Neutralizing monoclonal antibodies block human immunodeficiency virus type 1 infection of dendritic cells and transmission to T cells

Prevention of the initial infection of mucosal dendritic cells (DC) and interruption of the subsequent transmission of HIV-1 from DC to T cells are likely to be important attributes of an effective human immunodeficiency virus type 1 (HIV-1) vaccine. While anti-HIV-1 neutralizing antibodies have been difficult to elicit by immunization, there are several human monoclonal antibodies (MAbs) that effectively neutralize virus infection of activated T cells. We investigated the ability of three well-characterized neutralizing MAbs (IgG1b12, 2F5, and 2G12) to block HIV-1 infection of human DC. DC were generated from CD14+ blood cells or obtained from cadaveric human skin. The MAbs prevented viral entry into purified DC and the ensuing productive infection in DC/T-cell cultures. When DC were first pulsed with HIV-1, MAbs blocked the subsequent transmission to unstimulated CD3+ T cells. Thus, neutralizing antibodies can block HIV-1 infection of DC and the cell-to-cell transmission of virus from infected DC to T cells. These data suggest that neutralizing antibodies could interrupt the initial events associated with mucosal transmission and regional spread of HIV-1

A critical appraisal of guidelines for electronic communication between patients and clinicians: the need to modernize current recommendations

Background Patient-provider electronic communication has proliferated in recent years, yet there is a dearth of published research either leading to, or including, recommendations that improve clinical care and prevent unintended negative consequences. We critically appraise published guidelines and suggest an agenda for future work in this area. Objective To understand how existing guidelines align with current practice, evidence, and technology. Methods We performed a narrative review of provider-targeted guidelines for electronic communication between patients and providers, searching Ovid MEDLINE, Embase, and PubMed databases using relevant terms. We limited the search to articles published in English, and manually searched the citations of relevant articles. For each article, we identified and evaluated the suggested practices. Results Across 11 identified guidelines, the primary focus was on technical and administrative concerns, rather than on relational communication. Some of the security practices recommended by the guidelines are no longer needed because of shifts in technology. It is unclear the extent to which the recommendations that are still relevant are being followed. Moreover, there is no guideline-cited evidence of the effectiveness of the practices that have been proposed. Conclusion Our analysis revealed major weaknesses in current guidelines for electronic communication between patients and providers: the guidelines appear to be based on minimal evidence and offer little guidance on how best to use electronic tools to communicate effectively. Further work is needed to systematically evaluate and identify effective practices, create a framework to evaluate quality of communication, and assess the relationship between electronic communication and quality of care

Nonlinear equation for curved stationary flames

A nonlinear equation describing curved stationary flames with arbitrary gas expansion $\theta = \rho_{{\rm fuel}}/\rho_{{\rm burnt}}$, subject to the Landau-Darrieus instability, is obtained in a closed form without an assumption of weak nonlinearity. It is proved that in the scope of the asymptotic expansion for $\theta \to 1,$ the new equation gives the true solution to the problem of stationary flame propagation with the accuracy of the sixth order in $\theta - 1.$ In particular, it reproduces the stationary version of the well-known Sivashinsky equation at the second order corresponding to the approximation of zero vorticity production. At higher orders, the new equation describes influence of the vorticity drift behind the flame front on the front structure. Its asymptotic expansion is carried out explicitly, and the resulting equation is solved analytically at the third order. For arbitrary values of $\theta,$ the highly nonlinear regime of fast flow burning is investigated, for which case a large flame velocity expansion of the nonlinear equation is proposed.Comment: 29 pages 4 figures LaTe

Balancing torques in membrane-mediated interactions: Exact results and numerical illustrations

Torques on interfaces can be described by a divergence-free tensor which is fully encoded in the geometry. This tensor consists of two terms, one originating in the couple of the stress, the other capturing an intrinsic contribution due to curvature. In analogy to the description of forces in terms of a stress tensor, the torque on a particle can be expressed as a line integral along any contour surrounding the particle. Interactions between particles mediated by a fluid membrane are studied within this framework. In particular, torque balance places a strong constraint on the shape of the membrane. Symmetric two-particle configurations admit simple analytical expressions which are valid in the fully nonlinear regime; in particular, the problem may be solved exactly in the case of two membrane-bound parallel cylinders. This apparently simple system provides some flavor of the remarkably subtle nonlinear behavior associated with membrane-mediated interactions.Comment: 16 pages, 10 figures, REVTeX4 style. The Gaussian curvature term was included in the membrane Hamiltonian; section II.B was rephrased to smoothen the flow of presentatio

Kinetic energy and microcanonical nonanalyticities in finite and infinite systems

In contrast to the canonical case, microcanonical thermodynamic functions can show nonanalyticities also for finite systems. In this paper we contribute to the understanding of these nonanalyticities by working out the relation between nonanalyticities of the microcanonical entropy and its configurational counterpart. If the configurational microcanonical entropy $\omega_N^c(v)$ has a nonanalyticity at $v=v_c$, then the microcanonical entropy $\omega_N(\epsilon)$ has a nonanalyticity at the same value $\epsilon=v_c$ of its argument for any finite value of the number of degrees of freedom $N$. The presence of the kinetic energy weakens the nonanalyticities such that, if the configurational entropy is $p$ times differentiable, the entropy is $p+\lfloor N/2 \rfloor$-times differentiable. In the thermodynamic limit, however, the behaviour is very different: The nonanalyticities do not longer occur at the same values of the arguments, but the nonanalyticity of the microcanonical entropy is shifted to a larger energy. These results give a general explanation of the peculiar behaviour previously observed for the mean-field spherical model. With the hypercubic model we provide a further example illustrating our results.Comment: 14 pages, 2 figures; v2: minor corrections, final versio

A Mechanism Misregulating p27 in Tumors Discovered in a Functional Genomic Screen

The cyclin-dependent kinase inhibitor p27KIP1 is a tumor suppressor gene in mice, and loss of p27 protein is a negative prognostic indicator in human cancers. Unlike other tumor suppressors, the p27 gene is rarely mutated in tumors. Therefore misregulation of p27, rather than loss of the gene, is responsible for tumor-associated decreases in p27 protein levels. We performed a functional genomic screen in p27+/− mice to identify genes that regulate p27 during lymphomagenesis. This study demonstrated that decreased p27 expression in tumors resulted from altered transcription of the p27 gene, and the retroviral tagging strategy enabled us to pinpoint relevant transcription factors. inhibitor of DNA binding 3 (Id3) was isolated and validated as a transcriptional repressor of p27. We further demonstrated that p27 was a downstream target of Id3 in src-family kinase Lck-driven thymic lymphomagenesis and that p27 was an essential regulator of Lck-dependent thymic maturation during normal T-cell development. Thus, we have identified and characterized transcriptional repression of p27 by Id3 as a new mechanism decreasing p27 protein in tumors

Decline in subarachnoid haemorrhage volumes associated with the first wave of the COVID-19 pandemic

Background During the COVID-19 pandemic, decreased volumes of stroke admissions and mechanical thrombectomy were reported. The study’s objective was to examine whether subarachnoid haemorrhage (SAH) hospitalisations and ruptured aneurysm coiling interventions demonstrated similar declines. Methods We conducted a cross-sectional, retrospective, observational study across 6 continents, 37 countries and 140 comprehensive stroke centres. Patients with the diagnosis of SAH, aneurysmal SAH, ruptured aneurysm coiling interventions and COVID-19 were identified by prospective aneurysm databases or by International Classification of Diseases, 10th Revision, codes. The 3-month cumulative volume, monthly volumes for SAH hospitalisations and ruptured aneurysm coiling procedures were compared for the period before (1 year and immediately before) and during the pandemic, defined as 1 March–31 May 2020. The prior 1-year control period (1 March–31 May 2019) was obtained to account for seasonal variation. FindingsThere was a significant decline in SAH hospitalisations, with 2044 admissions in the 3 months immediately before and 1585 admissions during the pandemic, representing a relative decline of 22.5% (95% CI −24.3% to −20.7%, p Interpretation There was a relative decrease in the volume of SAH hospitalisations, aneurysmal SAH hospitalisations and ruptured aneurysm embolisations during the COVID-19 pandemic. These findings in SAH are consistent with a decrease in other emergencies, such as stroke and myocardial infarction

Insecure messaging: how clinicians approach potentially problematic messages from patients

Objective: Secure messaging has become an integrated function of patient portals, but misuse of secure messaging by both patients and clinicians can lead to miscommunication and errors, such as overlooked urgent messages. We sought to uncover variations in clinician approaches and responses to messaging with patients. Methods: In this two-part study, 20 primary care clinicians (1) composed message responses to five hypothetical patient vignettes and messages and (2) were subsequently interviewed for their perspectives on appropriate circumstances for secure messaging. Messages and interviews were analyzed for themes. Results: Clinicians have different experiences with, and perceptions of, secure messaging. The messages the clinicians wrote were uniformly respectful, but differed in degrees of patient-centeredness and level of detail. None of the clinicians found their messaging workload to be unmanageable. From the interviews, we found divergent clinician perspectives about when to use secure messaging and how to respond to emotional content. Conclusion: Clinicians have different opinions about the appropriateness of secure messaging in response to specific medical issues. Our results noted a desire and need for greater guidance about secure messaging. This aspect of informatics education warrants greater attention in clinical practice. Practical implications: We summarize the types of issues raised by the participants yet to be addressed by existing guidelines. Further guidance from hospitals, professional societies, and other institutions that govern clinician behavior on the appropriateness and effectiveness of delivering care through secure messaging may aid clinicians and patients

Cosmogenic ^(10)Be and ^(36)Cl geochronology of offset alluvial fans along the northern Death Valley fault zone: Implications for transient strain in the eastern California shear zone

The northern Death Valley fault zone (NDVFZ) has long been recognized as a major right-lateral strike-slip fault in the eastern California shear zone (ECSZ). However, its geologic slip rate has been difficult to determine. Using high-resolution digital topographic imagery and terrestrial cosmogenic nuclide dating, we present the first geochronologically determined slip rate for the NDVFZ. Our study focuses on the Red Wall Canyon alluvial fan, which exposes clean dextral offsets of seven channels. Analysis of airborne laser swath mapping data indicates ∼297 ± 9 m of right-lateral displacement on the fault system since the late Pleistocene. In situ terrestrial cosmogenic ^(10)Be and ^(36)Cl geochronology was used to date the Red Wall Canyon fan and a second, correlative fan also cut by the fault. Beryllium 10 dates from large cobbles and boulders provide a maximum age of 70 +22/−20 ka for the offset landforms. The minimum age of the alluvial fan deposits based on ^(36)Cl depth profiles is 63 ± 8 ka. Combining the offset measurement with the cosmogenic ^(10)Be date yields a geologic fault slip rate of 4.2 +1.9/−1.1 mm yr^(−1), whereas the ^(36)Cl data indicate 4.7 +0.9/−0.6 mm yr^(−1) of slip. Summing these slip rates with known rates on the Owens Valley, Hunter Mountain, and Stateline faults at similar latitudes suggests a total geologic slip rate across the northern ECSZ of ∼8.5 to 10 mm yr^(−1). This rate is commensurate with the overall geodetic rate and implies that the apparent discrepancy between geologic and geodetic data observed in the Mojave section of the ECSZ does not extend north of the Garlock fault. Although the overall geodetic rates are similar, the best estimates based on geology predict higher strain rates in the eastern part of the ECSZ than to the west, whereas the observed geodetic strain is relatively constant