IgG3 subclass antibodies recognize antigenically drifted influenza viruses and SARS-CoV-2 variants through efficient bivalent binding.

The constant domains of antibodies are important for effector functions, but less is known about how they can affect binding and neutralization of viruses. Here, we evaluated a panel of human influenza virus monoclonal antibodies (mAbs) expressed as IgG1, IgG2, or IgG3. We found that many influenza virus-specific mAbs have altered binding and neutralization capacity depending on the IgG subclass encoded and that these differences result from unique bivalency capacities of the subclasses. Importantly, subclass differences in antibody binding and neutralization were greatest when the affinity for the target antigen was reduced through antigenic mismatch. We found that antibodies expressed as IgG3 bound and neutralized antigenically drifted influenza viruses more effectively. We obtained similar results using a panel of SARS-CoV-2-specific mAbs and the antigenically advanced B.1.351 and BA.1 strains of SARS-CoV-2. We found that a licensed therapeutic mAb retained neutralization breadth against SARS-CoV-2 variants when expressed as IgG3, but not IgG1. These data highlight that IgG subclasses are not only important for fine-tuning effector functionality but also for binding and neutralization of antigenically drifted viruses.

Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses.

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, these mice remained protected from lethal influenza and SARS-CoV-2 challenges. We further found that IL-6, unlike neutrophils, was required to generate normal Tfh cells and antibody responses, but not for protection from influenza challenge. In summary, here we bring evidence that the mRNA-LNP platform can support the induction of protective immune responses in the absence of certain innate immune cells and cytokines.

Restrictive versus liberal red blood cell transfusion strategies for people with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without haematopoietic stem cell support.

BACKGROUND: An estimated one-quarter to one-half of people diagnosed with haematological malignancies experience anaemia. There are different strategies for red blood cell (RBC) transfusions to treat anaemia. A restrictive transfusion strategy permits a lower haemoglobin (Hb) level whereas a liberal transfusion strategy aims to maintain a higher Hb. The most effective and safest strategy is unknown. OBJECTIVES: To determine the efficacy and safety of restrictive versus liberal RBC transfusion strategies for people diagnosed with haematological malignancies treated with intensive chemotherapy or radiotherapy, or both, with or without a haematopoietic stem cell transplant (HSCT). SEARCH METHODS: We searched for randomised controlled trials (RCTs) and non-randomised studies (NRS) in MEDLINE (from 1946), Embase (from 1974), CINAHL (from 1982), Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2023, Issue 2), and eight other databases (including three trial registries) to 21 March 2023. We also searched grey literature and contacted experts in transfusion for additional trials. There were no language, date or publication status restrictions. SELECTION CRITERIA: We included RCTs and prospective NRS that evaluated restrictive versus liberal RBC transfusion strategies in children or adults with malignant haematological disorders receiving intensive chemotherapy or radiotherapy, or both, with or without HSCT. DATA COLLECTION AND ANALYSIS: Two authors independently screened references, full-text reports of potentially relevant studies, extracted data from the studies, and assessed the risk of bias. Any disagreement was discussed and resolved with a third review author. Dichotomous outcomes were presented as a risk ratio (RR) with a 95% confidence interval (CI). Narrative syntheses were used for heterogeneous outcome measures. Review Manager Web was used to meta-analyse the data. Main outcomes of interest included: all-cause mortality at 31 to 100 days, quality of life, number of participants with any bleeding, number of participants with clinically significant bleeding, serious infections, length of hospital admission (days) and hospital readmission at 0 to 3 months. The certainty of the evidence was assessed using GRADE. MAIN RESULTS: Nine studies met eligibility; eight RCTs and one NRS. Six hundred and forty-four participants were included from six completed RCTs (n = 560) and one completed NRS (n = 84), with two ongoing RCTs consisting of 294 participants (260 adult and 34 paediatric) pending inclusion. Only one completed RCT included children receiving HSCT (n = 6); the other five RCTs only included adults: 239 with acute leukaemia receiving chemotherapy and 315 receiving HSCT (166 allogeneic and 149 autologous). The transfusion threshold ranged from 70 g/L to 80 g/L for restrictive and from 80 g/L to 120 g/L for liberal strategies. Effects were reported in the summary of findings tables only for the trials that included adults to reduce indirectness due to the limited evidence contributed by the prematurely terminated paediatric trial. Evidence from RCTs Overall, there may be little to no difference in the number of participants who die within 31 to 100 days using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 451 participants; RR 1.00, 95% CI 0.27 to 3.70, P=0.99; very low-certainty evidence). There may be little to no difference in quality of life at 0 to 3 months using a restrictive compared to a liberal transfusion strategy, but the evidence is very uncertain (three studies; 431 participants; analysis unable to be completed due to heterogeneity; very low-certainty evidence). There may be little to no difference in the number of participants who suffer from any bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies; 448 participants; RR 0.91, 95% CI 0.78 to 1.06, P = 0.22; low-certainty evidence). There may be little to no difference in the number of participants who suffer from clinically significant bleeding at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (four studies; 511 participants; RR: 0.94, 95% CI 0.74 to 1.19, P = 0.60; low-certainty evidence). There may be little to no difference in the number of participants who experience serious infections at 0 to 3 months using a restrictive compared to a liberal transfusion strategy (three studies, 451 participants; RR: 1.20, 95% CI 0.93 to 1.55, P = 0.17; low-certainty evidence). A restrictive transfusion strategy likely results in little to no difference in the length of hospital admission at 0 to 3 months compared to a liberal strategy (two studies; 388 participants; analysis unable to be completed due to heterogeneity in reporting; moderate-certainty evidence). There may be little to no difference between hospital readmission using a restrictive transfusion strategy compared to a liberal transfusion strategy (one study, 299 participants; RR: 0.89, 95% CI 0.52 to 1.50; P = 0.65; low-certainty evidence). Evidence from NRS The evidence is very uncertain whether a restrictive RBC transfusion strategy: reduces the risk of death within 100 days (one study, 84 participants, restrictive 1 death; liberal 1 death; very low-certainty evidence); or decreases the risk of clinically significant bleeding (one study, 84 participants, restrictive 3; liberal 8; very low-certainty evidence). No NRS reported on the other eligible outcomes. AUTHORS' CONCLUSIONS: Findings from this review were based on seven studies and 644 participants. Definite conclusions are challenging given the relatively few included studies, low number of included participants, heterogeneity of intervention and outcome reporting, and overall certainty of evidence. To increase the certainty of the true effect of a restrictive RBC transfusion strategy on clinical outcomes, there is a need for rigorously designed and executed studies. The evidence is largely based on two populations: adults with acute leukaemia receiving intensive chemotherapy and adults with haematologic malignancy requiring HSCT. Despite the addition of 405 participants from three RCTs to the previous review's results, there is still insufficient evidence to answer this review's primary outcome. If we assume a mortality rate of 3% within 100 days, we would need a total of 1492 participants to have an 80% chance of detecting, at a 5% level of significance, an increase in all-cause mortality from 3% to 6%. Further RCTs are needed overall, particularly in children.

EVALUATION OF NONINVASIVE OSCILLOMETRIC BLOOD PRESSURE MONITORING IN ANESTHETIZED BENNETT'S WALLABIES (MACROPUS RUFOGRISEUS).

The objective of this study was to determine the accuracy of a noninvasive oscillometric method in relation to invasively measured blood pressure in anesthetized Bennett's wallabies (Macropus rufogriseus) and also to compare the accuracy of two commonly used oscillometric blood pressure monitors (manufactured by Cardell and Datascope). Eleven animals were anesthetized, and each animal was instrumented with an arterial catheter in the right medial metatarsal artery connected to a pressure transducer to obtain invasive measurements of systolic (SAP), diastolic (DAP), and mean (MAP) arterial blood pressure as well as a pressure waveform. A cuff connected to an oscillometric device was placed on the base of the tail for noninvasive measurements. Paired data from noninvasive and invasive blood pressure measurements (SAP, DAP, and MAP) were obtained every 5 min for 60 min. Bland-Altman plots were used to compare invasive and noninvasive measurements and calculate bias and 95% limits of agreement for SAP, DAP, and MAP. For both monitors, the bias of SAP, DAP, and MAP was significant, although the bias of the Cardell was consistently lower than that of the Datascope for all parameters. Limits of agreement were wide for all parameters. In conclusion, when using an oscillometric blood pressure monitor on anesthetized Bennett's wallabies, trends in blood pressure may be monitored, although all displayed readings may not represent the true blood pressure measurement. Indirect measurements of blood pressure made with the oscillometric device cannot substitute for direct measurements.

Effects of Isoflurane Anesthesia on the Hematologic Values of Rehabilitated Wild Owls.

Isoflurane anesthesia is commonly used for owls when they are being rehabilitated to minimize stress during treatments and procedures, as well as to ensure caretaker safety. However, the effects of isoflurane anesthesia on the hematologic response of owls are not known. To investigate the effects of isoflurane anesthesia on the hematology of owls, 3 phases of investigation were performed on the subject animals: 1) single, short manual- versus single, short isoflurane-restraint episodes (n = 12; 38%); 2) a single, prolonged isoflurane episode (n = 10; 31%); and 3) serial, short isoflurane episodes (n = 10; 31%). All owls were classified as adult, and the sex for most individuals was unknown. Twelve owls (38%) were included in phase 1: 5 great horned owls (Bubo virginianus; 42%), 2 eastern screech owls (Megascops asio; 17%), and 5 barred owls (Strix varia; 42%). A separate cohort of 10 novel owls (31%) were selected for inclusion in both phases 2 and 3: 4 great horned owls (40%), 2 eastern screech owls (20%), 2 barred owls (20%), 1 barn owl (Tyto alba; 10%), and 1 snowy owl (Bubo scandiacus; 10%). For each anesthetic episode, blood was collected within 3 minutes of capture and in 15-minute intervals according to the duration of the procedure. Phase 2 had additional blood collections with the patient awake at 2 and 24 hours after time 0 blood collection, whereas phase 3 had an additional blood collection at 24 hours after time 0 blood collection. Hematologic analyses included packed cell volume, total solids, total white blood cell count, heterophil to lymphocyte ratio, and absolute heterophil, lymphocyte, monocyte, eosinophil, and basophil counts. Total white blood cell count decreased significantly during phase 1; packed cell volume decreased significantly during phases 2 and 3; total solids decreased significantly in phase 2; phase 2 demonstrated a lymphopenia with a concurrent decrease in the heterophil to lymphocyte ratio; and phase 3 demonstrated a heteropenia and significant changes in the eosinophil count. All hematologic changes noted in the study were within appropriate reference intervals for the owls but do suggest that there are physiologic consequences of restraining and anesthetizing these avian patients.

Racial Differences in Prostate Cancer Treatment: The Role of Socioeconomic Status.

OBJECTIVE: This study examines whether socioeconomic status (SES), measured at both the individual and neighborhood levels, is associated with receipt of definitive treatment for localized prostate cancer and whether these associations mediate racial differences in treatment between non-Hispanic White and non-Hispanic Black men. DESIGN: The Philadelphia Area Prostate Cancer Access Study (P2 Access) is a mailed, cross-sectional survey of men sampled from the Pennsylvania Cancer Registry, combined with neighborhood Census data. SETTING: Eight counties in southeastern Pennsylvania. PARTICIPANTS: 2,386 men with prostate adenocarcinoma. MAIN MEASURES: Receipt of definitive treatment, race, self-reported income, education, employment status, and neighborhood SES. RESULTS: Overall, Black and White men were equally likely to receive definitive treatment. Men living in neighborhoods with higher SES were more likely to receive definitive treatment (OR 1.57, 95%CI 1.01, 2.42). Among men who received definitive treatment, Black men were significantly less likely to receive radical prostatectomy compared with White men (OR .71, 95% CI .52, .98), as were men with some college education compared with those with a high school education or less (OR .66, 95% CI .47, .94). SES does not mediate racial differences in receipt of definitive treatment or the type of definitive treatment received, and associations with income or employment status were not significant. CONCLUSIONS: These results stress the importance of examining racial disparities within geographic areas and highlight the unique associations that different measures of SES, particularly neighborhood SES and education, may have with prostate cancer treatment.

CHARACTERIZING THE 25-HYDROXYVITAMIN D STATUS OF TWO POPULATIONS OF FREE-RANGING EASTERN BOX TURTLES (TERRAPENE CAROLINA CAROLINA).

Ultraviolet B radiation is recommended for captive reptiles to stimulate production of adequate levels of vitamin D; however, little is known regarding the vitamin D status in many free-ranging populations. Current reference ranges for vitamin D in eastern box turtles have not yet been established. Sixty free-ranging eastern box turtles (Terrapene carolina carolina) from two well-studied populations in Illinois (n = 24) and Tennessee (n = 36) were assayed for plasma vitamin D concentration in 2014. There were no significant differences in concentrations between individuals in Illinois (mean: 117.5 nM/L) and Tennessee (mean: 98.7 nM/L) (P = 0.129) populations. Similarly, there were no differences in concentrations based on age class (P = 0.533) or sex (P = 0.532). There was a significant correlation between UV at the time of capture and vitamin D concentrations (R = 0.301, P = 0.030). Vitamin D was not correlated with total calcium (R = 0.018, P = 0.89) or Ca : P ratio (R = 0.025, P = 0.85). Diseases in captive individuals, including secondary nutritional hyperparathyroidism, may commonly be associated with vitamin D deficiencies, and clinical intervention relies on reference data. Vitamin D supplementation may be recommended if animals are deemed to be deficient. Data obtained can be used to improve the care of captive and free-ranging turtles by providing reference ranges, as well as better characterize the health of wild populations.

COMPARISON OF MEDETOMIDINE-KETAMINE AND BUTORPHANOL-AZAPERONE-MEDETOMIDINE IN CAPTIVE BENNETT'S WALLABIES (MACROPUS RUFOGRISEUS).

The objective of this study was to compare a traditional partially reversible medetomidine-ketamine sedation with a more reversible butorphanol-azaperone-medetomidine combination in Bennett's wallabies ( Macropus rufogriseus ) maintained in a zoological collection. Fourteen animals were divided into two treatment groups. Individuals in group 1 received an intramuscular (i.m.) injection of butorphanol (0.54 ± 0.05 mg/kg), azaperone (0.22 ± 0.02 mg/kg), and medetomidine (0.16 ± 0.02 mg/kg). Individuals in group 2 received an i.m. injection of ketamine (5.43 ±1.16 mg/kg) with medetomidine (0.05 ± 0.014 mg/kg). For group 1, sedation was reversed with atipamezole (0.81 ± 0.069 mg/kg i.m.) and naltrexone (1.08 ± 0.09 mg/kg i.m.). For group 2, sedation was reversed with atipamezole (0.27 ± 0.056 mg/kg i.m.). There were no significant differences between the groups in mean time to induction, time spent on gas anesthesia, or time to standing after reversal was administered. Animals in both groups required supplemental gas anesthesia to facilitate intubation. No adverse reactions or effects were noted with either protocol; however, the BAM protocol did not provide sufficient sedation for handling in all animals and may not be suitable for use in this species.

Consumer perception of whole watermelons.

There are many varieties of watermelons, providing distinct external and internal sensory attributes. This study used an online survey (n = 700) and focus groups (n = 25) to investigate consumer perception of whole watermelons. Rind color, sound of the melon, size, and price were the most important attributes for consumers when selecting a whole watermelon. Freshness was the most important whole watermelon characteristic, and watermelon freshness/quality was driven by sweetness, crispness, and juiciness. Consumers preferred seedless watermelons that had a light rind with dark green stripes, red flesh, an oval/oblong shape, firm and crisp flesh, a weight of approximately 2.2-5.5 kg, and labeling that described them as fresh, juicy, and sweet. Two consumer clusters were identified from quantitative survey data and were also representative of focus group participants: value consumers and watermelon enthusiasts. Watermelon enthusiasts were differentiated by a higher value for claims including local, product of USA, sustainably farmed, and organic. Watermelon purchase is quality driven: consumers will pay more for guaranteed sweetness and crispness. PRACTICAL APPLICATION: The ideal watermelon for all consumers is one that is dark green with stripes, is medium sized and oblong in shape, has a minimal rind-to-flesh ratio, and boasts dark, vibrant red flesh that is sweet, crisp, and juicy. All consumers want a better guarantee on watermelon quality because it is hard to predict sensory quality when selecting a melon. This study demonstrated the intrinsic and external drivers of liking for fresh watermelons and summarized a consumer watermelon purchase and consumption journey map that can guide further research and development of watermelons and provide insights on how to increase watermelon sales.

An Exploratory Analysis of Sociodemographic Factors Associated With Physical Functional Impairment in ICU Survivors.

IMPORTANCE: Physical functional impairment is one of three components of postintensive care syndrome (PICS) that affects up to 60% of ICU survivors. OBJECTIVES: To explore the prevalence of objective physical functional impairment among a diverse cohort of ICU survivors, both at discharge and longitudinally, and to highlight sociodemographic factors that might be associated with the presence of objective physical functional impairment. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of 37 patients admitted to the ICU in New Orleans, Louisiana, and Denver, Colorado between 2016 and 2019 who survived with longitudinal follow-up data. MAIN OUTCOMES AND MEASURES: Our primary outcome of physical functional impairment was defined by handgrip strength and the short physical performance battery. We explored associations between functional impairment and sociodemographic factors that included race/ethnicity, sex, primary language, education status, and medical comorbidities. RESULTS: More than 75% of ICU survivors were affected by physical functional impairment at discharge and longitudinally at 3- to 6-month follow-up. We did not see a significant difference in the proportion of patients with physical functional impairment by race/ethnicity, primary language, or education status. Impairment was relatively higher in the follow-up period among women, compared with men, and those with comorbidities. Among 18 patients with scores at both time points, White patients demonstrated greater change in handgrip strength than non-White patients. Four non-White patients demonstrated diminished handgrip strength between discharge and follow-up. CONCLUSIONS AND RELEVANCE: In this exploratory analysis, we saw that the prevalence of objective physical functional impairment among ICU survivors was high and persisted after hospital discharge. Our findings suggest a possible relationship between race/ethnicity and physical functional impairment. These exploratory findings may inform future investigations to evaluate the impact of sociodemographic factors on functional recovery.

Design, synthesis, and SAR of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1.

The design, synthesis, and structure-activity relationships (SAR) of a series of N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1) are described. Optimization of the benzamide and central ring components of the core scaffold led to the identification of a GlyT-1 inhibitor that demonstrated in vivo activity in a rodent cerebral spinal fluid (CSF) glycine model.

Bilateral carpal contracture in a neonatal addax (Addax nasomaculatus).

A neonate male addax calf displayed an inability to extend its forelimbs bilaterally (range of motion restricted to 45 degrees-50 degrees on full extension) with resultant inability to stand. Based on examination and radiographs, the congenital defect was attributed to contracted soft tissue structures (joint capsule and/or intercarpal ligaments). Splinting, support of the limbs, and physical therapy resulted in moderate improvement of the angle of contraction (full flexion to approximately 120 degrees on extension at day 10). The animal was able to walk with splints but died at 10 days from acute head trauma, presumably related to a traumatic fall caused by challenges with ambulation. Postmortem examination confirmed soft-tissue contracture of the forelimbs. Malposition of the calf in utero was considered a possible cause of the defect.

Shikonin and Alkannin inhibit ATP synthase and impede the cell growth in Escherichia coli.

Naturally occurring naphthoquinones, shikonin and alkannin, are important ingredients of traditional Chinese medicine Zicao. These constituents are reported to have many therapeutic uses, such as wound healing; scar treatment; and anti-inflammation, anti-acne, anti-ulcer, anti-HIV, anticancer, and antibacterial properties. The primary objective of this investigation was to explore the effect of shikonin and alkannin on Escherichia coli ATP synthase and its cell growth. Shikonin caused complete (100 %) inhibition, and alkannin caused partial (79 %) inhibition of wild-type E. coli ATP synthase. Both caused partial (4 %-27 %) inhibition of ATP synthase with genetically modified phytochemical binding site. The growth inhibition of strains expressing normal, deficient, and mutant ATP synthase by shikonin and alkannin, corroborated the inhibition observed in isolated normal wild-type and mutant ATP synthase. Trivial inhibition of mutant enzymes indicated αR283D, αE284R, ßV265Q, and γT273A are essential for formation of the phytochemical binding site where shikonin and alkannin bind. Further, shikonin was a potent inhibitor of ATP synthase than alkannin. The antimicrobial properties of shikonin and alkannin were tied to the binding at phytochemical site of microbial ATP synthase. Selective targeting of bacterial ATP synthase by shikonin and alkannin may be an advantageous alternative to address the antibiotic resistance issue.

Impact of iron supplementation on patient outcomes for women with abnormal uterine bleeding: a protocol for a systematic review and meta-analysis.

BACKGROUND: Abnormal uterine bleeding (AUB), which includes heavy menstrual bleeding (HMB), is a common condition placing women at increased risk for developing iron deficiency and iron deficiency anemia (IDA). Depletion of iron stores has negative implications on physical, social, and emotional health, as well as quality of life. Iron supplements are safe, effective, and readily available, while red blood cell (RBC) transfusions have inherent risks including infectious and immune reactions. Despite high prevalence of IDA among women with AUB, there are limited studies on the impact of iron therapies on patient outcomes. This systematic review and meta-analysis will evaluate the impact of iron supplementation on patient outcomes for women with AUB, when compared to combination therapy, no intervention, placebo, or standard of care. METHODS: We will conduct a systematic review and meta-analysis of randomized controlled trials and observational studies evaluating the impact of iron interventions on patient outcomes for women with AUB. Systematic literature searches will be conducted in major databases including MEDLINE, EMBASE, CENTRAL, CINAHL, and Web of Science. Studies assessing the impact of iron interventions on patient outcomes in women experiencing AUB, in comparison to combination therapy, no intervention, placebo, or standard of care, will be included in the review. Independent reviewers will screen for eligibility, assess risk of bias, and abstract data. Overall certainty of evidence for each outcome will be assessed using the GRADE approach. We will meta-analyze outcomes which are sufficiently homogeneous to summarize intervention effects and narratively synthesize nonhomogeneous outcomes. The main outcomes of interest are hemoglobin levels immediately prior to surgery and post-operatively, number of RBC transfusions, and adverse effects. Secondary outcomes will include length of hospital stay, intraoperative blood loss, adverse and side effects, quality of life, and iron indices. DISCUSSION: This review will evaluate the impact of iron interventions on patient outcomes in women with IDA secondary to AUB with focus on changes in hematological and iron indices, red blood cell utilization, quality of life, cost of treatment, and adverse events. The results will inform evidence-based clinical practice for the management of iron deficiency and IDA secondary to AUB. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019137282.

A Single Dose of the Deactivated Rabies-Virus Vectored COVID-19 Vaccine, CORAVAX, Is Highly Efficacious and Alleviates Lung Inflammation in the Hamster Model.

Without sufficient herd immunity through either vaccination or natural infection, the coronavirus disease 2019 pandemic is unlikely to be controlled. Waning immunity with the currently approved vaccines suggests the need to evaluate vaccines causing the induction of long-term responses. Here, we report the immunogenicity and efficacy of our adjuvanted single-dose Rabies-vectored SARS-CoV-2 S1 vaccine, CORAVAX, in hamsters. CORAVAX induces high SARS-CoV-2 S1-specific and virus-neutralizing antibodies (VNAs) that prevent weight loss, viral loads, disease, lung inflammation, and the cytokine storm in hamsters. We also observed high Rabies VNA titers. In summary, CORAVAX is a promising dual-antigen vaccine candidate for clinical evaluation against SARS-CoV-2 and Rabies virus.

Receipt of Recovery-Oriented Care Practices During Hospitalization for Sepsis.

Survivors of sepsis hospitalization are at high risk for postsepsis morbidity, readmission, and death, but these negative outcomes can be mitigated by receipt of recommended care practices. We sought to assess factors associated with the receipt of recommended recovery-oriented care practices during hospitalization for sepsis. We hypothesized that patients treated in the ICU may be more likely than ward-treated patients to receive recommended care practices given the increasing focus on survivorship in the critical care field. DESIGN: Observational cohort study. SETTING: Michigan Medicine, a tertiary academic medical center. PATIENTS: Adult patients discharged alive from a hospitalization with a primary diagnosis of sepsis or septic shock in 2019. We further limited our cohort to patients receiving longitudinal care viewable in the Michigan Medicine electronic health record to ensure ability to capture posthospital care and outcomes. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Three-hundred sixty-five sepsis hospitalizations met study inclusion criteria. Using structured chart review, we determined receipt of the following recovery-based care practices during hospitalization: medication optimization, functional status evaluation at discharge, sepsis education, and scheduled follow-up within 2 weeks. The cohort was 46.6% female, 81.1% White, with a median age of 64 years. 51.2% were treated in the ICU. Medication optimization occurred in 93.7%, functional status evaluation in 82.7%, sepsis education in 20.0%, and scheduled follow-up within 2 weeks in 54.5%. ICU-treated patients had lower receipt of medication optimization and follow-up scheduling but greater receipt of functional and mental health status evaluations. In multivariable models, ICU treatment was associated with lower odds of receiving medication optimization (adjusted odds ratio, 0.72; 95% CI, 0.03-0.69) and not associated with receipt of other care practices. CONCLUSIONS: Our study shows incomplete receipt of recommended recovery-based care practices during sepsis hospitalization in both ward and ICU-treated patients. Sepsis education and mental health evaluation were particularly uncommon.

Clinical and physiologic effects of sodium chloride baths in goldfish (Carassius auratus).

Sodium chloride (salt; NaCl) has been used for freshwater fish to decrease stress and manage a variety of disease conditions. Recommendations for dose and duration vary greatly. The purpose of this study was to determine the potential adverse clinical and physiologic side effects of different concentrations of saltwater baths on goldfish. Eleven goldfish (Carassius auratus) were used in a cross-over study to assess the effects of three different salt concentrations (5, 10, and 20 g/L) on plasma biochemistries and clinical response. Baseline plasma chemistries were obtained and analyzed immediately prior to placing the goldfish into the saltwater bath and after the fish was removed. A 2-wk washout period was used in-between each treatment. Significant differences were found in fish in the sodium (10 g/L, P = 0.007; 20 g/L, P = 0.01), chloride (10 g/L, P = 0.006; 20 g/L, P = 0.001), and alanine aminotransferase (10 g/L, P = 0.002; 20 g/L, P = 0.004) after their exposure to 10 and 20 g/L saltwater. Glucose levels were found to differ significantly after exposure to all three NaCl concentrations (5 g/L, P = 0.0009; 10 g/L, P = 0.0001; 20 g/L, P = 0.0005). Clinically, 5 g/L and 10 g/L saltwater baths were well tolerated by the fish for the duration of the intended 12-hr treatments, with only one goldfish being removed during the 10 g/L bath at 7 hr for listlessness. The average time goldfish spent in the 20 g/L salt bath was 43 min, with six (54%) of the fish remaining in the 20 g/L salt bath for the intended 60-min treatment period. The remaining 5 (46%) goldfish were removed because they became listless or dyspneic. All of the fish recovered from the treatments without complication. The results of this study suggest that goldfish tolerate saltwater baths but that physiologic disturbances can occur at the higher doses.

Diseases of the Reptile Renal System.

Renal disease accounts for a considerable amount of morbidity and mortality in reptiles, in part owing to inadequate husbandry practices, such as inappropriate temperature, humidity, and access to water. Inappropriate husbandry practices may lead to subclinical dehydration that can specifically impact the renal system, which relies on vascular perfusion to function. This article aims to highlight urinary pathophysiology and summarize infectious and noninfectious causes of renal disease in reptiles as a guide for differential diagnoses to consider during clinical evaluation.

Proposed grading scheme for inflammatory bowel disease in ferrets and correlation with clinical signs.

Inflammatory bowel disease (IBD) is an idiopathic, chronic, inflammatory disease of the gastrointestinal tract of companion animals, including ferrets (Mustela putorius furo). Clinical signs of IBD are nonspecific, and intestinal biopsies are necessary for a definitive diagnosis. A grading scheme has not been established for ferrets. Additionally, the association between histologic severity and clinical signs in ferrets is unknown. We evaluated enteric samples from ferrets diagnosed with IBD, compared histologic grading schemes, and correlated the results with the severity of clinical signs. Enteric sections from 23 ferrets with IBD were analyzed using grading schemes for intestinal inflammation in cats and dogs, and a correlation with clinical signs was evaluated. After dividing the histologic samples into groups based on the severity of clinical signs, main histologic differences were identified. Age and sex were also assessed for correlation with clinical signs. No significant correlation was found between the 2 grading schemes and clinical signs (rho = 0.02, p = 0.89; rho = 0.26, p = 0.18, respectively). Degree of villus fusion, hemorrhage and/or fibrin, epithelial damage, inflammation density, and crypt abscess formation were used retrospectively to create a ferret IBD grading scheme, which was significantly correlated with the severity of clinical signs (rho = 0.48, p = 0.01). A positive correlation was observed between age (p = 0.04) and females (p = 0.007) with severity of clinical signs. Our ferret grading scheme may have clinical utility in providing a more objective, consistent evaluation of IBD in ferrets.

Relation Between Cigarette Smoking and Heart Failure (from the Multiethnic Study of Atherosclerosis).

We studied the association between cigarette smoking and incident heart failure (HF) in a racially diverse US cohort. We included 6,792 participants from the Multi-Ethnic Study of Atherosclerosis with information on cigarette smoking at baseline, characterized by status, intensity, burden, and time since quitting. Adjudicated outcomes included total incident HF cases and HF stratified by ejection fraction (EF) into HF with reduced EF (HFrEF; EF ≤ 40%) and preserved EF (HFpEF; EF ≥ 50%). We used Cox proportional hazards models adjusted for traditional cardiovascular risk factors and accounted for competing risk of each HF type. Mean age was 62 ± 10 years; 53% were women, 61% were nonwhite, and 13% were current smokers. A total of 279 incident HF cases occurred over a median follow-up of 12.2 years. The incidence rates of HFrEF and HFpEF were 2.2 and 1.9 cases per 1000 person-years, respectively. Current smoking was associated with higher risk of HF compared with never smoking (hazard ratio [HR], 2.05; 95% confidence interval [CI], 1.36 to 3.09); this was similar for HFrEF (HR, 2.58; 95% CI, 1.27 to 5.25) and HFpEF (HR, 2.51; 95% CI, 1.15 to 5.49). Former smoking was not significantly associated with HF (HR, 1.17; 95% CI, 0.88 to 1.56). Smoking intensity, burden, and time since quitting did not provide additional information for HF risk after accounting for smoking status.