The clinical impact of maternal COVID-19 on mothers, their infants, and placentas with an analysis of vertical transfer of maternal SARS-CoV-2-specific IgG antibodies.

INTRODUCTION: The effect of SARS-CoV-2 severity or the trimester of infection in pregnant mothers, placentas, and infants is not fully understood. METHODS: A retrospective, observational cohort study in Chapel Hill, NC of 115 mothers with SARS-CoV-2 and singleton pregnancies from December 1, 2019 to May 31, 2021 via chart review to document the infants' weight, length, head circumference, survival, congenital abnormalities, hearing loss, maternal complications, and placental pathology classified by the Amsterdam criteria. RESULTS: Of the 115 mothers, 85.2% were asymptomatic (n = 37) or had mild (n = 61) symptoms, 13.0% had moderate (n = 9) or severe (n = 6) COVID-19, and 1.74% (n = 2) did not have symptoms recorded. Moderate and severe maternal infections were associated with increased C-section, premature delivery, infant NICU admission, and were more likely to occur in Type 1 (p = 0.0055) and Type 2 (p = 0.0285) diabetic mothers. Only one infant (0.870%) became infected with SARS-CoV-2, which was not via the placenta. Most placentas (n = 63, 54.8%) did not show specific histologic findings; however, a subset showed mild maternal vascular malperfusion (n = 26, 22.6%) and/or mild microscopic ascending intrauterine infection (n = 28, 24.3%). The infants had no identifiable congenital abnormalities, and all infants and mothers survived. DISCUSSION: Most mothers and their infants had a routine clinical course; however, moderate and severe COVID-19 maternal infections were associated with pregnancy complications and premature delivery. Mothers with pre-existing, non-gestational diabetes were at greatest risk of developing moderate or severe COVID-19. The placental injury patterns of maternal vascular malperfusion and/or microscopic ascending intrauterine infection were not associated with maternal COVID-19 severity.

'TAG, You're It!' The high-stakes game of handovers in the Emergency Department ­ Improving handover quality using a new 'TAG' Protocol

Aim To assess handover quality amongst Emergency Department (ED) physicians and improve quality by implementing a unique protocol entitled 'TAG, You're It!' (TAG protocol). Methods Patient charts assessed using set parameters prior to implementation of the 'TAG' protocol. 'TAG' protocol developed based on gaps in current practice and recommendations from literature. Identical parameters applied post-intervention, and results compared to those pre-intervention. Results 'TAG' protocol yielded positive impact on ED handover practices. A significant difference (p<0.05) between pre and post-TAG intervention values was seen across all parameters i.e. including the accepting physician's name in the computer system and ED chart, documenting a handover plan in the ED chart, and including a handover plan deemed sufficient by standards developed from relevant literature. Conclusion Shift-to-shift handover in the ED is a high risk time for patient safety. The 'TAG' protocol ensures that essential information is documented and communicated in a succinct and rapid way.

More new deep-reef basslets (Teleostei, Grammatidae, Lipogramma), with updates on the eco-evolutionary relationships within the genus.

Two new Lipogramma basslets are described, L. barrettorum and L. schrieri, captured during submersible diving to 300 m depth off Curaçao, southern Caribbean. Superficially resembling L. robinsi in having 11-12 bars of pigment on the trunk, L. barrettorum is distinct from L. robinsi in having a stripe of blue-white pigment along the dorsal midline of the head (vs. a cap of yellow pigment), in patterns of pigment on the median fins, and in having 8-10 gill rakers on the lower limb of the first arch (vs. 11-12). Lipogramma schrieri is distinct from all congeners in having seven or eight dark bars of pigment on the trunk and broad, irregular, whitish blue markings on the dorsal portion of the head. The new species are genetically distinct from one another and from seven other Lipogramma species for which genetic data are available. A phylogenetic hypothesis derived from mitochondrial and nuclear genes suggests that the new species belong to a clade that also comprises L. evides and L. haberi. Collectively those four species are the deepest-living members of the genus, occurring at depths predominantly below 140 m. This study thus provides further evidence of eco-evolutionary correlations between depth and phylogeny in Caribbean reef fishes. Tropical deep reefs are globally underexplored ecosystems, and further investigation of Caribbean deep reefs undoubtedly will provide samples of species for which no genetic material currently exists and reveal more cryptic species diversity in the genus.

Toward personalized medicine of lung cancer: response to nontargeted therapy in invasive pulmonary adenocarcinoma as a function of tumor cell differentiation.

We evaluated clinical parameters, histomorphology, and thyroid transcription factor 1 (TTF-1) immunoreactivity in 40 epidermal growth factor receptor (EGFR) mutation- and anaplastic lymphoma kinase (ALK) rearrangement-negative invasive pulmonary adenocarcinomas. Tumors were histomorphologically quantitated by a pulmonary pathologist and TTF-1 immunohistochemistry applied. EGFR mutation and ALK rearrangement status was determined with polymerase chain reaction/DNA sequencing and fluorescence in situ hybridization, respectively. Treatment response was related to type of treatment (P < .005) and clinical stage (P = .001). EGFR mutation- and ALK rearrangement-negative pulmonary adenocarcinomas containing papillary/micropapillary histology showed greater morphologic heterogeneity (P < .001), greater TTF-1 immunoreactivity (P = .004), and were more common in treatment responders (P < .05). These findings support that patients with pulmonary adenocarcinomas that are subject to nontargeted therapies may respond to treatment as a function of tumor cell differentiation with TTF-1 as a potential biomarker of this response.

Dressed return maps distinguish chaotic mechanisms.

Chaotic data generated by a three-dimensional dynamical system can be embedded into R(3) in a number of inequivalent ways. However, when lifted into R(5) they all become equivalent, indicating that they all belong to a single universality class sharing a common chaos-generating mechanism. We present a complete invariant determining this universality class and distinguishing attractors generated by distinct mechanisms. This invariant is easily computable from an appropriately "dressed" return map of any particular three-dimensional embedding.

Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders.

BACKGROUND: The European Network of Rare Bleeding Disorders (EN-RBD) was established to bridge the gap between knowledge and practise in the care of patients with RBDs. OBJECTIVES: To explore the relationship between coagulation factor activity level and bleeding severity in patients with RBDs. PATIENTS/METHODS: Cross-sectional study using data from 489 patients registered in the EN-RBD. Coagulation factor activity levels were retrieved. Clinical bleeding episodes were classified into four categories according to severity. RESULTS: The mean age of patients at data collection was 31 years (range, 7 months to 95 years), with an equal sex distribution. On linear regression analysis, there was a strong association between coagulation factor activity level and clinical bleeding severity for fibrinogen, factor (F) X, FXIII, and combined FV and FVIII deficiencies. A weaker association was present for FV and FVII deficiencies. There was no association between coagulation factor activity level and clinical bleeding severity for FXI. The coagulation factor activity levels that were necessary for patients to remain asymptomatic were: fibrinogen, > 100 mg dL(-1); FV, 12 U dL(-1); combined FV + VIII, 43 U dL(-1); FVII, 25 U dL(-1); FX, 56 U dL(-1) ; FXI, 26 U dL(-1); FXIII, 31 U dL(-1). Moreover, coagulation factor activity levels that corresponded with Grade III bleeding were: undetectable levels for fibrinogen, FV and FXIII, < 15 U dL(-1) for combined FV + VIII; < 8 U dL(-1) for FVI; < 10 U dL(-1) for FX; and < 25 U dL(-1) for FXI. CONCLUSIONS: There is a heterogeneous association between coagulation factor activity level and clinical bleeding severity in different RBDs. A strong association is only observed in fibrinogen, FX and FXIII deficiencies.

Low risk of inhibitor formation in haemophilia A patients following en masse switch in treatment to a third generation full length plasma and albumin-free recombinant factor VIII product (ADVATE®).

Previous studies have suggested that development of inhibitors in previously treated patients (PTPs) may be attributable to a switch in factor VIII (FVIII) therapeutic product. Consequently, it is widely recognized that inhibitor development must be assessed in PTPs following the introduction of any new FVIII product. Following a national tender process in 2006, all patients with haemophilia A in Ireland changed their FVIII treatment product en masse to a plasma and albumin-free recombinant full-length FVIII product (ADVATE(®)). In this study, we retrospectively reviewed the case records of Irish PTPs to evaluate risk of inhibitor formation following this treatment switch. One hundred and thirteen patients participated in the study. Most patients (89%) had severe haemophilia. Only one of 96 patients with no inhibitor history developed an inhibitor. Prior to the switch in his recombinant FVIII (rFVIII) treatment of choice, this child had only experienced three exposure days (EDs). Consequently, in total he had only received 6 EDs when his inhibitor was first diagnosed. In keeping with this lack of de novo inhibitor development, we observed no evidence of any recurrent inhibitor formation in any of 16 patients with previously documented inhibitors. Similarly, following a previous en masse switch, we have previously reported that changing from a Chinese hamster ovary cell-produced to a baby hamster kidney cell-produced rFVIII was also associated with a low risk of inhibitor formation in PTPs. Our cumulative findings from these two studies clearly emphasizes that the risk of inhibitor development for PTPs following changes in commercial rFVIII product is low, at least in the Irish population.

Differential embedding of the Lorenz attractor.

Ideally an embedding of an N -dimensional dynamical system is N -dimensional. Ideally, an embedding of a dynamical system with symmetry is symmetric. Ideally, the symmetry of the embedding is the same as the symmetry of the original system. This ideal often cannot be achieved. Differential embeddings of the Lorenz system, which possesses a twofold rotation symmetry, are not ideal. While the differential embedding technique happens to yield an embedding of the Lorenz attractor in three dimensions, it does not yield an embedding of the entire flow. An embedding of the flow requires at least four dimensions. The four dimensional embedding produces a flow restricted to a twisted three dimensional manifold in R4. This inversion symmetric three-manifold cannot be projected into any three dimensional Euclidean subspace without singularities.

Thrombin generation in haemophilia A patients with mutations causing factor VIII assay discrepancy.

Up to 40% of patients with mild haemophilia A have a discrepancy whereby factor VIII (FVIII) measurements by a two-stage chromogenic assay (FVIII:C(CH)) are disproportionately reduced compared with the FVIII one-stage clotting value (FVIII:C). Which assay best reflects the coagulation potential and clinical phenotype in this patient group is of clinical significance, yet remains unclear. We have assessed the global coagulant ability of haemophilia patients with FVIII assay discrepancy using calibrated automated thrombography (CAT). A total of 18 patients with mutations Arg531His/Cys or Arg698Trp causing FVIII discrepancy were investigated, together with 12 haemophilia patients with concordant FVIII values and 15 normal controls. Factor VIII levels in all patients and controls were measured using both one-stage clotting assay and two-stage chromogenic assay. Thrombin generation was assessed in platelet-poor plasma by CAT using a low tissue factor concentration (1 pm). FVIII:C(CH) values were below normal in all patients, and in the discrepant group were between 1.5- and 8-fold lower than FVIII:C values. CAT parameters were affected in all haemophilia patients. The endogenous thrombin potential (ETP) was reduced to 58-67% of the mean normal value (1301 nm min(-1)), whereas peak thrombin was further reduced to 27-30% of the mean normal value (178 nm) in both discrepant and concordant patient groups. Analysis of the discrepant patient group showed the most significant correlation between the one-stage FVIII:C assay and ETP (r(2) = 0.44) and peak thrombin parameters (r(2) = 0.27).

Complete set of representations for dissipative chaotic three-dimensional dynamical systems.

Embeddings are diffeomorphisms between some dynamical phase space and a reconstructed image. Different embeddings may or may not be equivalent under isotopy. We regard embeddings as representations of the dynamical phase space. We determine the topological labels required to distinguish inequivalent representations of three-dimensional dissipative dynamical systems when the embeddings are into R(k), k=3,4,5,…. Three representation labels are required for embeddings into R³, and only one is required in R4. In R5 there is a single "universal" representation.

Spatio-temporal tuning of coherent motion evoked responses in 4-6 month old infants and adults.

Motion cues provide a rich source of information about translations of the observer through the environment as well as the movements of objects and surfaces. While the direction of motion can be extracted locally these local measurements are, in general, insufficient for determining object and surface motions. To study the development of local and global motion processing mechanisms, we recorded Visual Evoked Potentials (VEPs) in response to dynamic random dot displays that alternated between coherent rotational motion and random motion at 0.8 Hz. We compared the spatio-temporal tuning of the evoked response in 4-6 months old infants to that of adults by recording over a range of dot displacements and temporal update rates. Responses recorded at the frequency of the coherent motion modulation were tuned for displacement at the occipital midline in both adults in infants. Responses at lateral electrodes were tuned for speed in adults, but not in infants. Infant responses were maximal at a larger range of spatial displacement than that of adults. In contrast, responses recorded at the dot-update rate showed a more similar parametric displacement tuning and scalp topography in infants and adults. Taken together, our results suggest that while local motion processing is relatively mature at 4-6 months, global integration mechanisms exhibit significant immaturities at this age.

Management of refractory venous thrombosis associated with malignancy using a supra-therapeutic enoxaparin regimen.

For many years, it has been recognised that venous thrombo-embolism (VTE) represents a common complication of malignancy. Moreover, VTE in the form of pulmonary embolism (PE) is life-threatening, and constitutes the second leading cause of death in patients with cancer. Consequently, overall survival is significantly reduced in cancer patients who develop thrombosis. In addition, treatment of VTE with anticoagulation is often difficult to manage in the context of cancer. Studies have shown that the risk of recurrent VTE, and the risk of major bleeding are both increased significantly in cancer patients on therapeutic anticoagulant therapy. In this case report, we describe a patient with metastatic carcinoma of the cervix, who developed recurrent thrombotic complications despite being maintained on standard therapeutic doses of both warfarin, and subsequently low molecular weight heparin. However, her refractory VTE was successfully managed using a supra-therapeutic dose low-molecular-weight-heparin (LMWH) regimen, together with close monitoring of plasma anti-Xa levels.

Representation theory for strange attractors.

Embeddings are diffeomorphisms between some unseen physical attractor and a reconstructed image. Different embeddings may or may not be equivalent under isotopy. We regard embeddings as representations of the attractor, review the labels required to distinguish inequivalent representations for an important class of dynamical systems, and discuss the systematic ways inequivalent embeddings become equivalent as the embedding dimension increases until there is finally only one "universal" embedding in a suitable dimension.

Activated protein C resistance, factor V Leiden and assessment of thrombotic risk.

Venous thromboembolism comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). Acute venous thromboembolism (VTE) is a serious and potentially fatal disorder which often complicates the course of hospitalized patients, but also affects ambulatory and otherwise healthy people. The annual incidence of venous thromboembolism is 1 to 2 cases per 1000 person and the risk of the disorder rises exponentially with age, from an annual rate of less than 5 per 100,000 children to greater than 400 per 100,000 adults older than 80 years.

Comparison of tests for embeddings.

It is possible to compare results for the classical tests for embeddings of chaotic data with the results of a recently proposed test. The classical tests, which depend on real numbers (fractal dimensions, Lyapunov exponents) averaged over an attractor, are compared with a topological test that depends on integers. The comparison can only be done for mappings into three dimensions. We find that the classical tests fail to predict when a mapping is an embedding and when it is not. We point out the reasons for this failure, which are not restricted to three dimensions.

Knowledge of signs, treatment and need for urgent management in patients presenting with an acute ischaemic stroke or transient ischaemic attack: a prospective study.

OBJECTIVE: To assess stroke awareness among patients presenting to the emergency department with an acute ischaemic stroke or transient ischaemic attack (TIA). METHODS: A consecutive cohort of patients presenting with a cerebrovascular event was prospectively enrolled over a 15-month period and questionnaires were administered. If the patient was unable to respond to the questions or answer the questionnaire, it was administered to the primary caregiver. Comprehension of having a cerebrovascular event, reason for delay in presentation, mode of arrival and knowledge of treatment modalities were determined. RESULTS: Only 42% of 400 patients thought they were having a stroke or TIA. The median time to presentation was 3.4 h. Delayed presentation was almost equal in men and women. When asked about onset, 19.4% thought that a stroke came on gradually and only 51.9% thought immediate presentation was crucial. 20.8% of patients had heard of thrombolysis. CONCLUSION: Community knowledge of ischaemic stroke needs to be enhanced so that individuals present earlier, leading to timely management.

When are projections also embeddings?

We study an autonomous four-dimensional dynamical system used to model certain geophysical processes. This system generates a chaotic attractor that is strongly contracting, with four Lyapunov exponents lambdai that satisfy lambda1+lambda2+lambda3<0 , so the Lyapunov dimension is DL=2+|lambda3|/lambda1<3 in the range of coupling parameter values studied. As a result, it should be possible to find three-dimensional spaces in which the attractors can be embedded so that topological analyses can be carried out to determine which stretching and squeezing mechanisms generate chaotic behavior. We study mappings into R3 to determine which can be used as embeddings to reconstruct the dynamics. We find dramatically different behavior in the two simplest mappings: projections from R4 to R3 . In one case the one-parameter family of attractors studied remains topologically unchanged for all coupling parameter values. In the other case, during an intermediate range of parameter values the projection undergoes self-intersections, while the embedded attractors at the two ends of this range are topologically mirror images of each other.

Pol I transcription and pre-rRNA processing are coordinated in a transcription-dependent manner in mammalian cells.

Pre-rRNA synthesis and processing are key steps in ribosome biogenesis. Although recent evidence in yeast suggests that these two processes are coupled, the nature of their association is unclear. In this report, we analyze the coordination between rDNA transcription and pre-rRNA processing in mammalian cells. We found that pol I transcription factor UBF interacts with pre-rRNA processing factors as analyzed by immunoprecipitations, and the association depends on active rRNA synthesis. In addition, injections of plasmids containing the human rDNA promoter and varying lengths of 18S rDNA into HeLa nuclei show that pol I transcription machinery can be recruited to rDNA promoters regardless of the product that is transcribed, whereas subgroups of pre-rRNA processing factors are recruited to plasmids only when specific pre-rRNA fragments are produced. Our observations suggest a model for sequential recruitment of pol I transcription factors and pre-rRNA processing factors to elongating pre-rRNA on an as-needed basis rather than corecruitment to sites of active transcription.