Derivation and validation of clinical prediction rules for diagnosis of infectious mononucleosis: a prospective cohort study.

OBJECTIVES: Infectious mononucleosis (IM) is a clinical syndrome that is characterised by lymphadenopathy, fever and sore throat. Although generally not considered a serious illness, IM can lead to significant loss of time from school or work due to profound fatigue, or the development of chronic illness. This study aimed to derive and externally validate clinical prediction rules (CPRs) for IM caused by Epstein-Barr virus (EBV). DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: 328 participants were recruited prospectively for the derivation cohort, from seven university-affiliated student health centres in Ireland. Participants were young adults (17-39 years old, mean age 20.6 years) with sore throat and one other additional symptom suggestive of IM. The validation cohort was a retrospective cohort of 1498 participants from a student health centre at the University of Georgia, USA. MAIN OUTCOME MEASURES: Regression analyses were used to develop four CPR models, internally validated in the derivation cohort. External validation was carried out in the geographically separate validation cohort. RESULTS: In the derivation cohort, there were 328 participants, of whom 42 (12.8%) had a positive EBV serology test result. Of 1498 participants in the validation cohort, 243 (16.2%) had positive heterophile antibody tests for IM. Four alternative CPR models were developed and compared. There was moderate discrimination and good calibration for all models. The sparsest CPR included presence of enlarged/tender posterior cervical lymph nodes and presence of exudate on the pharynx. This model had moderate discrimination (area under the receiver operating characteristic curve (AUC): 0.70; 95% CI: 0.62-0.79) and good calibration. On external validation, this model demonstrated reasonable discrimination (AUC: 0.69; 95% CI: 0.67-0.72) and good calibration. CONCLUSIONS: The alternative CPRs proposed can provide quantitative probability estimates of IM. Used in conjunction with serological testing for atypical lymphocytosis and immunoglobulin testing for viral capsid antigen, CPRs can enhance diagnostic decision-making for IM in community settings.

How has medical student learning changed with the pivot to online delivery of ophthalmology in the pandemic?

PURPOSE: This study aimed to measure stakeholder satisfaction with our usual delivery format, which previously relied on a blend of didactic lectures and clinical skills sessions compared to a revised format, which had more emphasis on online learning. We hypothesised that the online flipped classroom (OFC) would facilitate delivery of content in the wake of the pandemic, and result in improved levels of student satisfaction and knowledge gain. DESIGN: Non randomised intervention study. Group 1 = Traditional delivery (TD) and Group 2 = OFC group. METHODS: A validated course evaluation questionnaire (CEQ) compared perspectives of teaching faculty (n = 5) and students with the traditional delivery (TD) of the 4th year ophthalmology clinical attachment and an OFC approach (TD n = 129 v OFC n = 114). RESULTS: The OFC group (n = 114; response rate = 24.6%) reported significantly reduced satisfaction with staff motivation of students and provision of feedback, compared to TD (n = 129; response rate = 17.8%). OFC students also felt it was harder to determine what standard of work was expected and found the course less beneficial at helping develop problem-solving skills. Students were dissatisfied with the level of choice afforded by the OFC, specifically how they would learn and assessment options. No significant difference in exam score was observed between the TD and OFC groups. For faculty (n = 5), there was no evidence of a difference between OFC and TD. CONCLUSIONS: Students indicated a preference for the TD compared to the OFC approach. However, both delivery approaches led to comparable student performances as determined by MCQ examination.

Impact of changes to the delivery of opioid agonist treatment, introduced during the COVID-19 pandemic, on treatment access and dropout in Ireland: An interrupted time series analysis.

BACKGROUND: Following the emergence of COVID-19, Ireland introduced national contingency guidelines to ensure rapid and uninterrupted access to opioid agonist treatment (OAT). This study aims to assess the impact of changes introduced to the delivery of OAT on the number of people accessing treatment and treatment dropout. METHODS: The study conducted interrupted time series analyses, with separate segmented regression models (March 2019-February 2020) vs (April 2020-March 2021), for (A) total number of people accessing OAT, (B) the number initiating treatment, and (C) the number dropping out of treatment, using data from the National OAT treatment register. The study examined immediate (change in level or intercept: ß2) and long-term impacts (change in slope; i.e., the difference between the slope before and after the intervention: ß3). We performed total and stratified analyses by gender, age group (<40/≥40 years), and OAT drug (methadone or buprenorphine). RESULTS: A total of 10,251 people accessed OAT in Ireland in March 2019 (2 % buprenorphine, n = 178), increasing to 11,441 (4 % buprenorphine, n = 471) in March 2021. The study observed an immediate (ß2 = 504.3, p < 0.001) and continued (ß3 = 31.9, p < 0.001) increase of people accessing treatment following the introduction of the OAT contingency guidelines. In contrast, observed changes in level and slope were not significant for treatment initiation or dropout. The study did find, however, a modest reduction in dropout among those receiving buprenorphine (ß3 = -0.6, p = 0.036). CONCLUSIONS: Changes introduced to the delivery of OAT, under the COVID-19 contingency guidelines, are associated with increased access to OAT in Ireland, with no evidence of increase in treatment dropout. Whether these effects will be maintained over time remains to be seen.

Social communication skill attainment in babies born during the COVID-19 pandemic: a birth cohort study.

INTRODUCTION: The SARS-CoV-2 (COVID-19) pandemic was managed with sustained mass lockdowns to prevent spread of COVID-19 infection. Babies born during the early stages of the pandemic missed the opportunity of meeting a normal social circle of people outside the family home. METHODS: We compared 10 parentally reported developmental milestones at 12-month assessment in a cohort of 309 babies born at the onset of the pandemic (CORAL cohort) and 1629 babies from a historical birth cohort (BASELINE cohort recruited between 2008 and 2011). RESULTS: Compared with a historical cohort, babies born into lockdown appeared to have some deficits in social communication. Fewer infants in the pandemic cohort had one definite and meaningful word (76.6% vs 89.3%), could point (83.8% vs 92.8%) or wave bye-bye (87.7% vs 94.4%) at 12-month assessment. Adjusted log-binomial regression analyses demonstrated significant differences in social communication in the CORAL cohort compared with the BASELINE cohort: one definite and meaningful word (relative risk (RR): 0.86 (95% CI: 0.80 to 0.92)), pointing (RR: 0.91 (95% CI: 0.86 to 0.96)) and waving bye-bye (RR: 0.94 (95% CI: 0.90 to 0.99)). DISCUSSION: Parentally reported developmental outcomes in a birth cohort of babies born into lockdown during the COVID-19 pandemic may indicate some potential deficits in early life social communication. It must be noted that milestones are parentally reported and comparison is with a historical cohort with associated limitations. Further studies with standardised testing is required to validate these findings. CONCLUSION: Pandemic-associated social isolation may have impacted on the social communication skills in babies born during the pandemic compared with a historical cohort. Babies are resilient and inquisitive by nature, and it is hoped that with societal re-emergence and increase in social circles, their social communication skills will improve.

Text Messaging, Telephone, or In-Person Outpatient Visit to the Surgical Clinic: A Randomized Trial.

INTRODUCTION: Routine outpatient follow-up visits for surgical patients are a source of strain on health-care resources and patients. With the COVID-19 pandemic adding a new urgency to finding the safest follow-up arrangement, text message follow-up might prove an acceptable alternative to a phone call or an in-person clinic visit. METHODS: An open-label, three-arm, parallel randomized trial was conducted. The interventions were traditional in-person appointment, a telephone call, or a text message. The primary outcome was the number of postdischarge complications identified. The secondary outcomes were patient satisfaction with follow-up, future preference, default to follow-up, and preference to receiving medical information by text message. RESULTS: Two hundred eight patients underwent randomization: 50 in the in-person group, 80 in the telephone group, and 78 in the text message group. There was no difference in the number of reported complications: 5 (10%) patients in the in-person group, 7 (9%) patients in the text group, and 11 (14%) patients in the telephone group (P = 0.613). The preferred method of follow-up was by telephone (106, 61.6%). The least preferred was the in-person follow-up (15, 8.7%, P = 0.002), which also had the highest default rate (44%). CONCLUSIONS: There was no evidence that text messages and telephone calls are unsafe and ineffective methods of follow-up. Although most patients are happy to receive results by text message, the majority of patients would prefer a telephone follow-up and are less likely to default by this method. Health-care systems should develop telehealth initiatives when planning health-care services in the wake of the COVID-19 pandemic.

Consensus recommendations for opioid agonist treatment following the introduction of emergency clinical guidelines in Ireland during the COVID-19 pandemic: A national Delphi study.

BACKGROUND: Emergency contingency guidelines for opioid agonist treatment (OAT) were introduced in Ireland in March 2020, to ensure rapid and uninterrupted access to treatment while mitigating COVID-19 risk. The contingency guidelines deviated, across multiple clinical domains, from pre-pandemic clinical guidelines published in 2016. The objectives of this study are to (1) identify changes introduced to OAT clinical guidelines in Ireland during the pandemic; and (2) develop consensus on whether the new recommendations should be retained beyond the pandemic, using a national Delphi consensus methodology. METHODS: Clinical guidance recommendations ('statements') were generated by comparing the newly established contingency guidelines with the national 2016 Clinical Guidelines for OAT. Over two rounds of on-line Delphi testing, a panel of experts (people currently accessing OAT, psychiatrists, general practitioners, community pharmacists, a nurse, a psychologist and support/key workers) independently rated their agreement with each statement and provided comments. Statements with a median score of 4 or 5 and a lower quartile of ≥4 were classified as having reached consensus. RESULTS: Forty-eight panel members were recruited, with a high participation level at Round 2 (90%, n=43). Consensus was achieved for 12 of the 19 statements at Round 1. The 7 remaining statements were revised, with 2 new statements, resulting in 9 statements at Round 2. Four statements reached consensus at Round 2. The final list includes 16 clinical guidance statements; 9 relating to assessment, 3 to OAT drug choice and dosing, 1 to take-away doses, 2 to overdose prevention and 1 to the continuation of e-prescriptions. CONCLUSIONS: A wide range of stakeholders involved in the delivery and receipt of OAT agreed on 16 clinical guidance statements for inclusion in OAT clinical guidelines as we move beyond the pandemic, rather than reverting to pre-pandemic guidelines. The agreed statements relate to facilitating safe access to OAT with minimal waiting time, supporting patient-centred care to promote health and well-being, and preventing drug overdose. Notably, consensus was not achieved for OAT drug dosage and frequency of urine testing during the stabilisation and maintenance phase of care.

A randomized, double-blind, placebo-controlled trial of intravenous alpha-1 antitrypsin for ARDS secondary to COVID-19.

Background: Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15). Methods: Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1ß, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints. Findings: Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1ß, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients. Conclusions: In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic. Funding: ECSA-2020-009; Elaine Galwey Research Bursary.

Parenting a newborn baby during the COVID-19 pandemic: a qualitative survey.

OBJECTIVE: The COVID-19 pandemic caused long periods of lockdown, social isolation and intense challenges for parents. This study examines parenting in an infant cohort born at the pandemic onset. METHODS: The CORAL study is a prospective longitudinal observational study looking at allergy, immune function and neurodevelopmental outcome in babies born between March and May 2020. Demographic information was collected, babies were reviewed at 6-monthly intervals, and serology for COVID-19 infection was recorded. When babies were 12 months old, parents were asked for 3-5 words to describe raising a baby during the pandemic. Frequency of word usage was compared between first time parents and parents with other children, and parents of babies with and without a diagnosis of COVID-19 infection. RESULTS: 354 babies were recruited to CORAL study. Social circles were small. At 6 months the median number of people (including parents) who had kissed the baby was 3, and by 12 months one-quarter of babies had never met another child of similar age. 304 parents completed the word choice. Commonly reported words were lonely (44.4%), isolating (31.9%) and strong bond (15.8%). 12 of those 304 babies had COVID-19 in their first year of life and there was no significant difference in reported negative or positive word number compared with parents of babies without a COVID-19 infection, or by first time parents or those who already had children. CONCLUSION: The lockdowns and social restrictions made raising an infant challenging for all parents in Ireland. It is important parents know this was a shared experience.

A randomised, double-blind, placebo-controlled, pilot trial of intravenous plasma purified alpha-1 antitrypsin for SARS-CoV-2-induced Acute Respiratory Distress Syndrome: a structured summary of a study protocol for a randomised, controlled trial.

OBJECTIVES: The primary objective is to demonstrate that, in patients with PCR-confirmed SARS-CoV-2 resulting in Acute Respiratory Distress Syndrome (ARDS), administration of 120mg/kg of body weight of intravenous Prolastin®(plasma-purified alpha-1 antitrypsin) reduces circulating plasma levels of interleukin-6 (IL-6). Secondary objectives are to determine the effects of intravenous Prolastin® on important clinical outcomes including the incidence of adverse events (AEs) and serious adverse events (SAEs). TRIAL DESIGN: Phase 2, randomised, double-blind, placebo-controlled, pilot trial. PARTICIPANTS: The study will be conducted in Intensive Care Units in hospitals across Ireland. Patients with a laboratory-confirmed diagnosis of SARS-CoV-2-infection, moderate to severe ARDS (meeting Berlin criteria for a diagnosis of ARDS with a PaO2/FiO2 ratio <200 mmHg), >18 years of age and requiring invasive or non-invasive mechanical ventilation. All individuals meeting any of the following exclusion criteria at baseline or during screening will be excluded from study participation: more than 96 hours has elapsed from onset of ARDS; age < 18 years; known to be pregnant or breastfeeding; participation in a clinical trial of an investigational medicinal product (other than antibiotics or antivirals) within 30 days; major trauma in the prior 5 days; presence of any active malignancy (other than nonmelanoma skin cancer) which required treatment within the last year; WHO Class III or IV pulmonary hypertension; pulmonary embolism prior to hospital admission within past 3 months; currently receiving extracorporeal life support (ECLS); chronic kidney disease receiving dialysis; severe chronic liver disease with Child-Pugh score > 12; DNAR (Do Not Attempt Resuscitation) order in place; treatment withdrawal imminent within 24 hours; Prisoners; non-English speaking patients or those who do not adequately understand verbal or written information unless an interpreter is available; IgA deficiency. INTERVENTION AND COMPARATOR: Intervention: Either a once weekly intravenous infusion of Prolastin® at 120mg/kg of body weight for 4 weeks or a single dose of Prolastin® at 120mg/kg of body weight intravenously followed by once weekly intravenous infusion of an equal volume of 0.9% sodium chloride for a further 3 weeks. Comparator (placebo): An equal volume of 0.9% sodium chloride intravenously once per week for four weeks. MAIN OUTCOMES: The primary effectiveness outcome measure is the change in plasma concentration of IL-6 at 7 days as measured by ELISA. Secondary outcomes include: safety and tolerability of Prolastin® in the respective groups (as defined by the number of SAEs and AEs); PaO2/FiO2 ratio; respiratory compliance; sequential organ failure assessment (SOFA) score; mortality; time on ventilator in days; plasma concentration of alpha-1 antitrypsin (AAT) as measured by nephelometry; plasma concentrations of interleukin-1ß (IL-1ß), interleukin-8 (IL-8), interleukin-10 (IL-10), soluble TNF receptor 1 (sTNFR1, a surrogate marker for TNF-α) as measured by ELISA; development of shock; acute kidney injury; need for renal replacement therapy; clinical relapse, as defined by the need for readmission to the ICU or a marked decline in PaO2/FiO2 or development of shock or mortality following a period of sustained clinical improvement; secondary bacterial pneumonia as defined by the combination of radiographic findings and sputum/airway secretion microscopy and culture. RANDOMISATION: Following informed consent/assent patients will be randomised. The randomisation lists will be prepared by the study statistician and given to the unblinded trial personnel. However, the statistician will not be exposed to how the planned treatment will be allocated to the treatment codes. Randomisation will be conducted in a 1:1:1 ratio, stratified by site and age. BLINDING (MASKING): The investigator, treating physician, other members of the site research team and patients will be blinded to treatment allocation. The clinical trial pharmacy personnel and research nurses will be unblinded to facilitate intervention and placebo preparation. The unblinded individuals will keep the treatment information confidential. The infusion bag will be masked at the time of preparation and will be administered via a masked infusion set to maintain blinding. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 36 patients will be recruited and randomised in a 1:1:1 ratio to each of the trial arms. TRIAL STATUS: In March 2020, version 1.0 of the trial protocol was submitted to the local research ethics committee (REC), Health Research Consent Declaration Committee (HRCDC) and the Health Products regulatory Authority (HPRA). REC approval was granted on April 1st 2020, HPRA approval was granted on April 24th 2020 and the HRCDC provided a conditional declaration on April 17th 2020. In July 2020 a substantial amendment (version 2.0) was submitted to the REC, HRCDC and HPRA. Protocol changes in this amendment included: the addition of trial sites; extending the duration of the trial to 12 months from 3 months; removal of inclusion criteria requiring the need for vasopressors; amendment of randomisation schedule to stratify by age only and not BMI and sex; correction of grammatical error in relation to infusion duration; to allow for inclusion of subjects who may have been enrolled in a clinical trial involving either antibiotics or anti-virals in the past 30 days; to allow for inclusion of subjects who may be currently enrolled in a clinical trial involving either antibiotics or anti-virals; to remove the need for exclusion based on alpha-1 antitrypsin phenotype; removal of mandatory isoelectric focusing of plasma to confirm Pi*MM status at screening; removal of need for mandatory echocardiogram at screening; amendment on procedures around plasma analysis to reflect that this will be conducted at the central site laboratory (as trial is multi-site and no longer single site); wording amended to reflect that interim analysis of cytokine levels taken at 7 days may be conducted. HRCDC approved version 2.0 on September 14th 2020, and HPRA approved on October 22nd 2020. REC approved the substantial amendment on November 23rd. In November 2020, version 3.0 of the trial protocol was submitted to the REC and HPRA. The rationale for this amendment was to allow for patients with moderate to severe ARDS from SARS-CoV-2 with non-invasive ventilation. HPRA approved this amendment on December 1st 2020 and the REC approved the amendment on December 8th 2020. Patient recruitment commenced in April 2020 and the last patient will be recruited to the trial in April 2021. The last visit of the last patient is anticipated to occur in April 2021. At time of writing, patient recruitment is now complete, however follow-up patient visits and data collection are ongoing. TRIAL REGISTRATION: EudraCT 2020-001391-15 (Registered 31 Mar 2020). FULL PROTOCOL: The full protocol (version 3.0 23.11.2020) is attached as an additional file accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.