To quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)-related hospitalization and illness severity in type 1 diabetes.
We conducted a prospective cohort study to identify ...case subjects with COVID-19 across a regional health care network of 137 service locations. Using an electronic health record query, chart review, and patient contact, we identified clinical factors influencing illness severity.
We identified COVID-19 in 6,138, 40, and 273 patients without diabetes and with type 1 and type 2 diabetes, respectively. Compared with not having diabetes, people with type 1 diabetes had adjusted odds ratios of 3.90 (95% CI 1.75-8.69) for hospitalization and 3.35 (95% CI 1.53-7.33) for greater illness severity, which was similar to risk in type 2 diabetes. Among patients with type 1 diabetes, glycosylated hemoglobin (HbA
), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity.
Diabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA
) had significant but modest impact compared with comparatively static factors (e.g., race and insurance) in type 1 diabetes, indicating an urgent and continued need to mitigate severe acute respiratory syndrome coronavirus 2 infection risk in this community.
Summary
Purpose: High‐frequency oscillations (HFOs), termed ripples at 80–200 Hz and fast ripples (FRs) at >200/250 Hz, recorded by intracranial electroencephalography (EEG), may be a valuable ...surrogate marker for the localization of the epileptogenic zone. We evaluated the relationship of the resection of focal brain regions containing high‐rate interictal HFOs and the seizure‐onset zone (SOZ) determined by visual EEG analysis with the postsurgical seizure outcome, using extraoperative intracranial EEG monitoring in pediatric patients and automated HFO detection.
Methods: We retrospectively analyzed 28 pediatric epilepsy patients who underwent extraoperative intracranial video‐EEG monitoring prior to focal resection. Utilizing the automated analysis, we identified interictal HFOs during 20 min of sleep EEG and determined the brain regions containing high‐rate HFOs. We investigated spatial relationships between regions with high‐rate HFOs and SOZs. We compared the size of these regions, the surgical resection, and the amount of the regions with high‐rate HFOs/SOZs within the resection area with seizure outcome.
Key Findings: Ten patients were completely seizure‐free and 18 were not at 2 years after surgery. The brain regions with high‐rate ripples were larger than those with high‐rate FRs (p = 0.0011) with partial overlap. More complete resection of the regions with high‐rate FRs significantly correlated with a better seizure outcome (p = 0.046). More complete resection of the regions with high‐rate ripples tended to improve seizure outcome (p = 0.091); however, the resection of SOZ did not influence seizure outcome (p = 0.18). The size of surgical resection was not associated with seizure outcome (p = 0.22–0.39).
Significance: The interictal high‐rate FRs are a possible surrogate marker of the epileptogenic zone. Interictal ripples are not as specific a marker of the epileptogenic zone as interictal FRs. Resection of the brain regions with high‐rate interictal FRs in addition to the SOZ may achieve a better seizure outcome.
Type III secretion systems (T3SSs) are protein transport nanomachines that are found in Gram-negative bacterial pathogens and symbionts. Resembling molecular syringes, T3SSs form channels that cross ...the bacterial envelope and the host cell membrane, which enable bacteria to inject numerous effector proteins into the host cell cytoplasm and establish trans-kingdom interactions with diverse hosts. Recent advances in cryo-electron microscopy and integrative imaging have provided unprecedented views of the architecture and structure of T3SSs. Furthermore, genetic and molecular analyses have elucidated the functions of many effectors and key regulators of T3SS assembly and secretion hierarchy, which is the sequential order by which the protein substrates are secreted. As essential virulence factors, T3SSs are attractive targets for vaccines and therapeutics. This Review summarizes our current knowledge of the structure and function of this important protein secretion machinery. A greater understanding of T3SSs should aid mechanism-based drug design and facilitate their manipulation for biotechnological applications.
The phylum Apicomplexa comprises a group of obligate intracellular parasites of broad medical and agricultural significance, including Toxoplasma gondii and the malaria-causing Plasmodium spp. Key to ...their parasitic lifestyle is the need to egress from an infected cell, actively move through tissue, and reinvade another cell, thus perpetuating infection. Ca(2+)-mediated signaling events modulate key steps required for host cell egress, invasion and motility, including secretion of microneme organelles and activation of the force-generating actomyosin-based motor. Here we show that a plant-like Calcium-Dependent Protein Kinase (CDPK) in T. gondii, TgCDPK3, which localizes to the inner side of the plasma membrane, is not essential to the parasite but is required for optimal in vitro growth. We demonstrate that TgCDPK3, the orthologue of Plasmodium PfCDPK1, regulates Ca(2+) ionophore- and DTT-induced host cell egress, but not motility or invasion. Furthermore, we show that targeting to the inner side of the plasma membrane by dual acylation is required for its activity. Interestingly, TgCDPK3 regulates microneme secretion when parasites are intracellular but not extracellular. Indeed, the requirement for TgCDPK3 is most likely determined by the high K(+) concentration of the host cell. Our results therefore suggest that TgCDPK3's role differs from that previously hypothesized, and rather support a model where this kinase plays a role in rapidly responding to Ca(2+) signaling in specific ionic environments to upregulate multiple processes required for gliding motility.
The 2013–2016 West Africa Ebola virus disease pandemic was the largest, longest, deadliest, and most geographically expansive outbreak in the 40-year interval since Ebola was first identified. ...Fear-related behaviors played an important role in shaping the outbreak. Fear-related behaviors are defined as “individual or collective behaviors and actions initiated in response to fear reactions that are triggered by a perceived threat or actual exposure to a potentially traumatizing event. FRBs modify the future risk of harm.” This review examines how fear-related behaviors were implicated in (1) accelerating the spread of Ebola, (2) impeding the utilization of life-saving Ebola treatment, (3) curtailing the availability of medical services for treatable conditions, (4) increasing the risks for new-onset psychological distress and psychiatric disorders, and (5) amplifying the downstream cascades of social problems. Fear-related behaviors are identified for each of these outcomes. Particularly notable are behaviors such as treating Ebola patients in home or private clinic settings, the “laying of hands” on Ebola-infected individuals to perform faith-based healing, observing hands-on funeral and burial customs, foregoing available life-saving treatment, and stigmatizing Ebola survivors and health professionals. Future directions include modeling the onset, operation, and perpetuation of fear-related behaviors and devising strategies to redirect behavioral responses to mass threats in a manner that reduces risks and promotes resilience.
The exploration of a diarylsulfonamide series of free fatty acid receptor 4 (FFA4/GPR120) agonists is described. This work led to the identification of selective FFA4 agonist 8 (GSK137647A) and ...selective FFA4 antagonist 39. The in vitro profile of compounds 8 and 39 is presented herein.
Although seizures are a hallmark feature of temporal lobe epilepsy (TLE), psychiatric comorbidities, including psychosis, are frequently associated with TLE and contribute to decreased quality of ...life. Currently, there are no defined therapeutic protocols to manage psychosis in TLE patients, as antipsychotic agents may induce epileptic seizures and are associated with severe side effects and pharmacokinetic and pharmacodynamic interactions with antiepileptic drugs. Thus, novel treatment strategies are necessary. Several lines of evidence suggest that hippocampal hyperactivity is central to the pathology of both TLE and psychosis; therefore, restoring hippocampal activity back to normal levels may be a novel therapeutic approach for treating psychosis in TLE. In rodent models, increased activity in the ventral hippocampus (vHipp) results in aberrant dopamine system function, which is thought to underlie symptoms of psychosis. Indeed, we have previously demonstrated that targeting α5-containing γ-aminobutyric acid receptors (α5GABAARs), an inhibitory receptor abundant in the hippocampus, with positive allosteric modulators (PAMs), can restore dopamine system function in rodent models displaying hippocampal hyperactivity. Thus, we posited that α5-PAMs may be beneficial in a model used to study TLE. Here, we demonstrate that pilocarpine-induced TLE is associated with increased VTA dopamine neuron activity, an effect that was completely reversed by intra-vHipp administration of GL-II-73, a selective α5-PAM. Further, pilocarpine did not alter the hippocampal α5GABAAR expression or synaptic localization that may affect the efficacy of α5-PAMs. Taken together, these results suggest augmenting α5GABAAR function as a novel therapeutic modality for the treatment of psychosis in TLE.
The goal of this study was to examine rates of psychotropic medication use and identify associated child and family characteristics among children and adolescents with autism spectrum disorder (ASD) ...enrolled in an autism registry maintained by the Autism Treatment Network (ATN).
The sample, derived from the ATN registry, consists of 2853 children aged 2 to 17 years with diagnoses of ASD supported by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Autism Diagnostic Observation Schedule with available data on medication use. As part of initial enrollment in the registry, parents completed questionnaires on current psychotropic medication use, psychiatric and medical conditions, and demographics.
Of the 2853 children, 763 (27%) were taking ≥ 1 psychotropic medication; 15% were prescribed 1 medication, 7.4% received 2 medications, and 4.5% received ≥ 3. Among children aged 3 to 5 years, 11% were taking ≥ 1 psychotropic medication; among 6- to 11-year-old children, 46%; and 66% of adolescents aged 12 to 17 years were taking at ≥ 1 psychotropic medication. A parent report of comorbid diagnosis of attention-deficit/hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, depression, or anxiety was associated with a high rate of use, with 80% receiving ≥ 1 psychotropic medication. Only 15% of children with no comorbid psychiatric disorder were taking psychotropic medication. Psychotropic medication use was also related to sleep and gastrointestinal problems.
The prescription of psychotropic medications in this registry sample is highly related to comorbid psychiatric disorder. Other factors associated with use include medical comorbidities, race, ethnicity, and older age.
Ester and amide derivatives of hydroxycinnamic acids are found in black cohosh (
Actaea racemosa
) and other
Actaea
plants. These two compound groups were evaluated for authentication of black cohosh ...dietary supplements. The hydroxycinnamic acid esters (HCAE) were profiled by ultra-performance liquid chromatography-photodiode array detection (UPLC-PDA). The hydroxycinnamic acid amides (HCAA) were acquired simultaneously by mass spectrometry-multiple reaction monitoring (UPLC-MRM) mode. In contrast with the traditional HCAE method using 8 compounds, profiles of HCAA using only 4 feruloyl dopamine-
O
-hexosides was more convenient for peak by peak comparison. Partial least square discriminant analysis (PLS-DA) was applied to both HCAE and HCAA datasets. Authenticated plant samples of five
Actaea
species were randomly divided into training and test sets to build and validate the two PLS-DA models. Both models provided reasonable estimates for the classification of
A. racemosa
and other
Actaea
plant samples. However, HCAA model performs better in sensitivity, specificity, and accuracy. Assessment of supplement samples provided quite different results for the solid and liquid dietary supplement samples, indicating the dosage form could affect the composition of marker compounds.
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