVID-19 hospitals, the University Hospital ’Dr. Dragiša Mišović-Dedinje’ between July and October 2020, during the second wave of the epidemic in Serbia. All recruited patients had their nasopharyngeal and oropharyngeal swabs taken according to World Health Organization guidelines . All patThe principles of ICH Good Clinical Practice, the ‘Declaration of Helsinki’ and national and international ethical guidelines were strictly followed during this study. Approval from the Ethics Committee in The University Hospital ’Dr. Dragiša Mišović-Dedinje’, Belgrade, Serbia was obtained . Informed written consent was procured from all recruited subjects.All patients had their laboratory analysis and non-contrast chest CT estimated on the day of admission, on the 7th and on the 14th day, consecutively. All CT scans were acquired using the Canon (former Toshiba), Aquillion One (TSX-301C), 320 row MDCT System . Scans acquisition was conducted from the level of the thoracic entrance to the inferior level of the costophrenic angle, with the patient in a supine, arms raised, head forward position and with breath-holding manner during end inspiration. Unenhanced CT scans were obtained for all patients. The following parameters were used: tube voltage 120 kV with automatic tube current modulation, slice thickness 1.0 mm. All CT images were reviewed by two experienced radiologists with extensive experience in thoracic imaging on a diagnostic workstation  with multiplanar reconstruction (MPR) tools. All disagreements between them were resolved by consensus of acceptance by both radiologists. The images were viewed in the lung window settings  and mediastinal (soft tissue) window settings of width, 380 HU; level, 40 HU. Assessed CT pulmonary patterns comprised ground glass opacities (GGO), crazy paving (CP), consolidation (CON), residual ground glass opacities (rGGO), both individual or in respective combination.EDTA blood was collected for plasma separation. All recruited patients had their blood drawn by venipuncture on admission, 7 and 14 days upon admission. Immediately upon venipuncture, the samples were centrifuged and the obtained plasma aliquoted, frozen and kept at −80 °C until analysis. Malondialdehyde (MDA) was determined in plasma by ELISA kit  and 8-hydroxy-2’-deoxyguanosine (8-OHdG) by OxiSelect™ Oxidative DNA Damage ELISA Kit , whereas advanced oxidation protein products (AOPP) were measured by colorimetric OxiSelect™ AOPP Assay Kit .Depending on the type of variables and the normality of the distribution, results were presented as frequency (percent), median (range) and mean ± standard deviation. Statistical hypotheses were tested using ANOVA with repeated measures, Friedman test or Wilcoxon test. The correlation between the variables was estimated using Spearman’s correlation coefficient (rho). Changes in parameters  were compared between hospitalized and non-hospitalized patients across time  with linear mixed effects modeling approach using R package nlme version 3.1-147. Regarding the models fit, it was assessed using Akaike’s information criterion (AIC); AIC value is 2276.3 for MDA model, 757.0 for 8-OHdG and 2115.5 for AOPP model. Results were graphically presented using the R package ggplot2 version 3.3.2. Statistical hypotheses were analyzed at the level of significance of 0.05. Statistical data analysis was performed using IBM SPSS Statistics 22  and R-3.5.0 software .2  for each patient, as well as for each hospitalized patient and non-hospitalized patient are shown in p < 0.001, p = 0.008, p = 0.030) and AOPP (p = 0.006), compared to the second time point (p > 0.05). After being dichotomized into patients with COVID-19 pneumonia that required hospitalization and those that did not, the time course of changes in MDA levels was similar, except that an increase in MDA level was more pronounced in the hospitalized group on the 14th day (p = 0.009), reaching the values from the admission on day 14  or creatinine concentration  might suggest subclinical liver and/or kidney damage which contributes to systemic oxidative stress in the early phase of the disease , ferritin  and absolute number of neutrophils  was noted, while the correlation with multiorgan impairment biomarkers was not found (p = 0.029), ferritin , absolute number of monocytes  and multiorgan impairment biomarkers such as the activity of plasma non-functional enzymes AST  and LDH , which might indicate supposed heart and/or erythrocyte damage  infection that was caused by a previous viral strain . Indeed,So far, malondialdehyde (MDA), as an established biomarker of lipid oxidative damage, was determined in COVID-19 patients to be stratified according to disease severity; however, this was without any association ,14. Simi2 saturation, hemoglobin-heme iron oxidation, heme destruction and iron release [Since increased free radical production, as a hallmark of SARS-CoV2 infection, has the capacity to modify macromolecules over time, this cumulative oxidative macromolecular damage contributes to many mechanisms underlying COVID-19 disease progression. For that reason, it is of utmost importance not just to determine the level of oxidative stress parameters at one time point, but to evaluate their changes over time. Indeed, in our study, biomarkers of lipid, DNA and protein oxidative damage  varied in three time points over a 14-day period. Namely, significant decrease was observed in MDA and AOPP levels in contrast to increase in 8-OHdG levels at the second time point (7 days upon admission). However, 14 days upon admission, a noticeable increase was observed both in MDA and AOPP levels. Advanced oxidation protein products comprise dityrosine, pentosidine and carbonyl-containing protein products. It is important to note that AOPP is a well-known biomarker of protein oxidative modifications which can be produced in the presence of hypochlorous acid (HOCl), a main product of neutrophil myeloperoxidase activity as a part of the innate response to pulmonary viral infections ,31. Name release . Thus ouFurthermore, in some patients, a mild infection with upper respiratory tract symptoms might worsen and cause pneumonia by the end of the first week or the beginning of the second week. The so-called pulmonary phase can be divided into the pneumonia patient without hypoxia and those with hypoxia who will likely require hospitalization and oxygen supplementation. Therefore, in our study, a comparative analysis of redox biomarkers and possible multiorgan impairment has been determined in both hospitalized and non-hospitalized individuals with COVID-19 pneumonia. Indeed, although a similar pattern of changes was observed in all measured oxidative stress biomarkers, increase in MDA levels between the second and third time point was steeper in hospitalized patients in whom 8-OHdG remained elevated in this period.In addition to pneumonia, evidence suggests that COVID-19 may affect other parts of the body as well, leading to cardiac injury and early renal damage . This miIn this process, hypoxemia-related cascades have the central role, associated with increased generation of reactive oxygen species ,35. In oThere are certain limitations to this study, such as the relatively small number of patients. The effect of comorbidities was avoided by recruiting only subjects without diseases associated with marked oxidative stress, except for eight patients with regulated hypertension. Besides, the control group is lacking due to the obstacles in collecting blood samples from healthy individuals during the COVID-19 outbreak. However, we believe that all data clarifying the underlying role of oxidative stress in SARS-CoV-2 infection expand the possibilities of antioxidant therapy.In the acute course of the COVID-19 disease, redox biomarkers correlate with certain inflammatory and multiorgan impairment biomarkers and are associated with changes in the chest MDCT findings in patients with COVID-19 pneumonia. Special emphasis should be placed on the fact that the pattern of changes differs between non-hospitalized and hospitalized individuals. Our results are in favor of the suggested involvement of neutrophils networks, IL-6 production, along with different organ/tissue involvement in systemic oxidative stress in COVID-19.


Background: Anti-IgLON5 disease is a rare late-onset neurological disease associated with autoantibodies against IgLON5, neuronal accumulation of phosphorylated Tau protein (p-Tau), and sleep, respiratory, and motor alterations. Purpose: We performed a pilot study of whether the neuropathological and clinical features of anti-IgLON5 disease may be recapitulated in mice with chronic intracerebroventricular infusion of human anti-IgLON5 disease IgG (Pt-IgG). Methods: Humanized transgenic hTau mice expressing human Tau protein and wild-type (WT) control mice were infused intracerebroventricularly with Pt-IgG or with antibodies from a control subject for 14 days. The sleep, respiratory, and motor phenotype was evaluated at the end of the antibody infusion and at least 30 days thereafter, followed by immunohistochemical assessment of p-Tau deposition. Results: In female hTau and WT mice infused with Pt-IgG, we found reproducible trends of diffuse neuronal cytoplasmic p-Tau deposits in the brainstem and hippocampus, increased ventilatory period during sleep, and decreased inter-lick interval during wakefulness. These findings were not replicated on male hTau mice. Conclusion: The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with Pt-IgG may elicit neuropathological, respiratory, and motor alterations. These results should be considered as preliminary until replicated in larger studies taking account of potential sex differences in mice. We performed experiments both in hTau mice, which show a spontaneous tendency to p-Tau deposition and late-life neurodegeneration due to the expression of 3R and 4R human Tau protein instead of murine Tau ,24, and tm1(EGFP)Klt Tg(MAPT)8cPdav/J, the Jackson Laboratory stock n. 005491, www.jax.org, last accessed on 17 March 2022) with pure C57Bl/6J background (>10 generations of backcrossing). The hTau mice are homozygous for a null mutation of the mouse Mapt gene, which codes for the murine Tau protein, and hemizygous carriers of a transgene that includes the human MAPT gene, which codes for all six isoforms of the human Tau protein [The experimental study protocol complied with the EU Directive 2010/63/EU for animal experiments and was approved by the Committees on the Ethics of Animal Experiments of the University of Bologna and of the Italian Ministry of Education, University, and Research . Experiments were performed on C57Bl/6J wild-type (WT) mice and on congenic hTau mice   and WT (n = 8) mice because evidence at the time of study design indicated that brainstem p-Tau deposition was greater in female than in male hTau mice already at 4 months of age [We focused on female hTau . Mice employed in the experiments were housed singly from the time of surgery to prevent accidental damage by conspecifics.The Ethic Committee of Hospital Clinic, Barcelona, approved the study (R091217–12). Patients or proxies gave consent for the storage and use of serum, cerebrospinal fluid, and clinical information for research purposes. Informed consent was obtained from all subjects that provided antibodies employed in this study. Total G immunoglobulins (IgG) from sera of a patient with anti-IgLON5 disease (Pt-IgG) and of a control subject without the disease (Ctrl-IgG) were obtained and purified at the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain. The patient was a female aged 65 years with a typical clinical pattern, predominant bulbar phenotype, and chronic evolution, with positivity to HLA susceptibility alleles and IgG4 predominance. The control subject was matched for age and gender. Briefly, 1 mL of serum was incubated with 0.5 mL of protein A/G sepharose beads. Purification was performed with columns of protein A/G sepharose beads  for 30 min, eluted with 100 mM glycine, pH 2.5 and dialyzed against phosphate buffered saline (PBS). The concentration of total IgG was 2 mg/dL, which was well tolerated in mice by ICV infusion in a previous study on human anti-N-methyl D-aspartate (NMDA) receptor antibodies .The specificity of the binding of purified IgG was assessed on transfected HEK cells expressing human IgLON5 and on rat brain tissue as previously reported in detail , based o2). This procedure occurred after d45 recordings except for 5 mice , in which experiments were interrupted at 36 ± 1 days after surgery due to partial detachment of the head implant. Overall, mice were aged 27.7 ± 0.5 weeks at death. An overview of the experimental protocol is shown in We performed surgery and started ICV antibody infusion in young adult mice at 19–22 weeks of age, when p-Tau deposits in hTau mice are already detectable but not yet accompanied by cell loss ,24,29. ITwenty-four hours before surgery, two osmotic pumps per mouse  were each loaded with 100 μL of either Pt-IgG or Ctrl-IgG for different mice. The pumps were then connected to a 0.28 mm  vinyl tube  and left overnight in sterile saline at 37 °C to ensure that nominal pump flow could be reached immediately upon implantation. The total nominal pump flow of 0.5 μL/h was negligible with respect to the estimated cerebrospinal fluid production rate in mice (22.2 μL/h), thus minimizing the expected increases in intracranial pressure . The 14-2) with intra-operative analgesia (Carprofen 0.1 mg subcutaneously) and antibiotic prophylaxis . Mice were placed in a stereotaxic frame, and a bilateral cannula  was inserted into the cerebral ventricles . Each arm of the cannula was connected by a catheter to one osmotic pump, which was implanted subcutaneously on the back together with the catheter [Mouse weight at surgery was 23.3 ± 0.4 g, 21.4 ± 0.3 g, and 28.4 ± 0.3 g in female WT and in female and male hTau mice, respectively (means ± SEM). Mice underwent surgery under isoflurane anesthesia  on 4-µm paraffin sections, which were placed in a BOND-MAX Automated IHC Stainer . Tissues were deparaffinized and pre-treated with the Epitope Retrieval Solution 1  at 98 °C for 50 min. The monoclonal antibody against p-Tau  was incubated at 1/1000 concentration for 20 min. Subsequently, tissues were incubated with polymer for 8 min and developed with DAB-Chromogen for 10 min. Slides were counterstained with hematoxylin.Based on the pattern of AT8 staining particularly in the hippocampus and brainstem, mice were classified in two groups corresponding to higher vs. lower AT8 staining. These procedures were performed in the laboratory of neuroimmunology at the Institut d’Investigacions Biomèdiques August Pi I Sunier, Barcelona, Spain by three expert investigators blind to the source (Pt-IgG vs. CTRL-IgG) of the antibodies received by each mouse.Both at d14 and at d45, mice underwent 48-h continuous EEG and EMG recordings while freely behaving in their own cages, which were equipped with an electrical swivel and a balanced suspensor arm ,32. The Both at d14 and d45, mice underwent 8-h continuous recordings of EEG, EMG, and breathing, starting at the onset of the light period, while freely behaving in a modified whole-body plethysmograph equipped with an electrical swivel, as previously described in detail ,35. ScorBreathing during sleep was analyzed with procedures previously described in detail  focusingThe mouse motor function was assessed at d14 and d45 with a composite phenotype scoring system originally developed for evaluating mouse models of cerebellar ataxia . BrieflyWater-licking behavior  was recoThe statistical analysis was performed with SPSS . The ledge test scores at d14 and d45 were analyzed with Mann-Whitney U tests. The other results were analyzed with mixed-model analysis of variance (ANOVA) with general linear model procedure. The ANOVA within-subject factors for different analyses included time (2 levels: d14 vs. d45), the light-dark period , the sleep state (2 levels: NREM vs. REM sleep) and the NREM sleep bout duration bin . The ANOVA between-subject factors were the mouse strain (2 levels: WT vs. hTau mice) and the source of the IgG received by each mouse (2 levels: Pt-IgG vs. Ctrl-IgG). Normality of the data distributions was evaluated with repeated Shapiro-Wilk tests (SPSS EXAMINE command) with false-discovery rate correction. Data were square-root or log-transformed when necessary to ensure normality.p < 0.05. The sample size and the detailed statistical results of each test are reported in The main analysis was performed on the female WT and hTau mice that completed both the d14 and the d45 phenotyping rounds. Ancillary analyses were performed on all the female WT and hTau mice that completed the 14d phenotyping round, also including the mice whose implants failed before d45. Replication analyses were performed on male hTau mice that completed both the d14 and the d45 phenotyping rounds. All tests were two-tailed, with statistical significance set at The purified Pt-IgG showed the expected pattern of reactivity with IgLON5-espressing transfected HEK cells and with rat cerebellar and hippocampal tissue. Specific immunoabsorption with live HEK293 cells transfected to express human IgLON5 totally abrogated the reactivity, which was maintained instead after mock absorption with non-transfected cells (data not shown). Negative results were obtained with Ctrl-IgG .The neuropathological assessment blind to the Pt-IgG vs. Ctrl-IgG treatment revealed a mild, granular immunoreactivity in the cytoplasm of neurons of some mice, especially in the hippocampal CA4 region and mossy fibers and in the posterior sections around the ependyma . This imTreatment with Pt-IgG did not significantly disrupt the daily EMG activity profiles of female WT and hTau mice at d14 and d45, which showed the expected increase during the dark (active) period compared to the light (rest) period . SimilarDuring the first 8 h of the light (rest) period, female WT and hTau mice with ICV infusion of Pt-IgG did not show any significant difference in the time spent in wakefulness, NREM sleep, and REM sleep with respect to mice infused with Ctrl-IgG, spending most of the time in NREM sleep both at d14 and at d45, as expected . SimilarInspection of raw EEG, EMG, and ventilation tracings during NREM sleep and REM sleep did not reveal obviously abnormal patterns in the mice that received Pt-IgG . The disAs expected , sleep ap = 0.011, p = 0.237; p = 0.395; A reproducible trend for an increase in ventilatory period during sleep was found in female WT and hTau mice treated with Pt-IgG vs. Ctrl-IgG at d14 and d45 . Similarly, in male hTau mice, a score of 1 at the ledge test was assigned to 1/5 vs. 1/3 mice with Pt-IgG vs. Ctrl-IgG at d14, and to 0/4 mice vs. 3/3 mice with Pt-IgG vs. Ctrl-IgG at d45 . A mild impairment in walking in the open field (score 1 out of 3) and a mild hindlimb clasping (score 1 out of 3) were recorded only at d14 in one male hTau mouse with Pt-IgG, which also had a mildly impaired ledge test. Kyphosis was not observed in any mouse tested.The motor function tests did not reveal any obvious functional alteration due to Pt-IgG in mice . Among fp = 0.015; p = 0.101, p = 0.948, Inspection of raw tracings did not reveal any obvious alteration of licking behavior in mice with Pt-IgG A. Data iWe performed a pilot study of whether ICV infusion of mice with IgG from a patient with anti-IgLON5 disease (Pt-IgG) recapitulated the neuropathological and clinical features of the disease. Intriguingly, the brains of female WT and hTau mice that received Pt-IgG could be largely discriminated from those of the female mice that received Ctrl-IgG based on a greater extent of p-Tau deposition in the hippocampus and brainstem, as assessed by subjective evaluation of AT8 antibody IHC staining by three blind scorers. In female WT and hTau mice studied at the end of the 14-day antibody infusion period (d14) and, again, at least 30 days thereafter (d45), we found subtle but reproducible trends in the effects of Pt-IgG on ventilatory period during sleep (increased) and on the inter-lick interval during wakefulness (decreased), while sleep, respiratory, and motor control appeared otherwise preserved. However, we were unable to confirm these neuropathological and functional findings on a small group of male hTau mice studied at d14 and d45.Although our pilot study did not yield conclusive evidence in support of a direct pathogenic role of Pt-IgG, it nevertheless yielded useful information to move forward. This information may be summarized as follows: (1) our preliminary results on enhanced p-Tau deposition at least in female hTau and WT mice infused with Pt-IgG warrant replication on WT mice of either sex for generalizability, with the full set of control experiments that were not included in our pilot study (see limitations section below); (2) our data were not consistent with major effects of Pt-IgG on sleep, respiratory, and motor control in mice, which could be expected based on the severity of the human disease: future work on mice should aim for subtler effects and set sample size accordingly; (3) future work may attempt to replicate our findings on ventilatory period during sleep and inter-lick interval during wakefulness, which were not anticipated based on the clinical features of human disease.MAPT transgene expression. Substantial differences were, indeed, observed in AT8 staining between the brains of two intact hTau founder mice (data not shown). In addition, social isolation, which was meant to prevent damage from conspecifics after instrumentation (see Methods), may have contributed to increase Tau protein phosphorylation also in WT mice, as it has been shown to do in middle-aged WT rats [Multiple lines of evidence suggest that p-Tau deposits are a primary driver of neurodegeneration in Alzheimer disease , and thi WT rats .The total sample size of our pilot study was substantial given the complexity of the experimental procedures, yet our study was arguably underpowered to detect minor phenotypic differences. Nevertheless, our results can help design future studies with sufficient statistical power and suggest that chronic ICV infusion of Pt-IgG in mice may not recapitulate the dramatic clinical picture of the human anti-IgLON5 disease, at least up to more than 45 days after the start of the infusion.Minor alterations in ventilatory period during sleep and in inter-lick interval during wakefulness due to Pt-IgG were suggested, but not robustly demonstrated by our pilot study due to lack of internal replication. Neither of these alterations was expected based on the available clinical evidence on human anti-IgLON5 disease. Nevertheless, these results warrant replication on larger samples, as they may contribute to shed light on IgLON5 disease pathophysiology. Indeed, the unpredictability of the results of administration of human antibodies to experimental animal models has long been remarked . An incrWe were unable to replicate on male hTau mice the findings on p-Tau deposition, ventilatory period during sleep, and inter-lick interval during wakefulness, which we obtained on female WT and hTau mice. This discrepancy may have resulted from false-positive results on female WT and hTau mice, false-negative results on our small group of male hTau mice, or true sex-related differences. Since we did not study male WT mice, we are unable to suggest whether this sex difference may be generalized or limited to hTau mice, perhaps due to greater inter-individual variability in p-Tau deposition. Although no gender difference in human anti-IgLON5 disease is apparent, any protective or adverse pathophysiological effects of sex hormones might be obscured in human patients due to the late onset of the disease . Our datWe cannot exclude the contribution of other technical details of this pilot study design to the variability of the results. The mice we studied may have been too young to develop full-blown disease. In particular, we studied relatively young mice at 19–22 weeks of age in order to avoid a ceiling effect on p-Tau deposition in older hTau mice irrespective of Pt-IgG infusion ,24,29, wOur pilot study had several limitations, which should be addressed in future larger-scale experimentation. Our study was framed as a pilot study covering many approaches to provide us and the research community with useful advice. As a result, while the total sample size of our study was quite substantial, the sample size per group was limited, with the potential for false-negative statistical results. On the other hand, the analyses were specifically designed to minimize risk of false-positive results, by relying on ANOVAs instead of simple comparisons, and by explicitly differentiating between main analyses and confirmatory ancillary/replication analyses. Applying a family-wise significance correction would have been overly conservative for a pilot study. Nevertheless, we acknowledge that given the extensive phenotyping of multiple variables that we performed, a risk of false-positive results represented a study limitation.As previously discussed, we designed our pilot study focusing on female hTau mice, surmising that the propensity of hTau mice to p-Tau brain accumulation would boost effects of Pt-IgG, and taking account of the available evidence of greater brainstem p-Tau deposition in female than in male hTau mice . We inclIn our pilot study, we euthanized mice for brain harvesting a few weeks after the end of the antibody infusion period to account for possible delayed effects. However, the processes of antibody washout from cerebrospinal fluid and the clearance from brain tissue that occurred between the end of the infusion and the tissue fixation prevented our ability to correlate the phenotypic and neuropathological changes in individual mice with the effective extent of IgG penetration into the brain tissue. This represents a limitation of our work. Accordingly, no IgG deposits were detected in the brain sections of the mice under study (data not shown). In this respect, future studies may evaluate the kinetics of IgG clearance from the brain after the end of ICV antibody infusion.Another limitation of our pilot study is that p-Tau deposition was evaluated only based on AT8 IHC staining. Our results should be replicated using a range of antibodies targeting different p-Tau epitopes. Moreover, although the subjectivity in our procedures was mitigated because the analysis was performed by three blind researchers, our results should be replicated also with objective measurements of p-Tau deposition, such as by Western Blot. Future studies should also test whether Pt-IgG cause internalization of IgLON5 in vivo, as it has been shown to occur in vitro , and addWe employed antibodies that were carefully tested and purified from one patient with typical clinical features and from one control subject. While this was meant to limit variability in the data, the lack of replication groups with antibodies purified by other patients represents yet another limitation of our pilot study.The results of our pilot study suggest, but do not prove, that chronic ICV infusion of mice with IgG from a patient with anti-IgLON5 disease may elicit neuropathological, respiratory, and motor alterations. Considering the preliminary nature of our pilot study and acknowledging the difficulty of recapitulating clinical manifestations of a heterogeneous disease such as anti-IgLON5 disease, these results warrant replication and clarification on larger samples also taking account of potential sex-related differences. This research has the potential to shed light on the pathophysiology of this enigmatic disease at the borderland between autoimmunity and neurodegeneration.


Background and Objectives: Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide. Acute exacerbations (AECOPD) are common and often triggered by viral infection. During the COVID-19 pandemic social restrictions, including ‘shielding’ and ‘lockdowns’, were mandated. Multiple, worldwide studies report a reduction in AECOPD admissions during this period. This study aims to assess the effect of the pandemic and Lockdown on the rates of admission with AECOPD and severity of hospitalised exacerbations in the North-East of England. Materials and Methods: Data were extracted for patients presenting with a diagnosis of AECOPD or respiratory failure secondary to AECOPD during the ‘COVID-19 period’ (26/3/20–31/12/20) and a date-matched control period from the year previous. We present descriptive statistics and regression analysis of the effects of the COVID-19 period on the rates of hospital admission. Results: Compared to the matched control period, the COVID-19 period was associated with fewer AECOPD admissions  and shorter length of stay , with similar in-hospital plus 30-day post-discharge mortality. Demographics were similar between periods. Only six patients had a positive COVID-19 PCR test. Conclusion: During the COVID-19 period there was a substantial reduction in AECOPD admissions, but no increase in overall severity of exacerbations or mortality. Rather than fear driving delayed hospital presentation, physical and behavioural measures taken during this period to limit transmission of COVID-19 are likely to have reduced transmission of other respiratory viruses. This has important implications for control of future AECOPD. Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide and the sixth highest cause of death in the UK ,2. COPD Patients with COPD commonly suffer acute exacerbations (AECOPD), which require hospital admission when severe. AECOPD are not only disruptive to patients , but areA quarter of AECOPD are complicated by acute respiratory acidaemia and often require escalation to treatment with non-invasive ventilation (NIV) . RespiraIn December 2019 a novel respiratory disease was described in Wuhan, China, caused by the severe acute respiratory syndrome coronovarius-2 (SARS-CoV-2) . The disDuring 2020 worldwide governments instituted policy interventions to reduce COVID-19 transmission. Measures included reinforced hand hygiene, face coverings, social/physical distancing, and full lockdown. In England in 2020 the UK government implemented two major mandatory lockdown periods: Lockdown 1 26/3/20–15/6/20; and Lockdown 2 5/11/20–2/12/20 .Patients with COPD are more likely to develop respiratory complications and have an increased mortality rate secondary to COVID-19 . The UK Several studies have reported relatively low prevalence of COPD described as a comorbidity in patients admitted to hospital with a primary diagnosis of COVID-19 . FurtherThis study aims to characterise the patient demographic and the effect of Lockdown on the rates and severity of admission with AECOPD in a specialist emergency hospital in the North-East of England.Consecutive admissions with AECOPD during the COVID-19 pandemic (‘COVID-19 Period’: 26/3/20–31/12/20) and over a date-matched prior period (‘Pre-COVID-19 Period: 26/3/19–31/12/19) were retrospectively captured from coding data at a large general hospital in the Northeast of England, Northumbria Specialist Emergency Care Hospital. The hospital serves over 500,000 patients from urban and rural areas with considerable socioeconomic diversity. Included patients were 35 years and over coded as presenting with a diagnosis code of J44 (capturing exacerbation COPD) or J96 (capturing respiratory failure) with a secondary code of J44. Data were extracted between 26/3/19 and 31/12/20. Date and time points used for analysis, shown in Key clinical data were captured as described previously in a similar population admitted with AECOPD . Variablp < 0.1) were entered and variables independently associated with this outcome (p < 0.05) identified.Data analysis was performed using SPSS statistics . Patient characteristics are presented as mean (SD), median (IQR) and percentage; bivariate comparisons were performed using Student’s t-test, Mann–Whitney U test and Chi squared for parametric, non-parametric and categorical variables. Stepwise logistic regression with backwards elimination techniques were used to analyse the effects of the COVID-19 versus Pre-COVID-19 Period on hospital admission with an exacerbation of COPD. After assessing collinearity, variables associated with admission during the COVID-19 Period (p < 0.001). A total number of 1976 admissions with an exacerbation of COPD met the inclusion criteria. The total number of admissions in the COVID-19 period (719) were 57.2% fewer than the date-matched Pre-COVID-19 control period (1257) (p = 0.002) and there was a trend toward greater comorbidity (p = 0.072) in those patients that were admitted. There was no statistically significant difference in in-hospital plus 30-day mortality for those patients admitted with an AECOPD during COVID-19 when compared to the control period (p = 0.966). The point estimates of the presence of chest X-ray consolidation and oxygen therapy slightly higher during the COVID-19 Period, but this did not reach statistical significance. Rates of NIV were similar in both periods.Descriptive statistics for patient characteristics and markers of severity of COPD exacerbation are presented in p values for each variable are shown. A shorter length of stay, greater comorbidity, greater oxygen therapy and less NIV are shown to be associated with admission during COVID-19. The assumptions of uniform variance and linearity for the regression model have all been met.Admission to hospital with AECOPD during the COVID-19 period was used as the dependent variable in a logistic regression with independent variables as listed in Next, we explored the effects of Lockdown on AECOPD admission during the COVID-19 period. Descriptive statistics for the patient characteristics and measures of AECOPD severity for the date matched lockdown periods in pre-COVID-19 and COVID-19 periods are shown in p = 0.026) with increased comorbidity (10.1(9) versus 9.1(10), p = 0.022) presented with AECOPD. In the Post-Lockdown 2 period, similarly patients with increased comorbidity presented with an AECOPD (10.2(9) versus 9.0(10), p = 0.017), which was associated with an increased finding of consolidation on CXR .In a final set of analysis, we explored the effects of lockdown and the immediate “post-lockdown” period during the COVID-19 Period  shows deThis study shows there was an overall reduction in admissions of patients with an acute exacerbation of COPD during COVID-19. This was associated with a shorter length of stay in hospital, however no overall change in the rate of mortality.Several international studies have shown similar trends of reduced AECOPD admissions during the COVID-19 period ,26,27. ICOVID-19 infection has potentially serious consequences for those with respiratory disease, however interestingly, the present study supports other recent reports that there were less hospital admissions with AECOPD during the COVID-19 period . It is pThe present study captured hospitalised AECOPD over nine months from the commencement of the first Lockdown period in England (26/3/20) and assessed the impact of both lockdown periods and subsequent easing of restrictions compared to seasonally matched control periods. Other studies investigating the effect of COVID-19 on AECOPD admission captured a shorter period, typically the first 3 months of the pandemic . Coronaviruses are known triggers of AECOPD , howeverp = 0.966). This suggests that patients were indeed safely discharged more readily and not discharged too quickly only to die shortly after. Comparing the subdivided periods during the pandemic to their controls, there may have been a short-lived negative impact initially, with subsequent improvement as patients, clinicians and services adapted. However, caution is required due to the multiple comparisons in subdivided populations.We found that length of hospital stay was shorter during the COVID-19 period compared to the previous year. This effect was more prominent during Lockdown 1, the only period when we saw an increase in mortality. Rather than shorter length of stay reflecting less severe exacerbations occurring during the COVID-19 period, it is likely that this reflects an effect of both patient-led and clinician-led decisions to encourage prompt discharge at a time of fear of nosocomial transmission and high bed pressure. It is reassuring that overall, in-hospital and 30-day post discharge mortality did not increase across the COVID-19 Period  were more likely to be male; it is possible that women were more likely to maintain precautions after lockdown was lifted. Patients admitted during the post-lockdown 2 period (winter) were more likely to have increased comorbidity, suggesting, despite a reduction in overall number of exacerbations, that those with poorer baseline health still required hospitalisation. However, normalisation to a COVID-19-era alongside easing of restrictions may have encouraged patients to be more confident to seek medical support. One must be cautious in reading too much into the post-lockdown 2 period, as Tier 4 restrictions were implemented in the North-East from 19 December 2020, with greater restrictions than the post-Lockdown 1 period. Overall, our findings are consistent with a true reduction in AECOPD throughout the whole of the COVID-19 period, in particular during lockdown. The present study shows a reduced rate of admission for AECOPD during COVID-19, a finding reported by several others elsewhere worldwide, however we accept the limitations of generalisability from the study of a single centre in the North-East of England. A key limitation is the reliance on coding data rather than specialist review of all case records; this is mitigated by the consistent approach over both periods, and verification of both the provision of acute NIV (NIV and CPAP share the same code) and presence of consolidation. It would be pertinent to include the admission rates for AECOPD from other Trusts in the area as well as more broadly across the UK to see regional and national trends. Further analysis here may also reveal regional differences in admission and the wider effects of the COVID-19 pandemic on healthcare Trusts. Unfortunately, we were unable to access admission DECAF scores and arterial blood gas measurements, which would have provided additional objective data on AECOPD severity. Further work directed to investigate the influence of vaccination and more robust treatment strategies for COVID-19 pneumonitis on rates of admission of AECOPD would be an appropriate next step. In conclusion, this study describes reduced hospital admission rates for AECOPD during the COVID-19 pandemic, a trend observed by multiple authors worldwide. For the first time, we describe this trend in association with a shorter in-hospital length of stay, without negative implications on mortality. We suggest that the reduction in hospital admission during COVID-19 was primarily due to a reduction in true severe AECOPD rather than fear of attending healthcare settings, which would have led to more patients presenting in extremis. The reduction in admissions is much greater than that achieved by other strategies and therefore this provides an important means of controlling AECOPD moving forward. Whilst we would encourage patients with COPD to lead active lifestyles to prevent deconditioning and to limit social isolation in the interests of wellbeing, we recommend that they do so as safely as possible, and to adopt more stringent precautions during flu season. Precautions they may consider include avoiding contact with people with active respiratory infections, particularly young children; isolation from unwell household members, with increased hand washing, mask wearing and surface disinfection in shared areas; mask wearing on public transport and indoor spaces; choosing to socialize in well-ventilated uncrowded spaces  and avoidance of crowded indoor spaces.


This survey study investigates individuals' decision-making process for seeking emergency department treatment for conditions unrelated to COVID-19 during the COVID-19 pandemic using hypothetical scenarios. What do people prioritize when deciding whether to present to the emergency department during the COVID-19 pandemic for care unrelated to COVID-19?In this survey study of 933 US adults, we found that 16.9% and 25.5% of individuals confronted with scenarios consistent with myocardial infarction or appendicitis, respectively, prioritized avoidance of COVID-19 exposure in the emergency department over seeking appropriate care. Sociodemographics, political affiliations, and personal knowledge, attitudes, and beliefs regarding COVID-19 were not factors associated with decision-making regarding emergency care seeking.These findings suggest that health care systems and public health organizations should develop effective communications for patients and the community at large that reassure and encourage appropriate, timely health care for critical needs, not only during the ongoing COVID-19 pandemic, but also for future infectious outbreaks and other scenarios that could promote maladaptive pathogen-avoidance behaviors. Delaying critical care for treatable conditions owing to fear of contracting COVID-19 in the emergency department (ED) is associated with avoidable morbidity and mortality.To assess and quantify how people decided whether to present to the ED during the COVID-19 pandemic for care unrelated to COVID-19 using conjoint analysis, a form of trade-off analysis that examines how individuals make complex decisions.This cross-sectional survey study was conducted using a nationwide sample from June 1, 2020, during the initial peak of the COVID-19 pandemic. Included participants were adults aged 18 years or older in the US who self-reported that they had not tested positive for COVID-19. Data were analyzed from July 2020 through May 2021.Participants completed a self-administered online survey.Using a choice-based conjoint analysis survey, the relative importance was assessed for the following attributes for individuals in deciding whether to seek ED care for symptoms consistent with myocardial infarction or appendicitis: reduction in chance of dying because of ED treatment, crowdedness of ED with other patients, and chance of contracting COVID-19 in the ED. We also performed latent class analyses using conjoint data to identify distinct segments of the respondent population with similar choice patterns. Logistic regression was then used to explore whether patient sociodemographics and political affiliations were factors associated with decision-making.P = .001; appendicitis scenario: adjusted odds ratio, 0.57 ; P = .003), but most sociodemographic factors and political affiliations were not factors associated with decision-making.Among 1981 individuals invited to participate, 933 respondents (47.1%) completed the survey; participants’ mean (SD) age was 40.1 (13.0) years, and 491 (52.6%) were women. In latent class analyses, 158 individuals (16.9%) with symptoms of myocardial infarction and 238 individuals (25.5%) with symptoms of appendicitis prioritized avoidance of COVID-19 exposure in the ED  over seeking appropriate care for symptoms. Having a usual source of care was a factor associated with lower odds of prioritizing avoidance of COVID-19 exposure (myocardial infarction scenario: adjusted odds ratio, 0.49 ; This study found that up to one-quarter of individuals were willing to forgo potentially life-saving ED care to avoid exposure to COVID-19. These findings suggest that health care systems and public health organizations should develop effective communications for patients and the community at large that reassure and encourage timely health care for critical needs during the ongoing COVID-19 pandemic and other scenarios. Simultaneously, hospitals have reported decreases in the number of patients presenting for stroke, acute coronary syndrome, and uncontrolled hyperglycemia, among several other critical conditions.13 For example, Oseran et al4 observed decreases by 29.6% and 44.7% in cardiovascular and gastroenterology admissions, respectively, from March 1 to April 30, 2020, compared with the same period in 2019.As of May 20, 2021, there have been more than 33 million cases and 588 000 deaths in the US from COVID-19,13 a decision thought to be associated with the behavioral immune system, a set of cognitive responses that aid in avoiding social exposure to pathogens.15 Although pathogen-avoidance behaviors are evolutionarily adaptive, when applied excessively they may lead patients to incur far greater risk by staying home compared with the actual risk of contracting an infectious disease, such as COVID-19, by seeking care. Nonetheless, studies have found that patients have avoided receiving necessary emergency care during the pandemic13 despite evidence of a low risk of contracting COVID-19 in health care settings.16Fear of acquiring COVID-19 in health care settings has led many people to forego emergency care despite experiencing potentially life-threatening illnesses,13 and the potential for future outbreaks of COVID-19 or other community pathogens, we aimed to quantitively and qualitatively examine the willingness of a nationwide sample of US individuals to seek emergency care during the initial peak of COVID-19. This pandemic was used as a model health care crisis with potential to be associated with maladaptive pathogen-avoidance behaviors. Moreover, to examine the trade-offs these individuals made, we used conjoint analysis, a technique that evaluates how people navigate complex decisions by balancing competing factors. Additionally, we assessed whether sociodemographic factors, political affiliations, and knowledge, attitudes, and beliefs regarding COVID-19 were factors associated with emergency care decision-making.In light of the association of the COVID-19 pandemic with forgone medical careAAPOR) reporting guideline.17 We performed a cross-sectional, self-administered, online survey of a nationwide sample of US adults who had not tested positive for COVID-19. The objective was to understand the trade-offs individuals made when deciding to seek care at the ED for potentially life-threatening conditions during a pandemic.This survey study was approved by the Cedars-Sinai Institutional Review Board and followed the American Association for Public Opinion Research , a survey research firm, to recruit respondents. Cint drew from a sample of more than 20 million panelists in the US who signed up to receive invitations to complete surveys in exchange for Cint marketplace points, which we describe elsewhere.On June 1, 2020, during the initial peak of the COVID-19 pandemic in the US, Cint sent an invitation email to panelists aged 18 years or older. Respondents who clicked the survey link were informed that the goal was to “learn how people make decisions about whether to go to the emergency room (ER) for treatment during the COVID-19 pandemic.”The survey instrument is shown in eAppendix 1 in the 20 It is administered via an online interactive module in which respondents are presented with a series of unique, side-by-side scenarios and tasked with selecting their preferred scenario  analysis using Lighthouse Studio software version 9.8.1 (Sawtooth Software) to determine how patients made decisions regarding emergency care seeking during the COVID-19 pandemic. The CBC exercises were developed following International Society for Pharmacoeconomic and Outcomes Research best practices.21 or appendicitis23 without treatment but would have a 0% presumed chance of contracting COVID-19 by staying home. Forgoing treatment was presumed to be associated with a 40% risk of death for myocardial infarction21 and a 4% risk of death with appendicitis.23For myocardial infarction and appendicitis scenarios, participants were shown a random set of 10 side-by-side profiles  drawn frAs considerations other than the attributes presented in the CBC exercises may have influenced respondents’ decisions, we included 2 free-text questions: (1) During the COVID-19 pandemic, what other considerations might you have when deciding whether to go to the ER for treatment that were not listed in the previous sections? (2) In thinking about precautions that ERs take to protect patients from COVID-19, what would you require in order to consider seeking care in the ER?24 and was collected given that there may have been differences in decision-making among racial/ethnic groups. Participants were also asked about their self-reported health status,25 comorbidities,26 religious affiliation, political party affiliation, and news source. We also collected COVID-19–related data, including self-perceived chance of catching COVID-19 and chance of dying if COVID-19 contracted, related anxiety , beliefs on wearing face masks in public, whether they knew someone who tested positive for COVID-19, and whether anyone in their household was at increased risk for COVID-19 illness. The Coronavirus Anxiety Scale includes 5 items, each of which is scored on a 0 to 4 Likert scale; accumulated scores range from 0 to 20 (higher = more anxiety related to COVID-19).The survey collected self-reported sociodemographic information, including age, sex, race/ethnicity, educational attainment, marital status, income, employment status, insurance status, usual source of care, tobacco and alcohol use, household size, number of dependents, and US region. Race/ethnicity was defined using the UCLA Center for Health Policy Research classification of 5 mutually exclusive categories28 we aimed to recruit at least 300 individuals. However, to increase the number of meaningful responses to the open-ended questions, our goal was to recruit closer to 1000 individuals to collect a range of perspectives.Informed by conjoint analysis sample size precedents and recommendations from the software provider,30; attributes with higher scores were more highly valued in decision-making.31 We also used latent class analysis in this software to identify distinct segments of respondents with similar choice patterns.32After participants completed CBC exercises, we used hierarchical Bayes regression in conjoint analysis software to estimate individual-level importance scores for each tested attributeP < .05 was considered statistically significant. Descriptive analyses were used for importance scores and latent classes derived from myocardial infarction and appendicitis exercises. We performed multivariable logistic regression models on prioritizing avoidance of COVID-19 exposure in the ED as determined through latent class analyses for both scenarios. To adjust for confounding, regression models included covariates (see previous section) with a P < .10 in bivariate analyses.We performed statistical analyses on the unweighted data using Stata statistical software version 17.0 (StataCorp). A 2-tailed P < .01 to determine variables for inclusion in the regressions. Results were reported as adjusted odds ratios (aORs) with 95% CIs. For open-ended questions, we used summative content analysis to examine participants’ responses33; free texts  were coded and organized into categories and subcategories. Data were analyzed from July 2020 through May 2021.Given the large number of collected covariates, we also conducted a sensitivity analysis using a more restrictive Invitations were sent to 1981 individuals by Cint, and 1517 individuals (76.6%) accessed the survey. Among these individuals, we excluded 213 individuals (14.0%) who did not finish the survey, 133 individuals (8.8%) who did not consent to taking the survey, 95 individuals (6.3%) who gave implausible responses , 83 individuals (5.5%) who reported a positive COVID-19 test, and 60 individuals (4.0%) aged younger than 18 years.P < .001) and had a higher proportion of women  , occasional smokers , and those who did not consume news . Conversely, we found that respondents were less likely to prioritize avoidance of COVID-19 exposure if they had a usual source of care , worse self-reported health status , higher perceived chance of contracting COVID-19 , or annual household incomes of $100 001 or more . The remaining variables largely were not factors associated with decision-making. Results from the regression model using a more restrictive P value threshold for determining variable inclusion were similar to those of the primary analysis  importance scores were 53.4% (SD 21.8%) for reduction in chance of dying because of ED treatment, 25.0% (17.3%) for crowdedness of ED with other patients, and 21.6% (12.8%) for chance of contracting COVID-19 in the ED. In latent class analysis, 2 distinct groups shared similar choice preferences: 775 individuals (83.1%) prioritized seeking emergency care, and 158 individuals (16.9%) prioritized avoidance of COVID-19 exposure in the ED . P = .003) and a higher perceived chance of contracting COVID-19  were less likely to prioritize avoidance of COVID-19 exposure in the ED  importance scores were 36.6% (16.6%) for reduction in chance of dying because of ED treatment, 33.3% (17.9%) for crowdedness of ED with other patients, and 30.1% (11.0%) for chance of contracting COVID-19 in the ED. We noted 2 discrete groups in latent class analysis: 695 individuals (74.5%) equally prioritized all 3 attributes, and 238 individuals (25.5%) prioritized avoidance of COVID-19 exposure in the ED. In regression analysis, individuals with a usual source of care . Other considerations included safety measures implemented in the ED , ED wait times , financial considerations , proximity and transportation to the ED , local COVID-19 infection rate , alternatives to in-person care , and reputation of the ED or hospital .When asked about necessary precautions that EDs need to implement, participants reported physical separation from patients with COVID-19 in the waiting room and ED. Respondents also noted that hospital staff should wear personal protective equipment and use hand sanitizer frequently. Other respondents mentioned that patients and staff entering the ED should undergo temperature and symptom screening or rapid tests for COVID-19. Additionally, some participants said they expected facilities to be regularly sanitized.This survey study assessed the trade-offs individuals made when deciding whether to present to the ED during the COVID-19 pandemic for potentially life-threatening issues unrelated to COVID-19. Even when facing a scenario consistent with myocardial infarction, which carried a 40% risk of death without treatment, 16.9% of individuals prioritized avoidance of COVID-19 exposure in the ED over seeking appropriate care. When presented with a scenario consistent with appendicitis, which carried a 4% risk of death without treatment, 25.5% of individuals chose to forgo emergency care.13 Unlike prior studies that quantified decreases in these admissions, our study determined the relative importance of factors associated with individuals’ decisions on whether to seek care for acute symptoms. Moreover, while we did not present scenarios for routine or preventive care, it stands to reason that even more individuals may be willing to forgo nonemergent care. This assumption is supported by data showing that more than three-quarters of adults nationwide delayed routine medical care during the pandemic.35 While the association of forgone care with emergent issues was identified early in the pandemic,13 the outcomes associated with delayed routine and preventive care will inevitably lead to increased morbidity and mortality over time.36 For example, the National Cancer Institute conservatively estimated that over the next decade there will be 10 000 excess deaths associated with delayed screening and treatment of colorectal and breast cancers alone.37 These findings suggest that during the current pandemic, as well as during future infectious outbreaks, health care systems and public health organizations should emphasize to patients and the community the importance of continuing to seek care for both emergent and routine issues.Our finding that up to one-quarter of individuals indicated they were willing to forego potentially life-saving treatment during the first peak of the pandemic to avoid exposure to COVID-19 is consistent with prior literature demonstrating significant reductions in hospitalizations for many serious conditions during the pandemic.39 may be associated with improved access to medical care,40 experience in navigating health care systems,41 and established relationships with medical providers.45 These individuals may also have received correspondences from their providers alerting them about the continued importance of seeking care for emergency situations despite the pandemic.49 Notably, given that members of racial/ethnic minority groups and those from lower socioeconomic strata are less likely to have a usual source of care,51 the pandemic is likely exacerbating existing disparities in care unrelated to COVID-19 among these groups.With few exceptions, most sociodemographic factors, political leanings, and beliefs regarding COVID-19 were not factors associated with decision-making in our study. Having a usual source of care, however, was associated with higher odds for preferring to seek appropriate emergency care in both scenarios. The increased inclination to seek treatment among individuals with a usual source of care54 Higher perceived risk of contracting COVID-19 may also be associated with unmeasured hypervigilance, thereby leading these individuals to seek treatment when experiencing acute and potentially dangerous symptoms. Further research assessing the association between hypervigilance and care-seeking behaviors for emergent conditions during pandemics is needed.We also observed that individuals with a higher perceived chance of contracting COVID-19 were more likely to seek appropriate care. While this may appear counterintuitive prima facie, this association may be a surrogate for health-related anxiety; previous research has indicated a positive association between anxiety and health care use.49 Beyond media campaigns, investigators should further examine pathogen-avoidance psychology15; improved understanding of this maladaptive cognition may inform timely development of novel, effective interventions that encourage appropriate health care seeking during potential future flare-ups of COVID-19, other community-based infectious outbreaks, or any scenario that could promote maladaptive pathogen-avoidance behaviors.Our qualitative analyses suggest specific measures that health care facilities and public health organizations can implement to encourage appropriate care seeking and decrease morbidity and mortality associated with delaying care for emergent issues. These results suggest that communications regarding safety precautions that EDs and hospitals are implementing is important, given that many participants indicated this was a major factor in their decisions to seek care. These campaigns should also stress the importance of seeking appropriate care, highlight symptoms that require immediate evaluation, and reinforce the low likelihood of contracting COVID-19 in the ED.Our study has several strengths. We recruited a sample of nearly 1000 US individuals nationwide and examined the trade-offs they were willing to make when considering presenting for emergency care during a pandemic. We also employed a mixed-methods approach  to assess the most important factors associated with decision-making.55 in December 2020, nearly a year after the first reported cases of COVID-19 in the US, suggested that COVID-19 concerns were still associated with care-seeking behavior; 57% of adults remained hesitant to present to the ED for emergencies. Sixth, respondents were asked to assess hypothetical situations and report how they believe they would act when experiencing real symptoms; their actual decision-making processes may differ. However, a meta-analysis56 found that discrete choice experiments are 88% sensitive at predicting health-related choices that individuals make in reality.There were several limitations to our survey study. First, we recruited only US participants, so our findings may not be generalizable to other countries. Second, while the demographics of our study cohort mirrored those of the US population, we had fewer respondents aged 60 years or older than expected, which was likely associated with our use of an online survey. Our results may therefore not generalize to older individuals or to those who lack basic computing skills. Third, we limited the conjoint analysis to 3 attributes, but individuals may have many other considerations when deciding whether to present to the ED. For example, in qualitative analyses, some respondents noted that the local COVID-19 infection rate and reputation of the nearby ED or hospital would be important factors in their decision-making. However, because conjoint surveys can become unwieldy with too many attributes, we opted to focus on 3 core attributes with direct relevance to decision-making in the context of COVID-19. Fourth, despite the design of the conjoint analysis and limitation to 10 vignettes per scenario, the serial decision-making may have been challenging for some participants. We attempted to minimize this issue by consistently presenting probabilities as percentages. Fifth, our survey was conducted in June 2020, during the initial US peak of COVID-19. It is likely that attitudes toward the severity of the pandemic and its association with emergency care seeking behaviors have evolved over time. Nonetheless, the results of a national surveyWhen respondents were faced with hypothetical, serious symptoms, up to 1 in 4 had preferences consistent with forgoing potentially life-saving ED care to avoid COVID-19 exposure. This finding suggests that during the current COVID-19 pandemic and future infectious outbreaks, health care systems and public health organizations should develop communication strategies for patients and the community at large that describe the institutions’ safety measures to reassure and encourage timely health care for critical and routine needs. Moreover, additional research examining pathogen-avoidance psychology is needed to inform development of novel, effective strategies that support appropriate care seeking not only for current and potential future outbreaks of COVID-19, but also for any scenario that could promote maladaptive pathogen-avoidance behaviors.


College environments promote high-volume or binge alcohol consumption among youth, which may be especially harmful to those with type 1 diabetes (T1D). Little is known about the acceptability and effectiveness of interventions targeting reduced alcohol use by college students with T1D, and it is unclear whether intervention framing  matters with respect to affecting behavior change. Interventions promoted by peer educators may be highly relatable and socially persuasive, whereas those delivered by clinical providers may be highly credible and motivating.The aim of this study is to determine the acceptability and impacts of an alcohol use psychoeducational intervention delivered asynchronously through web-based channels to college students with T1D. The secondary aim is to compare the impacts of two competing versions of the intervention that differed by narrator (peer vs clinician).We recruited 138 college students (aged 17-25 years) with T1D through web-based channels and delivered a brief intervention to participants randomly assigned to 1 of 2 versions that differed only with respect to the audiovisually recorded narrator. We assessed the impacts of the exposure to the intervention overall and by group, comparing the levels of alcohol- and diabetes-related knowledge, perceptions, and use among baseline, immediately after the intervention, and 2 weeks after intervention delivery.Of the 138 enrolled participants, 122 (88.4%) completed all follow-up assessments; the participants were predominantly women , were White non-Hispanic , and had consumed alcohol in the past year . Both arms saw significant postintervention gains in the knowledge of alcohol’s impacts on diabetes-related factors, health-protecting attitudes toward drinking, and concerns about drinking. All participants reported significant decreases in binge drinking 2 weeks after the intervention  compared with the 2 weeks before the intervention . Changes in binge drinking after the intervention were affected by changes in concerns about alcohol use and T1D. Those who viewed the provider narrator were significantly more likely to rate their narrator as knowledgeable and trustworthy; there were no other significant differences in intervention effects by the narrator.The intervention model was highly acceptable and effective at reducing self-reported binge drinking at follow-up, offering the potential for broad dissemination and reach given the web-based format and contactless, on-demand content. Both intervention narrators increased knowledge, improved health-protecting attitudes, and increased concerns regarding alcohol use. The participants’ perceptions of expertise and credibility differed by narrator.ClinicalTrials.gov NCT02883829; https://clinicaltrials.gov/ct2/show/NCT02883829RR2-10.1177/1932296819839503 Effective management of chronic conditions such as type 1 diabetes (T1D) is affected by individual-, family-, community-, and health care system–level features , diseaseAlcogenic college environments  value, current insulin pump use, current continuous glucose monitoring [CGM] device use, average blood glucose tests per day, average HbA1c tests per year, and self-rated health) at baseline.The participants provided sociodemographic data  and clinical information . The paThe secondary outcomes relied on novel test batteries that were developed for a series of related studies and informed by clinical reviews and epidemiologic insights ,22,40,41At postintervention and follow-up assessments, the participants were asked about their impressions of the video (13 items rated from “strongly disagree” [score=1] to “strongly agree” [score=10]) and their intentions . To summarize impressions and intentions, the mean score across all items was determined for each; higher scores reflected more favorable impressions of the intervention  or greater intention to engage in lower-risk behaviors. The measures demonstrated reasonable internal consistency (Cronbach α=.8581 for impressions and .8294 for intentions). For aligning with intentions, the participants were asked at the final follow-up to specify actual behaviors, including (1) if they had talked in the past 2 weeks with friends, health care providers, or someone else about how alcohol affects diabetes and (2) the frequency with which they tested their blood sugar before, during, or after drinking during the past 2 weeks.The participants were also prompted with open-response questions on their diabetes care or alcohol use, first impressions of the video (after the intervention), and final thoughts about the video . The participants who endorsed learning something new or having unanswered questions were prompted for further clarification. These open-ended questions were intended to complement the quantitative impression measures by providing a more subjective and nuanced perspective on intervention acceptability.P<.05. All individuals who were randomized into the study and completed the follow-up were included in the analyses (N=122). Differences in characteristics between the arms were assessed using appropriate bivariate tests , known association with diabetes knowledge , or imbalance across treatment arm . We additionally evaluated the secondary outcomes  as predictors of the overall change in binge drinking . The participants’ responses to the open-response questions were analyzed using an iterative process, including open coding, to identify emergent themes [P=.40).The analyses followed a mixed methods protocol, investigating structured survey data and thematically coding optional comment data. Quantitative analyses were performed using SAS version 9.4 (SAS Institute Inc). Statistical significance was set at te tests . Differete tests . Multivate tests ; adjustete tests . Adjustelyses N=1. Differe1c value was 7.65 (SD 1.20), and 82.8% (101/122) self-reported past-year alcohol use (P=.02) than their counterparts.The participants were aged 20.46 (SD 1.44) years; 80.3% (98/122) were women, 83.6% (102/122) were White and non-Hispanic, 68.9% (84/122) had a parent with a bachelor’s degree or higher, 82.8% (101/122) used insulin pumps, 60.7% (74/122) used CGM devices, their last HbAohol use . The chaP<.001; P<.001); the improvements after the intervention and at follow-up were not significantly different by arm . The improvements were driven by an increased understanding of the impact of alcohol on the liver, the distinction between being drunk and low blood glucose, the interaction between alcohol and glucagon, and alcohol-related dehydration . Attitudes did not differ between the follow-up and baseline . Postintervention changes were driven by attitudes related to telling friends that they cannot drink because of diabetes, and at follow-up, fewer college students agreed that college students with diabetes could drink if they are careful . Concerns were not different at follow-up versus baseline . Postintervention changes were driven by increased concern for the effectiveness of glucagon while drinking, whereas increased concerns about the impact of alcohol on HbA1c tests were greater for those in the provider arm than for those in the peer arm , whereas those in the peer arm had lower impressions than those in the provider arm , but their impressions were stable over time . The adjusted ratings of narrator knowledge and trust were significantly higher for the provider arm than for the peer arm . The change in concerns from baseline to after the intervention was significantly associated with a reduction in binge drinking at follow-up , whereas the changes in knowledge and attitudes were not .Overall, the intervention was associated with a 52% adjusted relative reduction in self-reported binge drinking  were not sustained at the final follow-up, the single-dose intervention appeared to alert the participants to possible dangers, generating a near-term response of increased concern. The lack of sustained change may reflect recalibration of concern, given time to absorb new information (knowledge and experience), growth in perceived self-efficacy for navigating drinking, or retrenchment from the initial state of alarm. A model that delivers multiple doses (boosters) may help to reinforce and sustain the response; hence, future studies should investigate changes over longer periods for a single and possibly multiple-dose intervention. Both narrators in this trial were unknown to the participants; intervention delivery from someone with whom participants have an established relationship, such as a trusted provider  or closeAlthough in-person anticipatory conversations between adolescents or young adults and their diabetes care teams about the effects of alcohol on their health and strategies for avoiding risk may be the gold standard for delivering a preventive intervention, this model may not be practical. Providers are increasingly tasked with covering a myriad of topics during short clinical encounters , and heaFinally, many of the participants noted that they would have liked to receive this intervention earlier . As the intervention materials were not specific only to college, the current intervention might be generalizable for use with younger individuals or young adults not attending college, and such extensions could be tested. However, as this intervention was designed to focus on harm reduction, further investigation, including with respect to timing of or age at delivery, is needed to determine if these materials are suitable for the goal of preventing drinking initiation.denominator) [best case scenario. Second, this study was designed as a pilot trial to gauge the acceptability and relative impacts of the narrator and lacked a nonintervention control group. The observed effects could stem from test-retest bias, carryover effects, or regression to the mean; future controlled evaluations might mitigate these concerns. Third, all outcomes (and diabetes status) were self-reported, and only the alcohol use questions relied on validated items. To our knowledge, there are no pre-existing validated tools to assess knowledge, attitudes, and concerns regarding the intersection of alcohol use and diabetes. The survey items were extensively pretested and have been used in other surveys [This study includes several limitations. First, as with all internet-based recruitment, the underlying population (minator)  is uncleminator) , this saminator) ). This s surveys ,37,38; hcare as usual and should determine what further modifications are needed to enhance intervention effects.We demonstrate the acceptability and impacts of a psychoeducational intervention for mitigating binge alcohol use among college students with T1D. We further determine that peer and provider narrators have similar short-term impacts as framing devices for this educational content. As this pilot demonstrates the feasibility of delivering this intervention to a hard-to-reach group through web-based channels, similar outreach methods could be used to deliver this content more broadly. In light of these promising findings, future work should further test these materials against the control of