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Abstract We describe the development and analysis of a new teletherapy modality that, through a novel approach to targeted radiation delivery, has the potential to provide greater conformality than conventional photon-based treatments. The proposed system uses an X-ray lens to reflect photons from a conventional X-ray tube toward a focal spot. The resulting dose distributions have a highly localized peak dose, with lower doses in the converging radiation cone. Physical principles governing the design of this system are presented, along with a series of measurements analyzing various characteristics of the converging beam. The beam was designed to be nearly monoenergetic (~ 59 keV), with an energy bandwidth of approximately 10 keV allowing for treatment energies lower than conventional therapies. The focal spot was measured to be approximately 2.5 cm long and 4 mm wide. Mounting the proposed X-ray delivery system on a robotic arm would allow sub-millimeter accuracy in focal spot positioning, resulting in highly conformal dose distribution via the optimal placement of individual focal spots within the target volume. Aspects of this novel radiation beam are discussed considering their possible clinical application as a treatment approach that takes maximum advantage of the unique properties afforded by converging X-ray beam therapy.

Background: Latency remains a major obstacle to finding a cure for HIV despite the availability of antiretroviral therapy. Due to virus dormancy, limited biomarkers are available to identify latent HIV-infected cells. Profiling of individual HIV-infected cells is needed to explore potential latency biomarkers and to study the mechanisms of persistence that maintain the HIV reservoir. Methods: Single cell spatial transcriptomic characterization using the CosMx Spatial Molecular Imager platform was conducted to analyze HIV-infected cells in formalin-fixed paraffin-embedded sections of splenic tissue surgically obtained from an HIV-infected humanized mouse model. Regulation of over a thousand human genes was quantified in both viremic and aviremic specimens. In addition, in situ hybridization and immunohistochemistry were performed in parallel to identify HIV viral RNA- and p24-containing cells, respectively. Finally, initial findings from CosMx gene profiling were confirmed by isolating RNA from CD4 + T cells obtained from a person living with HIV on antiretroviral therapy following either PMA/Ionomycin or DMSO treatment. RNA was quantified using qPCR for a panel of targeted human host genes. Results: Supervised cell typing revealed that most of the HIV-infected cells in the mouse spleen sections were differentiated CD4 + T cells. A significantly higher number of infected cells, 2781 (1.61%) in comparison to 112 (0.06%), and total HIV transcripts per infected cell were observed in viremic samples compared to aviremic samples, respectively, which was consistent with the data obtained from ISH and IHC. Notably, the expression of 55 genes was different in infected cells within tissue from aviremic animals compared to viremic. In particular, both spleen tyrosine kinase (SYK) and CXCL17, were expressed approximately 100-fold higher. This data was further evaluated against bulk RNA isolated from HIV-infected human primary CD4 + T cells. A nearly 6-fold higher expression of SYK mRNA was observed in DMSO-treated CD4 + T cells compared to those stimulated with PMA/Ionomycin. Conclusion: This study found that the CosMx SMI platform is valuable for assessing HIV infection and providing insights into host biomarkers associated with HIV reservoirs. Higher relative expression of the SYK gene in aviremic-infected cells from the humanized mouse HIV model was consistent with levels found in CD4 + T cells of aviremic donors. [ABSTRACT FROM AUTHOR]

Transcatheter mitral valve repair using the MitraClip (Abbott Vascular, Santa Clara, CA) is a reasonable option for the treatment of patients with severe symptomatic degenerative mitral regurgitation (MR) who are at prohibitive surgical risk. The occurrence of recurrent severe MR after initial successful MitraClip repair is uncommon. Data are sparse on the management of recurrent severe MR after initial successful repair using the MitraClip. We describe a successful case of redo MitraClip repair for late recurrent severe MR secondary to progressive degenerative mitral valve disease after a successful initial MitraClip procedure and review the literature. Résumé: La réparation transcathéter de la valve mitrale au moyen d’un dispositif MitraClip (Abbott Vascular, Santa Clara, CA) constitue une bonne option pour le traitement de l’insuffisance mitrale (IM) dégénérative symptomatique grave lorsque la chirurgie représente un risque prohibitif pour le patient. Il est rare qu’une IM grave récurrente survienne après l’implantation réussie d’un dispositif MitraClip. On dispose de très peu de données sur la prise en charge de l’IM grave récurrente après une première réparation au moyen d’un dispositif MitraClip. Nous présentons le cas d’une seconde réparation au moyen d’un dispositif MitraClip pour remédier à une IM grave récurrente tardive secondaire à une atteinte dégénérative évolutive de la valve mitrale survenue après une première intervention efficace au moyen d’un dispositif MitraClip, et nous passons en revue les publications portant sur cette question.

This article outlines a pilot study conducted with persisting and non-persisting students in a mid-sized public university in the West. Based on those findings, a retention initiative was developed. The study and initiative both utilize the ASCA [American School Counselor Association] framework, making a case that this model has application in institutions of higher education as well as public schools. The significance of collaborations between school counseling programs and college advising centers is also portrayed.

This case demonstrates the feasibility and procedural success of a novel supra-annular transcatheter mitral valve, the AltaValve via transapical approach in a patient with severe symptomatic mitral regurgitation who was a prohibitive surgical risk candidate. (Level of Difficulty: Advanced.)

Clearance of apoptotic neutrophils by macrophages is important for the resolution of inflammation. Here, the authors show that interferon-β produced by resolution phase macrophages promotes neutrophil apoptosis and efferocytosis and induces macrophage reprogramming to a pro-resolving phenotype, thereby identifying IFN-β as a multi-pronged pro-resolution cytokine.

Introduction HIV cure remains elusive because of latent but replication-competent HIV DNA within host [CD4.sup.+] T cells during long-term suppressive antiretroviral therapy (ART) (1, 2). HIV latency is maintained by [...], Latency reveRsaI strategies for HIV cure using inhibitor of apoptosis protein (IAP) antagonists (IAPi) induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reveRsaI with bromodomain (BD) and extraterminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single-cell RNA-Seq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bD-selective BET, or selective BET isoform targeting in [CD4.sup.+] T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA, but lesser induction of fully elongated and tat-rev RNA compared with T cell activation-positive controls. IAPi+BETi resulted in HIV protein induction in bulk cultures of [CD4.sup.+] T cells using an ultrasensitive p24 assay, but did not result in enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. This study defines HIV transcriptional elongation and splicing as important barriers to latent HIV protein expression following latency reveRsaI, delineates the roles of BET proteins and their BDs in HIV latency, and provides a rationale for exploration of IAPi+BETi in animal models of HIV latency.