Prolonged Hourly Neurologic Examinations are Associated with Increased Delirium and No Discernible Benefit in Mild/Moderate Geriatric Traumatic Brain Injury.

BACKGROUND: Serial neurologic examinations (NE) are routinely recommended in the ICU within the first 24 hours following a TBI. There are currently no widely accepted guidelines for the frequency of NE. Disruptions to the sleep-wake cycles increase the delirium rate. We aimed to evaluate whether there is a correlation between prolonged Q1-NE and development of delirium and to determine if this practice reduces the likelihood of missing the detection of a process requiring emergent intervention. METHODS: Retrospective analysis of patients with mild/moderate TBI, admitted to the ICU with serial-NE. Cohorts were stratified by the duration of exposure to Q1-NE, into Prolonged(≥24 h) and Not Prolonged(<24 h). Our primary outcomes of interest was delirium, evaluated using the Confusion Assessment Method (CAM-ICU), radiological progression from baseline images, neurological deterioration (focal neurological deficit, abnormal pupillary exam, or GCS decrease >2), and neurosurgical procedures. RESULTS: A total of 522 patients were included. No significant differences were found in demographics. Patients in the Prolonged Q1-NE group (26.1%) had higher ISS with similar AIS Head, and significantly higher delirium rate [59% vs 35%, p < .001], and a longer Hospital/ICU length of stay when compared to the Not Prolonged Q1-NE group. No neurosurgical interventions were found to be performed emergently as a result of findings on NE. Multivariate analysis demonstrated that Prolonged Q1-NE was the only independent risk factor associated with a 2.5-fold increase in delirium rate. The Number Needed to Harm for prolonged Q1-NE was 4. CONCLUSIONS: Geriatric patients with mild/moderate TBI exposed to Q1-NE for periods longer than 24 h had nearly a 3-fold increase in ICU-Delirium rate. One out of five patients exposed to prolonged Q1-NE is harmed by the development of delirium. No patients were found to directly benefit as a result of more frequent neurological examinations.

Ludwig's Angina: Higher Incidence and Worse Outcomes Associated With the Onset of the Coronavirus Disease 2019 Pandemic.

Background: Ludwig's angina (LA) is a diffuse cellulitis of the submandibular space and adjacent tissues. During the coronavirus disease 2019 (COVID-19) pandemic, odontogenic treatments were often delayed because of the implementation of safety measures to avoid the spread of the virus. We hypothesized that delayed odontogenic treatments associated with the onset of the COVID-19 pandemic would be associated with an increase in the incidence of LA and worse outcomes related to these infections. Patients and Methods: Patients from June 2018 to June 2022 with computed tomography images suggestive of LA and confirmed by ear, nose, throat (ENT) consult were included. We abstracted demographics, outcomes, clinical management, and microbiology. Patients were stratified into pre-COVID and COVID-onset. Our primary outcome, incidence of LA, was defined as: (new LA cases) ÷ (ED evaluations of oral or dental infections × 1.5 years). Results: In the pre-COVID group, we identified 32 of 1,301 patients with LA for an incidence of 0.02 per year. The COVID-onset group consisted of 41 of 641 patients, with an incidence of 0.04 per year. In the COVID-onset group, progression to necrotizing fasciitis was more likely (0% vs. 15%; p < 0.024), and they returned to the operating room for repeated debridement (3% vs. 22%; p < 0.020). Likewise, hospital length of stay, intensive care unit (ICU) length of stay, and ventilator days were higher (4.3 ± 3.5 vs. 9.5 ± 11.3; 1.1 ± 1.2 vs. 9.5 ± 7.1; 0.3 ± 1 vs. 3.6 ± 7.1; p < 0.001). Conclusions: Although the prognosis for dental infections diagnosed early is generally favorable, we observed a notable increase in the incidence of LA after the onset of the COVID-19 pandemic. Moreover, complications stemming from these infections became more severe in the COVID-onset era. Specifically, the likelihood of necrotizing fasciitis showed a substantial increase, accompanied by an increased risk of respiratory failure and mediastinitis.

Laser writing of spin defects in nanophotonic cavities.

High-yield engineering and characterization of cavity-emitter coupling is an outstanding challenge in developing scalable quantum network nodes. Ex situ defect formation systems prevent real-time analysis, and previous in situ methods are limited to bulk substrates or require further processing to improve the emitter properties1-6. Here we demonstrate the direct laser writing of cavity-integrated spin defects using a nanosecond pulsed above-bandgap laser. Photonic crystal cavities in 4H-silicon carbide serve as a nanoscope monitoring silicon-monovacancy defect formation within the approximately 200 nm3 cavity-mode volume. We observe spin resonance, cavity-integrated photoluminescence and excited-state lifetimes consistent with conventional defect formation methods, without the need for post-irradiation thermal annealing. We further find an exponential reduction in excited-state lifetime at fluences approaching the cavity amorphization threshold and show the single-shot annealing of intrinsic background defects at silicon-monovacancy formation sites. This real-time in situ method of localized defect formation, paired with cavity-integrated defect spins, is necessary towards engineering cavity-emitter coupling for quantum networking.

Metal and Activating Group Free C-4 Alkylation of Isoquinolines via a Temporary Dearomatization Strategy.

A simple method for the C-4 alkylation of isoquinolines is described using benzoic acid as a nucleophilic reagent and vinyl ketones as an electrophile. The reaction shows tolerance for substitution at C-3, and C-5-C-8 positions as well as allowing some variation of the vinyl ketone electrophiles. The products contain a carbonyl that can act as a synthetic handle for further manipulations giving esters, amines, or simple alkyl products.

Extension of hydrogen borrowing alkylation reactions for the total synthesis of (-)-γ-lycorane.

The total synthesis of (-)-γ-lycorane (10 steps) and synthesis of (±)-γ-lycorane (8 steps) was completed from cyclohexenone. A new two step hydrogen borrowing alkylation of an aziridinyl alcohol, coupled with a Ph* (Me5C6) deprotection/cyclisation procedure was developed for de novo formation of the fused 6,5 heterocyclic ring. This work is one of the first examples of hydrogen borrowing C-C bond formation being used as a key step in a total synthesis project.

Biomimetic synthesis of the non-canonical PPAP natural products yezo'otogirin C and hypermogin D, and studies towards the synthesis of norascyronone A.

Oxidative degradation and rearrangement of polycyclic polyprenylated acylphloroglucinols (PPAPs) has created diverse families of unique natural products that are attractive targets for biomimetic synthesis. Herein, we report a racemic synthesis of hyperibrin A and its oxidative radical cyclization to give yezo'otogirin C, followed by epoxidation and House-Meinwald rearrangement to give hypermogin D. We also investigated the biomimetic synthesis of norascyronone A via a similar radical cyclization pathway, with unexpected results that give insight into its biosynthesis.

Comprehensive Immunologic Evaluation of Bronchoalveolar Lavage Samples from Human Patients with Moderate and Severe Seasonal Influenza and Severe COVID-19.

Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or seasonal influenza may lead to respiratory failure requiring intubation and mechanical ventilation. The pathophysiology of this respiratory failure is attributed to local immune dysregulation, but how the immune response to viral infection in the lower airways of the human lung differs between individuals with respiratory failure and those without is not well understood. We used quantitative multiparameter flow cytometry and multiplex cytokine assays to evaluate matched blood and bronchoalveolar lavage (BAL) samples from control human subjects, subjects with symptomatic seasonal influenza who did not have respiratory failure, and subjects with severe seasonal influenza or SARS-CoV-2 infection with respiratory failure. We find that severe cases are associated with an influx of nonclassical monocytes, activated T cells, and plasmablast B cells into the lower airways. Cytokine concentrations were not elevated in the lower airways of moderate influenza patients compared with controls; however, 28 of 35 measured cytokines were significantly elevated in severe influenza, severe SARS-CoV-2 infection, or both. We noted the largest elevations in IL-6, IP-10, MCP-1, and IL-8. IL-1 family cytokines and RANTES were higher in severe influenza infection than severe SARS-CoV-2 infection. Interestingly, only the concentration of IP-10-correlated between blood and BAL during severe infection. Our results demonstrate inflammatory immune dysregulation in the lower airways during severe viral pneumonia that is distinct from lower airway responses seen in human patients with symptomatic, but not severe, illness and suggest that measurement of blood IP-10 concentration may predict this unique dysregulation.

Increased complement activation is a distinctive feature of severe SARS-CoV-2 infection.

Complement activation has been implicated in the pathogenesis of severe SARS-CoV-2 infection. However, it remains to be determined whether increased complement activation is a broad indicator of critical illness (and thus, no different in COVID-19). It is also unclear which pathways are contributing to complement activation in COVID-19, and, if complement activation is associated with certain features of severe SARS-CoV-2 infection, such as endothelial injury and hypercoagulability. To address these questions, we investigated complement activation in the plasma from patients with COVID-19 prospectively enrolled at two tertiary care centers. We compared our patients to two non-COVID cohorts: (a) patients hospitalized with influenza, and (b) patients admitted to the intensive care unit (ICU) with acute respiratory failure requiring invasive mechanical ventilation (IMV). We demonstrate that circulating markers of complement activation (i.e., sC5b-9) are elevated in patients with COVID-19 compared to those with influenza and to patients with non-COVID-19 respiratory failure. Further, the results facilitate distinguishing those who are at higher risk of worse outcomes such as requiring ICU admission, or IMV. Moreover, the results indicate enhanced activation of the alternative complement pathway is most prevalent in patients with severe COVID-19 and is associated with markers of endothelial injury (i.e., Ang2) as well as hypercoagulability (i.e., thrombomodulin and von Willebrand factor). Our findings identify complement activation to be a distinctive feature of COVID-19, and provide specific targets that may be utilized for risk prognostication, drug discovery and personalized clinical trials.

Biomimetic Total Synthesis of the Rubiginosin Meroterpenoids.

Total synthesis of the Rhododendron meroterpenoids rubiginosins A and G, which both contain unusual 6-6-6-4 ring systems, has been achieved using a bioinspired cascade approach. Stepwise synthesis of these natural products, and the related 6-6-5-4 meroterpenoids fastinoid B and rhodonoid B, from naturally occurring chromene precursors is also reported.

Isolation and Biomimetic Oxidation of Prenylbruceol A, an Anticipated Meroterpenoid Natural Product from Philotheca myoporoides.

Reinvestigation of the coumarin meroterpenoids of Philotheca myoporoides using pressurized hot water extraction (PHWE) procedures led to the isolation of prenylbruceol A, a proposed biosynthetic precursor of seven previously reported bruceol derivatives, prenylbruceols B-H. Protobruceol-I, ostruthin, dipetalactone, and a new dihydrocoumarin natural product were isolated alongside prenylbruceol A. A biomimetic singlet oxygen ene reaction of prenylbruceol A allowed the semisynthesis of prenylbruceols B, C, and D.

Impaired Cellular Immune Responses During the First Week of Severe Acute Influenza Infection.

BACKGROUND: Cellular immune responses are not well characterized during the initial days of acute symptomatic influenza infection. METHODS: We developed a prospective cohort of human subjects with confirmed influenza illness of varying severity who presented within a week after symptom onset. We characterized lymphocyte and monocyte populations as well as antigen-specific CD8+ T-cell and B-cell responses from peripheral blood mononuclear cells using flow cytometry and enzyme-linked immunospot assays. RESULTS: We recruited 68 influenza-infected individuals on average 3.5 days after the onset of symptoms. Three patients required mechanical ventilation. Influenza-specific CD8+ T-cell responses expanded before the appearance of plasmablast B cells. However, the influenza-specific CD8+ T-cell response was lower in infected subjects than responses seen in uninfected control subjects. Circulating populations of inflammatory monocytes were increased in most subjects compared with healthy controls. Inflammatory monocytes were significantly reduced in the 3 subjects requiring mechanical ventilation. Inflammatory monocytes were also reduced in a separate validation cohort of mechanically ventilated patients. CONCLUSIONS: Antigen-specific CD8+ T cells respond early during acute influenza infection at magnitudes that are lower than responses seen in uninfected individuals. Circulating inflammatory monocytes increase during acute illness and low absolute numbers are associated with very severe disease.

SARS-CoV-2 Viral RNA Shedding for More Than 87 Days in an Individual With an Impaired CD8+ T Cell Response.

Prolonged shedding of viral RNA occurs in some individuals following SARS-CoV-2 infection. We perform comprehensive immunologic evaluation of one individual with prolonged shedding. The case subject recovered from severe COVID-19 and tested positive for SARS-CoV-2 viral RNA repeatedly as many as 87 days after the first positive test, 97 days after symptom onset. The subject did not have any associated rise in anti-Spike protein antibody titers or plasma neutralization activity, arguing against re-infection. This index subject exhibited a profoundly diminished circulating CD8+ T cell population and correspondingly low SARS-CoV-2-specific CD8+ T cell responses when compared with a cohort of other recovering COVID-19 subjects. CD4+ T cell responses and neutralizing antibody responses developed as expected in this individual. Our results demonstrate that detectable viral RNA shedding in the upper airway can occur more than 3 months following infection in some individuals with COVID-19 and suggest that impaired CD8+ T cells may play a role in prolonged viral RNA shedding.

Biomimetic Synthetic Studies on the Bruceol Family of Meroterpenoid Natural Products.

A biomimetic approach to total synthesis can offer several benefits, including the development of cascade reactions for the rapid generation of molecular complexity, and guidance in the structure revision of old natural products and the anticipation of new ones. Herein, we describe how a biomimetic synthesis of bruceol, a pentacyclic meroterpenoid, led to the anticipation, isolation, and synthesis of isobruceol. The key step in the synthesis of both bruceol and isobruceol was an intramolecular hetero-Diels-Alder reaction of an o-quinone methide that was formed by dearomatization of an electron-rich chromene. The synthesis of an elusive biosynthetic intermediate also allowed a concise synthesis of eriobrucinol via a photochemical [2 + 2] cycloaddition. Furthermore, some speculation on the biosynthesis of prenylated bruceol derivatives inspired the development of a Claisen/Cope/Diels-Alder cascade reaction. We also report the generation of halogenated bruceol derivatives and the synthesis of several protobruceol natural products using singlet oxygen ene reactions.

Visible-Light Photoredox Catalysis Enables the Biomimetic Synthesis of Nyingchinoids†A, B, and D, and Rasumatranin†D.

The total synthesis of nyingchinoids A and B has been achieved through successive rearrangements of a 1,2-dioxane intermediate that was assembled using a visible-light photoredox-catalysed aerobic [2+2+2] cycloaddition. Nyingchinoid D was synthesised with a competing [2+2] cycloaddition. Based on NMR data and biosynthetic speculation, we proposed a structure revision of the related natural product rasumatranin D, which was confirmed through total synthesis. Under photoredox conditions, we observed the conversion of a cyclobutane into a 1,2-dioxane through retro-[2+2] cycloaddition followed by aerobic [2+2+2] cycloaddition.

Biomimetic and Biocatalytic Synthesis of Bruceol.

The first total synthesis of bruceol has been achieved using a biomimetic cascade cyclization initiated by a stereoselective Jacobsen-Katsuki epoxidation (and kinetic resolution) of racemic protobruceol-I. A bacterial cytochrome P450 monooxygenase was also found to catalyze the conversion of protobruceol-I into bruceol. The first full analysis of the NMR data of natural bruceol suggested that "isobruceol" was a previously unrecognized natural product also isolated from Philotheca brucei. This was confirmed by the re-isolation, synthesis, and X-ray analysis of isobruceol. In total, eight stereoisomers and structural isomers of bruceol have been synthesized in a highly divergent approach.

Biomimetic Total Synthesis of Rhodonoids C and D, and Murrayakonine D.

A divergent, three-step total synthesis of rhodonoids C and D has been achieved using a biosynthetically inspired, acid-catalyzed cascade cyclization of an epoxy-chromene that involves the presumed intermediacy of o-quinone methides. Application of a similar strategy also allowed synthesis of the alkaloid murrayakonine D.

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia.

Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.