Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot safety and feasibility randomised controlled trial.

PURPOSE: Critically ill patients are vulnerable to penicillin allergy labels that may be incorrect. The validity of skin testing in intensive care units (ICUs) is uncertain. Many penicillin allergy labels are low risk, and validated tools exist to identify those amenable to direct oral challenge. This pilot randomised controlled trial explored the feasibility, safety, and validity of direct enteral challenge for low-risk penicillin allergy labels in critical illness. METHODS: Consenting patients with a low-risk penicillin allergy label (PAL) (PEN-FAST risk assessment score < 3) in four ICUs (Melbourne, Australia) were randomised 1:1 to penicillin (250 mg amoxicillin or implicated penicillin) direct enteral challenge versus routine care (2-h post-randomisation observation for each arm). Repeat challenge was performed post -ICU in the intervention arm. Patients were reviewed at 24 h and 5 days after each challenge/observation. RESULTS: We screened 533 patients. 130 (24.4%) were eligible and 80/130 (61.5%) enrolled (age median 64.5 years (interquartile range, IQR 53.5, 74), PEN-FAST median 1 (IQR 0,1)), with 40 (50%) randomised to direct enteral challenge. A positive challenge rate of 2.5% was identified. No antibiotic-associated serious adverse events were identified. 32/40 (80%) received a repeat challenge (zero positive). Post-randomisation, 13 (32%) of the intervention arm and 4 (10%) of the control arm received penicillin (odds ratio, OR 4.33 [1.27, 14.78] p = 0.019). CONCLUSION: These findings support the safety, validity, and feasibility of direct enteral challenge for critically ill patients with PEN-FAST assessed low-risk penicillin allergy. The absence of false negative results was confirmed by subsequent negative repeat challenges. A relatively low recruitment to screened ratio suggests that more inclusive eligibility criteria and integration of allergy assessment into routine ICU processes are needed to optimise allergy delabelling in critical illness.

Clinical utility of maternal TORCH screening in fetal growth restriction: A retrospective two-centre study.

OBJECTIVE: The aim of this study was to evaluate the indications for maternal TORCH (Toxoplasma gondii, rubella, cytomegalovirus (CMV), and herpes simplex virus (HSV)) serology, with a focus on the yield in isolated fetal growth restriction (FGR). MATERIALS AND METHODS: A retrospective review of antenatal TORCH testing between January 2014 and December 2018 was carried out at two hospitals in Melbourne, Australia. TORCH testing ordered for pregnancy losses and stillbirth was excluded. RESULTS: Medical records of 718 pregnancies were reviewed, representing 760 fetuses. Isolated FGR was the indication for TORCH screening in 71.2% of pregnancies. Screens ordered for isolated FGR were positive in 7.4% (95% CI 5.5-10.0%). There were 49 positive maternal immunoglobulin M (CMV = 34, Toxoplasma = 15). Two acute maternal infections during pregnancy were diagnosed (CMV = 1, Toxoplasma = 1), with both screens ordered to assess symptomatic maternal illness. There was one neonatal CMV infection, born to a woman with symptomatic primary CMV. No maternal or neonatal rubella or HSV infections were identified. We found a diagnostic yield of TORCH screening for isolated FGR of 0.0% (95% CI 0.00-0.8%). An estimated AUD$64 269.75 was expended on maternal TORCH screens in this study. CONCLUSION: Maternal TORCH testing for isolated FGR is of no diagnostic yield and should be abandoned.

SARS-CoV-2 antibodies and their neutralizing capacity against live virus in human milk after COVID-19 infection and vaccination: prospective cohort studies.

BACKGROUND: There is limited understanding of the impact of coronavirus disease 2019 (COVID-19) infection and vaccination type and interval on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) human milk antibodies and their neutralizing capacity. OBJECTIVES: These cohort studies aimed to determine the presence of antibodies and live virus neutralizing capacity in milk from females infected with COVID-19, unexposed milk bank donors, and vaccinated females and examine impacts of vaccine interval and type. METHODS: Milk was collected from participants infected with COVID-19 during pregnancy or lactation (Cohort-1) and milk bank donors (Cohort-2) from March 2020-July 2021 at 3 sequential 4-wk intervals and COVID-19 vaccinated participants with varying dose intervals (Cohort-3) (January-October 2021). Cohort-1 and Cohort-3 were recruited from Sinai Health (patients) and through social media. Cohort-2 included Ontario Milk Bank donors. Milk was examined for SARS-CoV-2 antibodies and live virus neutralization. RESULTS: Of females with COVID-19, 53% (Cohort-1, n = 55) had anti-SARS-CoV-2 IgA antibodies in ≥1 milk sample. IgA+ samples (40%) were more likely neutralizing than IgA- samples (odds ratio [OR]: 2.18; 95% confidence interval [CI]: 1.03, 4.60; P = 0.04); however, 25% of IgA- samples were neutralizing. Both IgA positivity and neutralization decreased ∼6 mo after symptom onset (0-100 compared with 201+ d: IgA OR: 14.30; 95% CI: 1.08, 189.89; P = 0.04; neutralizing OR: 4.30; 95% CI: 1.55, 11.89; P = 0.005). Among milk bank donors (Cohort-2, n = 373), 4.3% had IgA antibodies; 23% of IgA+ samples were neutralizing. Vaccination (Cohort-3, n = 60) with mRNA-1273 and shorter vaccine intervals (3 to <6 wk) resulted in higher IgA and IgG than BNT162b2 (P < 0.04) and longer intervals (6 to <16 wk) (P≤0.02), respectively. Neutralizing capacity increased postvaccination (P = 0.04) but was not associated with antibody positivity. CONCLUSIONS: SARS-CoV-2 infection and vaccination (type and interval) impacted milk antibodies; however, antibody presence did not consistently predict live virus neutralization. Although human milk is unequivocally the best way to nourish infants, guidance on protection to infants following maternal infection/vaccination may require more nuanced messaging. This study was registered at clinicaltrials.gov as NCT04453969 and NCT04453982.

Invasive pneumococcal disease serotype 23B1 causing multifocal septic arthritis, myositis and retroperitoneal abscess.

We describe a case of a previously healthy unvaccinated man in his 70s who developed penicillin-susceptible bacteraemic invasive pneumococcal disease due to non-vaccine serotype 23B with the unusual manifestations of multifocal myositis, intramuscular abscesses, polyarticular septic arthritis and synovitis. Blood cultures drawn prior to antibiotic therapy and culture of iliopsoas collection were helpful in making the diagnosis. At follow-up, he had persistent hip pain attributed to avascular necrosis of the head of femur, a possible late complication of his pyomyositis.

Mice possess a more limited natural antihuman factor VIII antibody repertoire than humans that is produced disproportionately by marginal zone B cells.

BACKGROUND: One-third of patients with severe hemophilia A develop neutralizing antibodies to the factor VIII (FVIII) protein in response to intravenous replacement therapy. Patients may also generate natural, nonneutralizing antibodies to FVIII before FVIII exposure. These patients are at increased risk of developing neutralizing antibodies to FVIII. However, natural anti-FVIII antibodies are also present in healthy human donors. OBJECTIVES: To further characterize the natural antihuman (h) FVIII antibody repertoire in mice and humans. METHODS: An in-house ELISA was developed using a purified polyclonal immunoglobulin (Ig) standard to quantify anti-hFVIII Ig in cell culture supernatant or plasma from mice (wild-type and FVIII-/-) and adult human donors. RESULTS: All naïve wild-type and FVIII-/- mice, as well as healthy human donors, possess natural anti-hFVIII antibodies. Mice only have natural anti-hFVIII IgM, which is present in germ-free mice, suggesting that they are germline encoded. Although murine marginal zone B cells (MZBs) contribute 44% to all circulating natural IgM, they contribute disproportionately to the anti-hFVIII IgM repertoire (82%). This naturally occurring murine MZB-derived IgM is not B-domain specific and is reduced by intravenously administered hFVIII, suggesting that it may form immune complexes immediately upon hFVIII administration. Natural anti-hFVIII antibodies of IgG, IgM, and IgA isotypes can be detected in adult human donors. There were increased levels of B-domain-favoring anti-hFVIII IgG in 14% of healthy donors, which were markedly different from the rest of the "low-titer" population. CONCLUSIONS: There is a preponderance of natural anti-hFVIII antibodies in both mice and healthy adult human donors.

Natural language processing diagnosed behavioural disturbance phenotypes in the intensive care unit: characteristics, prevalence, trajectory, treatment, and outcomes.

BACKGROUND: Natural language processing (NLP) may help evaluate the characteristics, prevalence, trajectory, treatment, and outcomes of behavioural disturbance phenotypes in critically ill patients. METHODS: We obtained electronic clinical notes, demographic information, outcomes, and treatment data from three medical-surgical ICUs. Using NLP, we screened for behavioural disturbance phenotypes based on words suggestive of an agitated state, a non-agitated state, or a combination of both. RESULTS: We studied 2931 patients. Of these, 225 (7.7%) were NLP-Dx-BD positive for the agitated phenotype, 544 (18.6%) for the non-agitated phenotype and 667 (22.7%) for the combined phenotype. Patients with these phenotypes carried multiple clinical baseline differences. On time-dependent multivariable analysis to compensate for immortal time bias and after adjustment for key outcome predictors, agitated phenotype patients were more likely to receive antipsychotic medications (odds ratio [OR] 1.84, 1.35-2.51, p < 0.001) compared to non-agitated phenotype patients but not compared to combined phenotype patients (OR 1.27, 0.86-1.89, p = 0.229). Moreover, agitated phenotype patients were more likely to die than other phenotypes patients (OR 1.57, 1.10-2.25, p = 0.012 vs non-agitated phenotype; OR 4.61, 2.14-9.90, p < 0.001 vs. combined phenotype). This association was strongest in patients receiving mechanical ventilation when compared with the combined phenotype (OR 7.03, 2.07-23.79, p = 0.002). A similar increased risk was also seen for patients with the non-agitated phenotype compared with the combined phenotype (OR 6.10, 1.80-20.64, p = 0.004). CONCLUSIONS: NLP-Dx-BD screening enabled identification of three behavioural disturbance phenotypes with different characteristics, prevalence, trajectory, treatment, and outcome. Such phenotype identification appears relevant to prognostication and trial design.

Decompensated metabolic acidosis in the emergency department: Epidemiology, sodium bicarbonate therapy, and clinical outcomes.

Objective: This article aims to describe the epidemiology of decompensated metabolic acidosis, the characteristics of sodium bicarbonate (SB) administration and outcomes in emergency department (ED) patients. Design: This is a retrospective cohort study. Setting: ED of a tertiary referral hospital in Melbourne, Australia. Participants: Adult patients presenting to the ED between 1 July 2011 and 20 September 2020 with decompensated metabolic acidosis diagnosed on arterial blood gas (ABG). Main outcome measures: We compared characteristics between those treated with or without SB. We studied SB administration characteristics, change in laboratory variables, factors associated with use and dose, and clinical outcomes. Results: Among 753,613 ED patients, 314 had decompensated metabolic acidosis on ABG, with 17.8% receiving SB. Patients in the SB group had lower median pH, CO2, bicarbonate, and base excess (BE) levels compared with the No SB group (P < 0.01). The median number of SB doses in the SB group was one treatment. This was given at a median total dose of 100 mmol and at a median of 2.8 h after the diagnostic blood gas results. Only 42% of patients in the SB group had a subsequent blood gas measured. In such patients, there was no significant change in pH, bicarbonate, or BE. SB therapy was not independently associated with mortality. Conclusions: ABG-confirmed decompensated metabolic acidosis was rare but associated with a high mortality. SB administration occurred in a minority of patients and in more acidaemic patients. However, SB dose was stereotypical and not tailored to acidosis severity. Assessment of SB effect was infrequent and showed no correction of acidosis. Systematic studies of titrated SB therapy are required to inform current practice.

A statistical genomics framework to trace bacterial genomic predictors of clinical outcomes in Staphylococcus aureus bacteremia.

Outcomes of severe bacterial infections are determined by the interplay between host, pathogen, and treatments. While human genomics has provided insights into host factors impacting Staphylococcus aureus infections, comparatively little is known about S. aureus genotypes and disease severity. Building on the hypothesis that bacterial pathoadaptation is a key outcome driver, we developed a genome-wide association study (GWAS) framework to identify adaptive mutations associated with treatment failure and mortality in S. aureus bacteremia (1,358 episodes). Our research highlights the potential of vancomycin-selected mutations and vancomycin minimum inhibitory concentration (MIC) as key explanatory variables to predict infection severity. The contribution of bacterial variation was much lower for clinical outcomes (heritability <5%); however, GWASs allowed us to identify additional, MIC-independent candidate pathogenesis loci. Using supervised machine learning, we were able to quantify the predictive potential of these adaptive signatures. Our statistical genomics framework provides a powerful means to capture adaptive mutations impacting severe bacterial infections.

Oral challenge vs routine care to assess low-risk penicillin allergy in critically ill hospital patients (ORACLE): a pilot randomised controlled trial.

BACKGROUND: Self-reported penicillin allergies are highly prevalent in hospitalised patients and are associated with poor health and health service outcomes. Critically ill patients have historically been underrepresented in prospective delabelling studies in part due to concerns around clinical stability and reliability of penicillin skin testing. Allergy assessment tools exist to identify low-risk penicillin allergy phenotypes and facilitate direct oral challenge delabelling. PEN-FAST is a clinical decision rule that has been validated to predict true penicillin allergy in a cohort of non-critically ill patients. There is however limited evidence regarding the feasibility, safety and efficacy of direct oral challenges and the use of delabelling clinical decisions rules in the intensive care setting. METHODS: Critically ill patients in the intensive care unit (ICU) with low-risk penicillin allergy phenotypes (PEN-FAST score < 3) will be randomised 1:1 to direct oral penicillin challenge (single dose 250 mg oral amoxicillin or implicated penicillin) or routine care, followed by a 2-h observation period. Patients will receive a second oral challenge/observation prior to hospital discharge (with subsequent observation for 2 h). An assessment for antibiotic-associated adverse events will also be undertaken at 24 h and 5 days post each challenge/observation and again at 90 days post-randomisation. The primary outcome measures are feasibility (proportion of eligible patients recruited and protocol compliance) and safety (proportion of patients who experience an antibiotic-associated immune-mediated adverse event or serious adverse event). DISCUSSION: We will report the feasibility and safety of point-of-care penicillin direct oral challenge in this first randomised controlled trial of low-risk penicillin allergy in critically ill hospitalised patients. Upon completion of the project, important findings will inform the design of planned large prospective multi-centre clinical trials in Australian and international ICUs, further examining safety and efficacy and exploring antimicrobial prescribing-related outcomes following penicillin oral challenge. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Registration Number: ACTRN12621000051842 Date registered: 20/01/2021 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=379735&isReview=true.

Efficacy of a Clinical Decision Rule to Enable Direct Oral Challenge in Patients With Low-Risk Penicillin Allergy: The PALACE Randomized Clinical Trial.

Importance: Fewer than 5% of patients labeled with a penicillin allergy are truly allergic. The standard of care to remove the penicillin allergy label in adults is specialized testing involving prick and intradermal skin testing followed by an oral challenge with penicillin. Skin testing is resource intensive, limits practice to specialist-trained physicians, and restricts the global population who could undergo penicillin allergy delabeling. Objective: To determine whether a direct oral penicillin challenge is noninferior to the standard of care of penicillin skin testing followed by an oral challenge in patients with a low-risk penicillin allergy. Design, Setting, and Participants: This parallel, 2-arm, noninferiority, open-label, multicenter, international randomized clinical trial occurred in 6 specialized centers, 3 in North America (US and Canada) and 3 in Australia, from June 18, 2021, to December 2, 2022. Eligible adults had a PEN-FAST score lower than 3. PEN-FAST is a prospectively derived and internationally validated clinical decision rule that enables point-of-care risk assessment for adults reporting penicillin allergies. Interventions: Patients were randomly assigned to either direct oral challenge with penicillin (intervention arm) or a standard-of-care arm of penicillin skin testing followed by oral challenge with penicillin (control arm). Main Outcome and Measure: The primary outcome was a physician-verified positive immune-mediated oral penicillin challenge within 1 hour postintervention in the intention-to-treat population. Noninferiority was achieved if a 1-sided 95% CI of the risk difference (RD) did not exceed 5 percentage points (pp). Results: A total of 382 adults were randomized, with 377 patients (median [IQR] age, 51 [35-65] years; 247 [65.5%] female) included in the analysis: 187 in the intervention group and 190 in the control group. Most patients had a PEN-FAST score of 0 or 1. The primary outcome occurred in 1 patient (0.5%) in the intervention group and 1 patient (0.5%) in the control group, with an RD of 0.0084 pp (90% CI, -1.22 to 1.24 pp). The 1-sided 95% CI was below the noninferiority margin of 5 pp. In the 5 days following the oral penicillin challenge, 9 immune-mediated adverse events were recorded in the intervention group and 10 in the control group (RD, -0.45 pp; 95% CI, -4.87 to 3.96 pp). No serious adverse events occurred. Conclusions and Relevance: In this randomized clinical trial, direct oral penicillin challenge in patients with a low-risk penicillin allergy was noninferior compared with standard-of-care skin testing followed by oral challenge. In patients with a low-risk history, direct oral penicillin challenge is a safe procedure to facilitate the removal of a penicillin allergy label. Trial Registration: ClinicalTrials.gov Identifier: NCT04454229.

Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis.

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI. Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m2). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model. Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88). Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.

Identification of an Optimized Receptor-Binding Domain Subunit Vaccine against SARS-CoV-2.

Current vaccine efforts to combat SARS-CoV-2 are focused on the whole spike protein administered as mRNA, viral vector, or protein subunit. However, the SARS-CoV-2 receptor-binding domain (RBD) is the immunodominant portion of the spike protein, accounting for 90% of serum neutralizing activity. In this study, we constructed several versions of RBD and together with aluminum hydroxide or DDA (dimethyldioctadecylammonium bromide)/TDB (d-(+)-trehalose 6,6'-dibehenate) adjuvant evaluated immunogenicity in mice. We generated human angiotensin-converting enzyme 2 knock-in mice to evaluate vaccine efficacy in vivo following viral challenge. We found that 1) subdomain (SD)1 was essential for the RBD to elicit maximal immunogenicity; 2) RBDSD1 produced in mammalian HEK cells elicited better immunogenicity than did protein produced in insect or yeast cells; 3) RBDSD1 combined with the CD4 Th1 adjuvant DDA/TDB produced higher neutralizing Ab responses and stronger CD4 T cell responses than did aluminum hydroxide; 4) addition of monomeric human Fc receptor to RBDSD1 (RBDSD1Fc) significantly enhanced immunogenicity and neutralizing Ab titers; 5) the Beta version of RBDSD1Fc provided a broad range of cross-neutralization to multiple antigenic variants of concern, including Omicron; and 6) the Beta version of RBDSD1Fc with DDA/TDB provided complete protection against virus challenge in the knock-in mouse model. Thus, we have identified an optimized RBD-based subunit vaccine suitable for clinical trials.

Estimating baseline creatinine to detect acute kidney injury in patients with chronic kidney disease.

BACKGROUND: Accurately estimating baseline kidney function is essential for diagnosing acute kidney injury (AKI) in patients with chronic kidney disease (CKD). We developed and evaluated novel equations to estimate baseline creatinine in patients with AKI on CKD. METHODS: We retrospectively analysed 5649 adults with AKI out of 11 254 CKD patients, dividing them evenly into derivation and validation groups. Using quantiles regression, we created equations to estimate baseline creatinine, considering historical creatinine values, months since measurement, age, and sex from the derivation dataset. We assessed performance against back-estimation equations and unadjusted historical creatinine values using the validation dataset. RESULTS: The optimal equation adjusted the most recent creatinine value for time since measurement and sex. Estimates closely matched the actual baseline at AKI onset, with median (95% confidence interval) differences of just 0.9% (-0.8% to 2.1%) and 0.6% (-1.6% to 3.9%) when the most recent value was within 6 months to 30 days and 2 years to 6 months before AKI onset, respectively. The equation improved AKI event reclassification by an additional 2.5% (2.0% to 3.0%) compared to the unadjusted most recent creatinine value and 7.3% (6.2% to 8.4%) compared to the CKD-EPI 2021 back-estimation equation. CONCLUSION: Creatinine levels drift in patients with CKD, causing false positives in AKI detection without adjustment. Our novel equation adjusts the most recent creatinine value for drift over time. It provides more accurate baseline creatinine estimation in patients with suspected AKI on CKD, which reduces false-positive AKI detection, improving patient care and management.

Serological screening for cytomegalovirus during pregnancy: A systematic review of clinical practice guidelines and consensus statements.

BACKGROUND: Congenital cytomegalovirus (cCMV) is the most common congenital infection worldwide. cCMV can lead to severe long-term sequelae, including neurological impairment and developmental delay. We performed a systematic review of clinical practice guidelines containing recommendations concerning serological screening for CMV during pregnancy. METHOD: We performed a search of MEDLINE, Turning Research into Practice (TRIP) database and the grey literature for clinical practice guidelines or consensus statements published in the English language from Jan 2010 to June 2022. The quality of the included guidelines was assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Textual synthesis was used to summarise and compare the recommendations on CMV serological screening in pregnancy. RESULTS: Eleven guidelines and two consensus statements were included. None recommended universal serological screening for CMV in pregnant women; five recommended screening for high-risk women (those with frequent contact with young children). The overall quality of the guidelines varied; most were medium or low. CONCLUSIONS: Although clinical practice guidelines do not actively recommend routine serological screening in pregnancy, most did not meet standard processes for development and predated the emerging data on valaciclovir as a potential intervention. Existing recommendations are underpinned by limited, low-level evidence, exposing the lack of robust data in this area of practice. Further high-level evidence and methodologically robust guidelines are needed to guide clinical practice in this rapidly changing field.

The epidemiology of ketosis and low bicarbonate concentration in inpatients treated with sodium-glucose linked cotransporter inhibitors or dipeptidyl peptidase-4 inhibitors.

AIMS: To compare the level of ketones and bicarbonate in inpatients treated with sodium-glucose linked cotransporter 2 inhibitors (SGLT2i) and those treated with dipeptidyl peptidase-4 inhibitors (DPP4i). METHODS: We conducted an electronic medical records-based cohort study. We identified patients with type 2 diabetes, with ketone measurements available, who received SGLT2i (n = 82) or DPP4i (n = 308) during admission. We compared ketone levels between those who received SGLT2i or DPP4i using mixed ordinal logistic regression. The primary outcome was level of ketosis (<0.6, 0.6-1.5, 1.6-3.0, >3 mmol/L). Secondary outcomes included bicarbonate levels, hospital complications, ICU admission, and death. RESULTS: SGLT2i use was not associated with greater ketosis than DPP4i use, after adjusting for age, weight, Charlson Comorbidity Index, HbA1c, estimated glomerular filtration rate, principal diagnosis category, admission type and insulin administration (OR 4.52 95 % CI (0.33, 61.82)). After adjustment, there was no difference in complications (p = 0.14), ICU admissions (p = 0.64), mortality (p = 0.30), or bicarbonate levels (p = 0.97). CONCLUSION: Ketone levels were not greater in patients who received SGLT2i than those who received DPP4i. There were no differences in bicarbonate levels, complications, ICU admissions, or mortality, implying that, in inpatients, SGLT2i use is neither associated with ketosis nor adverse clinical outcomes.

Comparing study features is easy but identifying next steps is hard: Evaluating critical thinking through the Biology Lab Inventory of Critical Thinking in Ecology.

Critical thinking, which can be defined as the evidence-based ways in which people decide what to trust and what to do, is an important competency included in many undergraduate science, technology, engineering, and mathematics (STEM) courses. To help instructors effectively measure critical thinking, we developed the Biology Lab Inventory of Critical Thinking in Ecology (Eco-BLIC), a freely available, closed-response assessment of undergraduate students' critical thinking in ecology. The Eco-BLIC includes ecology-based experimental scenarios followed by questions that measure how students decide on what to trust and what to do next. Here, we present the development of the Eco-BLIC using tests of validity and reliability. Using student responses to questions and think-aloud interviews, we demonstrate the effectiveness of the Eco-BLIC at measuring students' critical thinking skills. We find that while students generally think like experts while evaluating what to trust, students' responses are less expert-like when deciding on what to do next.

A multi-specific, multi-affinity antibody platform neutralizes sarbecoviruses and confers protection against SARS-CoV-2 in vivo.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has been responsible for a global pandemic. Monoclonal antibodies (mAbs) have been used as antiviral therapeutics; however, these therapeutics have been limited in efficacy by viral sequence variability in emerging variants of concern (VOCs) and in deployment by the need for high doses. In this study, we leveraged the multi-specific, multi-affinity antibody (Multabody, MB) platform, derived from the human apoferritin protomer, to enable the multimerization of antibody fragments. MBs were shown to be highly potent, neutralizing SARS-CoV-2 at lower concentrations than their corresponding mAb counterparts. In mice infected with SARS-CoV-2, a tri-specific MB targeting three regions within the SARS-CoV-2 receptor binding domain was protective at a 30-fold lower dose than a cocktail of the corresponding mAbs. Furthermore, we showed in vitro that mono-specific MBs potently neutralize SARS-CoV-2 VOCs by leveraging augmented avidity, even when corresponding mAbs lose their ability to neutralize potently, and that tri-specific MBs expanded the neutralization breadth beyond SARS-CoV-2 to other sarbecoviruses. Our work demonstrates how avidity and multi-specificity combined can be leveraged to confer protection and resilience against viral diversity that exceeds that of traditional monoclonal antibody therapies.