Updated Bivalent COVID-19 Vaccines Reduce Risk of Hospitalization and Severe Outcomes in Adults: An Observational Cohort Study.

Background: This study evaluates the real-world effectiveness of updated bivalent coronavirus disease 2019 (COVID-19) vaccines in adults, as the virus evolves and the need for new vaccinations increases. Methods: In this observational, retrospective, multi-center, cohort analysis, we examined emergency care encounters with COVID-19 in metro Detroit, Michigan, from January 1, 2022, to March 9, 2023. Patients were categorized by vaccination status: unvaccinated, fully vaccinated, fully vaccinated and boosted (FV&B), or fully vaccinated and bivalent boosted (FV&BB). The primary outcome was to assess the impact of bivalent COVID-19 vaccinations on the risk of composite severe outcomes (intensive care unit (ICU) admission, mechanical ventilation, or death) among patients presenting to a hospital with a primary diagnosis of COVID-19. Results: A total of 21,439 encounters met inclusion criteria: 9,630 (44.9%) unvaccinated, 9,223 (43.0%) vaccinated, 2,180 (10.2%) FV&B, and 406 (1.9%) FV&BB. The average age was 48.8, with 59.6% female; 61.1% were White, 32.8% Black, and 6.0% other races. Severe disease affected 5.5% overall: 5.0% unvaccinated, 5.7% vaccinated, 7.0% FV&B, and 4.7% FV&BB (P = 0.001). Severe disease rates among admitted patients were 13.3% unvaccinated, 11.9% vaccinated, 12.2% boosted, and 8.1% FV&BB (P = 0.052). The FV&BB group showed a 4.0% (P = 0.0369) lower risk of severe disease compared to FV&B and a 5.1% (P = 0.0203) lower probability of hospitalization. Conclusions: As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to mutate and evolve, updated vaccines are necessary to better combat COVID-19. In a real-world hospital-based population, this investigation demonstrates the incremental benefit of the bivalent booster vaccine in reducing the risk of hospitalization and severe outcomes in those diagnosed with COVID-19 compared to all other forms of vaccination.

Risk of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC) Among Patients with Type 2 Diabetes Mellitus on Anti-Hyperglycemic Medications.

Background: Observed activity of metformin in reducing the risk of severe COVID-19 suggests a potential use of the anti-hyperglycemic in the prevention of post-acute sequelae of SARS-CoV-2 infection (PASC). We assessed the 3-month and 6-month risk of PASC among patients with type 2 diabetes mellitus (T2DM) comparing metformin users to sulfonylureas (SU) or dipeptidyl peptidase-4 inhibitors (DPP4i) users. Methods: We used de-identified patient level electronic health record data from the National Covid Cohort Collaborative (N3C) between October 2021 and April 2023. Participants were adults ≥ 18 years with T2DM who had at least one outpatient healthcare encounter in health institutions in the United States prior to COVID-19 diagnosis. The outcome of PASC was defined based on the presence of a diagnosis code for the illness or using a predicted probability based on a machine learning algorithm. We estimated the 3-month and 6-month risk of PASC and calculated crude and weighted risk ratios (RR), risk differences (RD), and differences in mean predicted probability. Results: We identified 5596 (mean age: 61.1 years; SD: 12.6) and 1451 (mean age: 64.9 years; SD 12.5) eligible prevalent users of metformin and SU/DPP4i respectively. We did not find a significant difference in risk of PASC at 3 months (RR = 0.86 [0.56; 1.32], RD = -3.06 per 1000 [-12.14; 6.01]), or at 6 months (RR = 0.81 [0.55; 1.20], RD = -4.91 per 1000 [-14.75, 4.93]) comparing prevalent users of metformin to prevalent users of SU/ DPP4i. Similar observations were made for the outcome definition using the ML algorithm. Conclusion: The observed estimates in our study are consistent with a reduced risk of PASC among prevalent users of metformin, however the uncertainty of our confidence intervals warrants cautious interpretations of the results. A standardized clinical definition of PASC is warranted for thorough evaluation of the effectiveness of therapies under assessment for the prevention of PASC.

Previous research suggests that metformin, due to its anti-viral, anti-inflammatory, and anti-thrombotic properties may reduce the risk of severe COVID-19. Given the shared etiology of COVID-19 and the post-acute sequelae of SARS-CoV-2 (PASC), and the proposed inflammatory processes of PASC, metformin may also be a beneficial preventive option. We investigated the benefit of metformin for PASC prevention in a population of type 2 diabetes mellitus patients with a COVID-19 diagnosis who were on metformin or two other anti-hyperglycemic medications prior to infection with SARS-CoV-2. Our results were consistent with a reduction in the risk of PASC with the use of metformin, however, the imprecise confidence intervals obtained warrants further investigation of this association of the potential beneficial effect of metformin for preventing PASC in patients with medication-managed diabetes.

Granulomatous Inflammation of the Skull Base: A Rare Case of Mycobacterium tuberculosis in the United States.

The differential for an ill-defined, bone-destructive, granulomatous lesion of the skull base includes malignancy, as well as autoimmune and infectious processes. Suspicion for tuberculosis of the skull base in high-risk patients is particularly necessary given the difficulty to culture on standard cultures, need for specific and prolonged antibiotic therapy, and dire morbidity if not diagnosed and treated in a timely manner. Repeat biopsies and cultures were necessary to diagnose this case of Mycobacterium tuberculosis of the skull base after initial biopsy was non-diagnostic. Laryngoscope, 2024.

Transmission of quantum-secured images.

The secure transmission of an image can be accomplished by encoding the image information, securely communicating this information, and subsequently reconstructing the image. Alternatively, here we show how the image itself can be directly transmitted while ensuring that the presence of any eavesdropper is revealed in a way akin to quantum key distribution (QKD). We achieve this transmission using a photon-pair source with the deliberate addition of a thermal light source as background noise. One photon of the pair illuminates the object, which is masked from an eavesdropper by adding indistinguishable thermal photons, the other photon of the pair acts as a time reference with which the intended recipient can preferentially filter the image carrying photons from the background. These reference photons are themselves made sensitive to the presence of an eavesdropper by traditional polarisation-based QKD encoding. Interestingly the security verification is performed in the two-dimensional polarisation-basis, but the image information is encoded in a much higher-dimensional, hence information-rich, pixel basis. In our example implementation, our image comprises of 152 independent pixels. Beyond the secure transmission of images, our approach to the distribution of secure high-dimensional information may offer new high-bandwidth approaches to QKD.

Discovery of a Tunable Heterocyclic Electrophile 4-Chloro-pyrazolopyridine That Defines a Unique Subset of Ligandable Cysteines.

Electrophilic small molecules with novel reactivity are powerful tools that enable activity-based protein profiling and covalent inhibitor discovery. Here, we report a reactive heterocyclic scaffold, 4-chloro-pyrazolopyridine (CPzP) for selective modification of proteins via a nucleophilic aromatic substitution (SNAr) mechanism. Chemoproteomic profiling reveals that CPzPs engage cysteines within functionally diverse protein sites including ribosomal protein S5 (RPS5), inosine monophosphate dehydrogenase 2 (IMPDH2), and heat shock protein 60 (HSP60). Through the optimization of appended recognition elements, we demonstrate the utility of CPzP for covalent inhibition of prolyl endopeptidase (PREP) by targeting a noncatalytic active-site cysteine. This study suggests that the proteome reactivity of CPzPs can be modulated by both electronic and steric features of the ring system, providing a new tunable electrophile for applications in chemoproteomics and covalent inhibitor design.

Noise Tolerant Photonic Bowtie Grating Environmental Sensor.

Resonant photonic refractive index sensors have made major advances based on their high sensitivity and contact-less readout capability, which is advantageous in many areas of science and technology. A major issue for the technological implementation of such sensors is their response to external influences, such as vibrations and temperature variations; the more sensitive a sensor, the more susceptible it also becomes to external influences. Here, we introduce a novel bowtie-shaped sensor that is highly responsive to refractive index variations while compensating for temperature changes and mechanical (linear and angular) vibrations. We exemplify its capability by demonstrating the detection of salinity to a precision of 0.1%, corresponding to 2.3 × 10-4 refractive index units in the presence of temperature fluctuations and mechanical vibrations. As a second exemplar, we detected bacteria growth in a pilot industrial environment. Our results demonstrate that it is possible to translate high sensitivity resonant photonic refractive index sensors into real-world environments.

In Vivo Mapping of Myocardial Injury Outside the Infarct Zone: Tissue at an Intermediate Pathological State.

BACKGROUND: The goal was to determine the feasibility of mapping the injured-but-not-infarcted myocardium using 99mTc-duramycin in the postischemic heart, with spatial information for its characterization as a pathophysiologically intermediate tissue, which is neither normal nor infarcted. METHODS AND RESULTS: Coronary occlusion was conducted in Sprague Dawley rats with preconditioning and 30-minute ligation. In vivo single-photon emission computed tomography was acquired after 3 hours (n=6) using 99mTc-duramycin, a phosphatidylethanolamine-specific radiopharmaceutical. The 99mTc-duramycin+ areas were compared with infarct and area-at-risk (n=8). Cardiomyocytes and endothelial cells were isolated for gene expression profiling. Cardiac function was measured with echocardiography (n=6) at 4 weeks. In vivo imaging with 99mTc-duramycin identified the infarct (3.9±2.4% of the left ventricle and an extensive area 23.7±2.2% of the left ventricle) with diffuse signal outside the infarct, which is pathologically between normal and infarcted (apoptosis 1.8±1.6, 8.9±4.2, 13.6±3.8%; VCAM-1 [vascular cell adhesion molecule 1] 3.2±0.8, 9.8±4.1, 15.9±4.2/mm2; tyrosine hydroxylase 14.9±2.8, 8.6±4.4, 5.6±2.2/mm2), with heterogeneous changes including scattered micronecrosis, wavy myofibrils, hydropic change, and glycogen accumulation. The 99mTc-duramycin+ tissue is quantitatively smaller than the area-at-risk (26.7% versus 34.4% of the left ventricle, P=0.008). Compared with infarct, gene expression in the 99mTc-duramycin+-noninfarct tissue indicated a greater prosurvival ratio (BCL2/BAX [B-cell lymphoma 2/BCL2-associated X] 7.8 versus 5.7 [cardiomyocytes], 3.7 versus 3.2 [endothelial]), and an upregulation of ion channels in electrophysiology. There was decreased contractility at 4 weeks (regional fractional shortening -8.6%, P<0.05; circumferential strain -52.9%, P<0.05). CONCLUSIONS: The injured-but-not-infarcted tissue, being an intermediate zone between normal and infarct, is mapped in vivo using phosphatidylethanolamine-based imaging. The intermediate zone contributes significantly to cardiac dysfunction.

Delayed Diagnosis of Ectopic Cushing Syndrome.

Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers.

Structural basis of directional switching by the bacterial flagellum.

The bacterial flagellum is a macromolecular protein complex that harvests energy from uni-directional ion flow across the inner membrane to power bacterial swimming via rotation of the flagellar filament. Rotation is bi-directional, with binding of a cytoplasmic chemotactic response regulator controlling reversal, though the structural and mechanistic bases for rotational switching are not well understood. Here we present cryoelectron microscopy structures of intact Salmonella flagellar basal bodies (3.2-5.5 Å), including the cytoplasmic C-ring complexes required for power transmission, in both counter-clockwise and clockwise rotational conformations. These reveal 180° movements of both the N- and C-terminal domains of the FliG protein, which, when combined with a high-resolution cryoelectron microscopy structure of the MotA5B2 stator, show that the stator shifts from the outside to the inside of the C-ring. This enables rotational switching and reveals how uni-directional ion flow across the inner membrane is used to accomplish bi-directional rotation of the flagellum.

An Improved Definition and SAFE Rule for Predicting Difficult Intravascular Access (DIVA) in Hospitalized Adults.

Patients with difficult intravascular access (DIVA) are common, yet the condition is often ignored or poorly managed, leading to patient dissatisfaction and misuse of health care resources. This study sought to assess all published risk factors associated with DIVA in order to promote prospective identification and improved management of patients with DIVA. A systematic literature review on risk factors associated with DIVA was conducted. Risk factors published in ≥4 eligible studies underwent a multivariate meta-analysis of multiple factors (MVMA-MF) using the Bayesian framework. Of 2535 unique publications identified, 20 studies were eligible for review. In total, 82 unique DIVA risk factors were identified, with the 10 factors found in ≥4 studies undergoing MVMA-MF. Significant predictors of DIVA included vein visibility, vein palpability, history of DIVA, obesity (body mass index [BMI] >30), and history of intravenous (IV) drug abuse, which were combined to create the mnemonic guideline, SAFE: See, Ask (about a history of DIVA or IV drug abuse), Feel, and Evaluate BMI. By recognizing patients with DIVA before the first insertion attempt and treating them from the outset with advanced vein visualization techniques, patients with DIVA could be subject to less frequent painful venipunctures, fewer delays in treatment, and a reduction in other DIVA-associated burdens.

Convergent evolutionary patterns of heterostyly across angiosperms support the pollination-precision hypothesis.

Since the insights by Charles Darwin, heterostyly, a floral polymorphism with morphs bearing stigmas and anthers at reciprocal heights, has become a model system for the study of natural selection. Based on his archetypal heterostylous flower, including regular symmetry, few stamens and a tube, Darwin hypothesised that heterostyly evolved to promote outcrossing through efficient pollen transfer between morphs involving different areas of a pollinator's body, thus proposing his seminal pollination-precision hypothesis. Here we update the number of heterostylous and other style-length polymorphic taxa to 247 genera belonging to 34 families, notably expanding known cases by 20%. Using phylogenetic and comparative analyses across the angiosperms, we show numerous independent origins of style-length polymorphism associated with actinomorphic, tubular flowers with a low number of sex organs, stamens fused to the corolla, and pollination by long-tongued insects. These associations provide support for the Darwinian pollination-precision hypothesis as a basis for convergent evolution of heterostyly across angiosperms.

Promoting Learning Health System Cycles by Optimizing EHR Data Clinical Concept Encoding Processes.

Electronic health records (EHRs) and other real-world data (RWD) are critical to accelerating and scaling care improvement and transformation. To efficiently leverage it for secondary uses, EHR/RWD should be optimally managed and mapped to industry standard concepts (ISCs). Inherent challenges in concept encoding usually result in inefficient and costly workflows and resultant metadata representation structures outside the EHR. Using three related projects to map data to ISCs, we describe the development of standard, repeatable processes for precisely and unambiguously representing EHR data using appropriate ISCs within the EHR platform lifecycle and mappings specific to SNOMED-CT for Demographics, Specialty and Services. Mappings in these 3 areas resulted in ISC mappings of 779 data elements requiring 90 new concept requests to SNOMED-CT and 738 new ISCs mapped into the workflow within an accessible, enterprise-wide EHR resource with supporting processes.

Nectar cardenolides and floral volatiles mediate a specialized wasp pollination system.

Specialization in plant pollination systems can arise from traits that function as filters of flower visitors. This may involve chemical traits such as floral volatiles that selectively attract favoured visitors and non-volatile nectar constituents that selectively deter disfavoured visitors through taste or longer-term toxic effects or both. We explored the functions of floral chemical traits in the African milkweed Gomphocarpus physocarpus, which is pollinated almost exclusively by vespid wasps, despite having nectar that is highly accessible to other insects such as honeybees. We demonstrated that the nectar of wasp-pollinated G. physocarpus contains cardenolides that had greater toxic effects on Apis mellifera honeybees than on Vespula germanica wasps, and also reduced feeding rates by honeybees. Behavioural experiments using natural compositions of nectar compounds showed that these interactions are mediated by non-volatile nectar chemistry. We also identified volatile compounds with acetic acid as a main component in the floral scent of G. physocarpus that elicited electrophysiological responses in wasp antennae. Mixtures of these compounds were behaviourally effective for attraction of V. germanica wasps. The results show the importance of both volatile and non-volatile chemical traits as filters that lead to specialization in plant pollination systems.

Comprehensive genomic profiling reveals molecular subsets of ASXL1-mutated myeloid neoplasms.

A large-scale genomic analysis of patients with ASXL1-mutated myeloid disease has not been performed to date. We reviewed comprehensive genomic profiling results from 6043 adults to characterize clinicopathologic features and co-mutation patterns by ASXL1 mutation status. ASXL1 mutations occurred in 1414 patients (23%). Mutation co-occurrence testing revealed strong co-occurrence (p < 0.01) between mutations in ASXL1 and nine genes (SRSF2, U2AF1, RUNX1, SETBP1, EZH2, STAG2, CUX1, CSF3R, CBL). Further analysis of patients with these co-mutations yielded several novel findings. Co-mutation patterns supported that ASXL1/SF3B1 co-mutation may be biologically distinct from ASXL1/non-SF3B1 spliceosome co-mutation. In AML, ASXL1/SRSF2 co-mutated patients frequently harbored STAG2 mutations (42%), which were dependent on the presence of both ASXL1 and SRSF2 mutation (p < 0.05). STAG2 and SETBP1 mutations were also exclusive in ASXL1/SRSF2 co-mutated patients and associated with divergent chronic myeloid phenotypes. Our findings support that certain multi-mutant genotypes may be biologically relevant in ASXL1-mutated myeloid disease.

Non-equilibrium dynamics of spin-lattice coupling.

Quantifying the dynamics of normal modes and how they interact with other excitations is of central importance in condensed matter. Spin-lattice coupling is relevant to several sub-fields of condensed matter physics; examples include spintronics, high-Tc superconductivity, and topological materials. However, experimental approaches that can directly measure it are rare and incomplete. Here we use time-resolved X-ray diffraction to directly access the ultrafast motion of atoms and spins following the coherent excitation of an electromagnon in a multiferroic hexaferrite. One striking outcome is the different phase shifts relative to the driving field of the two different components. This phase shift provides insight into the excitation process of such a coupled mode. This direct observation of combined lattice and magnetization dynamics paves the way to access the mode-selective spin-lattice coupling strength, which remains a missing fundamental parameter for ultrafast control of magnetism and is relevant to a wide variety of materials.

Pneumocystis jirovecii pneumonia complicating methotrexate treatment in a patient with low-risk post-molar gestational trophoblastic neoplasia: A case report and review of the literature.

Low-risk gestational trophoblastic neoplasia (GTN) is generally treated with single agent chemotherapy, including methotrexate (MTX) or dactinomycin. We present a case of a patient with low-risk GTN who underwent single agent MTX therapy, developed Pneumocystis jirovecii pneumonia (PJP), recovered, and ultimately completed consolidation treatment for GTN on single agent MTX. While MTX administration is associated with an increased risk of PJP, this association is best described in rheumatology literature. This is the first case of PJP complicating MTX therapy within the gynecologic oncology literature.

The economy of pollen dispersal in flowering plants.

Mating success of flowering plants depends strongly on the efficiencies of pollen removal from flowers and its subsequent dispersal to conspecific stigmas. We characterized the economy of pollen dispersal in flowering plants by analysing pollen fates and their correlates for 228 species. The mean percentage of pollen removed from flowers (removal efficiency) varied almost twofold according to the type of pollen-dispersal unit, from less than 45% for orchids and milkweeds with solid pollinia, to greater than 80% for species with granular monads or sectile (segmented) pollinia. The mean percentage of removed pollen reaching stigmas (pollen transfer efficiency, PTE) varied from 2.4% for species with separate monads to 27.0% for orchids with solid pollinia. These values tended to be higher in plants with single pollinator species and in those with non-grooming pollinators. Nectar production increased removal efficiency, but did not influence PTE. Among types of pollen-dispersal units, the net percentage of produced pollen that was dispersed to stigmas varied negatively with removal efficiency and positively with PTE, indicating the relative importance of the latter for overall pollen economy. These findings confirm the key importance of floral traits, particularly pollen packaging, for pollen dispersal outcomes and highlight the under-appreciated pollination efficiency of non-grooming pollinators.

Nanophotonic and hydrogel-based diagnostic system for the monitoring of chronic wounds.

Chronic wounds present a major healthcare burden, yet most wounds are only assessed superficially, and treatment is rarely based on the analysis of wound biomarkers. This lack of analysis is based on the fact that sampling of wound biomarkers is typically invasive, leading to a disruption of the wound bed while biomarker detection and quantification is performed in a remote laboratory, away from the point of care. Here, we introduce the diagnostic element of a novel theranostic system that can non-invasively sample biomarkers without disrupting the wound and that can perform biomarker quantification at the point of care, on a short timescale. The system is based on a thermally switchable hydrogel scaffold that enhances wound healing through regeneration of the wound tissue and allows the extraction of wound biomarkers non-destructively. We demonstrate the detection of two major biomarkers of wound health, i.e., IL-6 and TNF-α, in human matrix absorbed into the hydrogel dressing. Quantification of the biomarkers directly in the hydrogel is achieved using a chirped guided mode resonant biosensor and we demonstrate biomarker detection within the clinically relevant range of pg/mL to µg/mL concentrations. We also demonstrate the detection of IL-6 and TNF-α at concentration 1 ng/mL in hydrogel dressing absorbed with clinical wound exudate samples. The high sensitivity and the wide dynamic range we demonstrate are both essential for the clinical relevance of our system. Our test makes a major contribution towards the development of a wound theranostic for guided treatment and management of chronic wounds.

Multimaterial fiber as a physical simulator of a capillary instability.

Capillary breakup of cores is an exclusive approach to fabricating fiber-integrated optoelectronics and photonics. A physical understanding of this fluid-dynamic process is necessary for yielding the desired solid-state fiber-embedded multimaterial architectures by design rather than by exploratory search. We discover that the nonlinearly complex and, at times, even chaotic capillary breakup of multimaterial fiber cores becomes predictable when the fiber is exposed to the spatiotemporal temperature profile, imposing a viscosity modulation comparable to the breakup wavelength. The profile acts as a notch filter, allowing only a single wavelength out of the continuous spectrum to develop predictably, following Euler-Lagrange dynamics. We argue that this understanding not only enables designing the outcomes of the breakup necessary for turning it into a technology for materializing fiber-embedded functional systems but also positions a multimaterial fiber as a universal physical simulator of capillary instability in viscous threads.

Short Sequence Aligner Benchmarking for Chromatin Research.

Much of today's molecular science revolves around next-generation sequencing. Frequently, the first step in analyzing such data is aligning sequencing reads to a reference genome. This step is often taken for granted, but any analysis downstream of the alignment will be affected by the aligner's ability to correctly map sequences. In most cases, for research into chromatin structure and nucleosome positioning, ATAC-seq, ChIP-seq, and MNase-seq experiments use short read lengths. How well aligners manage these reads is critical. Most aligner programs will output mapped reads and unmapped reads. However, from a biological point of view, reads will fall into one of three categories: correctly mapped, incorrectly mapped, and unmapped. While increased sequencing depth can often compensate for unmapped reads, incorrectly and correctly mapped reads appear algorithmically identical but can produce biologically significant alterations in the results. For this reason, we are benchmarking various alignment programs to determine their propensity to incorrectly map short reads. As short-read alignment is an important step in ATAC-seq, ChIP-seq, and MNase-seq experiments, caution should be taken in mapping reads to ensure that the most accurate conclusions can be made from the data generated. Our analysis is intended to help investigators new to the field pick the alignment program best suited for their experimental conditions. In general, the aligners we tested performed well. BWA, Bowtie2, and Chromap were all exceptionally accurate, and we recommend using them. Furthermore, we show that longer read lengths do in fact lead to more accurate mappings.