Doxycycline treatment of high-risk COVID-19-positive patients with comorbid pulmonary disease.

Infection with novel SARS-CoV-2 carries significant morbidity and mortality in patients with pulmonary compromise, such as lung cancer, autoimmune disease, and pneumonia. For early stages of mild to moderate disease, care is entirely supportive.Antiviral drugs such as remdesivir may be of some benefit but are reserved for severe cases given limited availability and potential toxicity. Repurposing of safer, established medications that may have antiviral activity is a possible approach for treatment of earlier-stage disease. Tetracycline and its derivatives (e.g. doxycycline and minocycline) are nontraditional antibiotics with a well-established safety profile, potential efficacy against viral pathogens such as dengue fever and chikungunya, and may regulate pathways important in initial infection, replication, and systemic response to SARS-CoV-2. We present a series of four high-risk, symptomatic, COVID-19+ patients, with known pulmonary disease, treated with doxycycline with subsequent rapid clinical improvement. No safety issues were noted with use of doxycycline.Doxycycline is an attractive candidate as a repurposed drug in the treatment of COVID-19 infection, with an established safety profile, strong preclinical rationale, and compelling initial clinical experience described here.The reviews of this paper are available via the supplemental material section.

Studies on the allostimulatory function of dendritic cells from HCV-HIV-1 co-infected patients.

There is increasing recognition of the potential morbidity and mortality associated with HIV-1 and hepatitis C (HCV) co-infection. HIV appears to adversely affect HCV disease while the reciprocal effect of HCV on HIV remains controversial. We therefore studied the effect of co-infection on dendritic cell function versus HIV infection alone, as previous work has shown that HCV impairs dendritic cell (DC) function. HIV-1 positive individuals with HCV were matched for CD4 count, HIV-1 RNA viral load and therapy, to HIV-1 positive patients without HCV. Monocyte-derived DC were generated and mixed leukocyte reactions were performed. We assessed allostimulatory capacity with and without administration of exogenous Th1 cytokines, using thymidine uptake and cell division analyses with the vital dye CFSE. We found that monocyte-derived DC from co-infected individuals showed no significant differences in allostimulatory capacity to ex vivo generated DC from HIV-1 infected individuals without HCV. Unlike the situation with HCV infection alone, this impairment was not reversed by increasing concentrations of either interleukin-2 or -12. Monocyte-derived DC from HIV-1 and HCV co-infected individuals have a similar allostimulatory capacity to DC from matched patients with HIV-1 alone. These findings are compatible with results of prior clinical studies that found no evidence that HCV co-infection altered HIV disease progression and has implications for immunotherapeutic approaches in co-infected individuals.

Topology and graph theory applied to cortical anatomy may help explain working memory capacity for three or four simultaneous items.

Cognitive experimentation suggests that at any single instant only three or four items ("chunks") are simultaneously prominent as a working memory (WM) trace, if we disregard the rehearsal component of WM. The reason for small WM capacity may concern combinatorial manageability. How might the neural representations of these few coactive chunks occupy a spatially distributed set of areas of the sheet-like cortex, while providing both order and flexibility to associate items in WM? Each attribute of each simultaneously active WM item must have broad access to the representational facilities of the cortical sheet, comprising tens of thousands of modular "cortical columns." The two hypothesized neural levels of WM during any moment of cognition comprise (a) "binding" together of many distributed attribute representations within each respective WM chunk, and (b) combinatorial play among three or four WM chunk-representations. Anatomical and functional evidence of cortical unity through its depth suggests that cortex may be viewed as essentially planar in its distribution of activations. Thus, a moment's WM is hypothesized here to reside in myriad activated cortical planar "patches," each subdivided into up to four amoeboid "subpatches." Two different lines of topological reasoning suggest orderly associations of such representations. (1) The four-color principle of map topology, and the related K(4) is planar theorem of graph theory, imply that if a small cortical area is dynamically subdivided into no more than four, discretely bounded planar subareas, then each such segment has ample free access to each of the others. (2) A hypothetical alternative to such associative adjacency of simultaneously active cortical representations of chunk-attributes is associative overlap, whereby, in dense cortical neuropil, activated subpatches behave like Venn diagrams of intersecting sets. As the number of Venn-like coactive subpatches within a patch increases, maintaining ad hoc associativity among all combinations requires exponentially proliferating intersections. Beyond four, serpentine subpatch shapes are required, which could easily lead to pathologies of omission or commission. As hypothesized by many researchers, the binding of the widely distributed cortical modules that represent a given chunk may involve synchrony or coherence of a single EEG frequency. Elsewhere, I have conjectured that such a binding frequency for a single chunk may bear a harmonic relationship with the additional EEG frequencies that are simultaneously binding the other WM chunks. Other possible mechanisms of binding have also been hypothesized. Whatever the mechanism, the many attributes of a moment's complement of three or four WM chunks must generally have an accidental relationship with the spatial distribution of the cortical feature analyzers that must be activated to represent those attributes. Therefore, the cortex may need, and have, comprehensive anatomical connections of each of its modules for representing an attribute (or of small redundant module groupings) with every other. If such whole-part cortico-cortical connections are somehow exploited not only to fully represent each cognitive chunk in its bound-together attributes, but also to bring the major business of intensive WM information processing down to the level of local circuits, in the sorts of topological patterning hypothesized here, there may be two adaptive results: (1) Time and other economies would be achieved in the reduction of activity in distant cortico-cortical connections to lower-energy global orchestration, or binding processes. (2) The piecemeal local topological limit to four subpatches would be writ large, across the entire cortex, preventing an unconstrained combinatorial explosion of associations among all attributes of all three or four simultaneously active chunks. Such hypothetical convergence to foci in local subpatch interactions might take place primarily in association cortex, and/or it might involve temporary shifts in response properties in some cortical subpat might involve temporary shifts in response properties in some cortical subpatches. Quantitative studies of the densely packed cortical fine structure, by Braitenberg and Schüz, and others, seem potentially consistent with this vision of cortical function in cognition.