Vaccination with nanoparticles displaying gH/gL from Epstein-Barr virus elicits limited cross-protection against rhesus lymphocryptovirus.

Epstein-Barr virus (EBV) is associated with infectious mononucleosis, cancer, and multiple sclerosis. A vaccine that prevents infection and/or EBV-associated morbidity is an unmet need. The viral gH/gL glycoprotein complex is essential for infectivity, making it an attractive vaccine target. Here, we evaluate the immunogenicity of a gH/gL nanoparticle vaccine adjuvanted with the Sigma Adjuvant System (SAS) or a saponin/monophosphoryl lipid A nanoparticle (SMNP) in rhesus macaques. Formulation with SMNP elicits higher titers of neutralizing antibodies and more vaccine-specific CD4+ T cells. All but one animal in the SMNP group were infected after oral challenge with the EBV ortholog rhesus lymphocryptovirus (rhLCV). Their immune plasma had a 10- to 100-fold lower reactivity against rhLCV gH/gL compared to EBV gH/gL. Anti-EBV neutralizing monoclonal antibodies showed reduced binding to rhLCV gH/gL, demonstrating that EBV gH/gL neutralizing epitopes are poorly conserved on rhLCV gH/gL. Prevention of rhLCV infection despite antigenic disparity supports clinical development of gH/gL nanoparticle vaccines against EBV.

Ophthalmological Care of Patients With Craniofacial Disorders.

Patients presenting with craniofacial conditions present a unique challenge from an ophthalmological view point. There are no set guidelines as to their management or their long-term monitoring and follow-up. Largely, this should be the remit of a dedicated craniofacial team. Here we present pertinent ophthalmological pathology occurring in combination with craniosynostosis alongside the protocol employed in Birmingham Children's Hospital for the management of these patients.

γ-Secretase inhibition increases efficacy of BCMA-specific chimeric antigen receptor T cells in multiple myeloma.

B-cell maturation antigen (BCMA) is a validated target for chimeric antigen receptor (CAR) T-cell therapy in multiple myeloma (MM). Despite promising objective response rates, most patients relapse, and low levels of BCMA on a subset of tumor cells has been suggested as a probable escape mechanism. BCMA is actively cleaved from the tumor cell surface by the ubiquitous multisubunit γ-secretase (GS) complex, which reduces ligand density on tumor cells for CAR T-cell recognition and releases a soluble BCMA (sBCMA) fragment capable of inhibiting CAR T-cell function. Sufficient sBCMA can accumulate in the bone marrow of MM patients to inhibit CAR T-cell recognition of tumor cells, and potentially limit efficacy of BCMA-directed adoptive T-cell therapy. We investigated whether blocking BCMA cleavage by small-molecule GS inhibitors (GSIs) could augment BCMA-targeted CAR T-cell therapy. We found that exposure of myeloma cell lines and patient tumor samples to GSIs markedly increased surface BCMA levels in a dose-dependent fashion, concurrently decreased sBCMA concentrations, and improved tumor recognition by CAR T cells in vitro. GSI treatment of MM tumor-bearing NOD/SCID/γc-/- mice increased BCMA expression on tumor cells, decreased sBCMA in peripheral blood, and improved antitumor efficacy of BCMA-targeted CAR T-cell therapy. Importantly, short-term GSI administration to MM patients markedly increases the percentage of BCMA+ tumor cells, and the levels of BCMA surface expression in vivo. Based on these data, a US Food and Drug Administration (FDA)-approved clinical trial has been initiated, combining GSI with concurrent BCMA CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT03502577.

Trabeculectomy or Transscleral Cyclophotocoagulation as Initial Treatment of Secondary Childhood Glaucoma in Northern Tanzania.

PURPOSE: The purpose is to describe the outcome of trabeculectomy with transscleral cyclophotocoagulation (TSCPC) as an initial intervention for secondary childhood glaucoma in Northern Tanzania. METHODS: A retrospective, consecutive case series was analyzed of all children with secondary childhood glaucoma who underwent initial trabeculectomy or TSCPC between 2000 and 2013 at a referral eye unit in Northern Tanzania. Retrospective data were collected on causes of glaucoma, intraocular pressure (IOP), visual acuity, complications, and subsequent interventions. Outcomes were evaluated using Kaplan-Meier survival analysis and compared with Cox regression analysis. The main outcome measure was failure (IOP>21 mm Hg). RESULTS: Thirty-six eyes of 27 children (male, 21; median age, 9 y; range, 0.3 to 15 y) with secondary childhood glaucoma underwent trabeculectomy (19 eyes, 53%) or TSCPC (17 eyes, 47%). Causes included ocular trauma (13, 36%), previous cataract surgery (12, 33%), congenital aniridia (5, 14%), Sturge-Weber syndrome (2, 6%), steroid-induced glaucoma (2, 6%), uveitis (1, 3%), and unspecified leucoma (1, 3%). After 12 months, success was achieved in 48% after trabeculectomy and 18% after TSCPC, with visual acuity remaining unchanged in 11 of 14 (79%) and 4 of 5 eyes (80%), respectively. One third of the children did not return for follow-up after 1 year. Distance to the hospital (>100 km) was a significant risk factor for trabeculectomy failure (P=0.031). CONCLUSIONS: A high proportion of secondary childhood glaucoma in Northern Tanzania was caused by trauma and previous cataract surgery. Trabeculectomy was associated with better IOP control but also a higher complication rate. The ability to maintain visual function was comparable after both interventions. Failure was associated with a journey to the eye hospital (>100 km) possibly leading to late presentation with advanced disease and erratic follow-up.

From menorrhagia to manometers.

We present a case that illustrates the challenges in making a unifying diagnosis and bringing together symptoms which, at first, seem unrelated. We aim to illustrate the process of decision-making and the practice of working along several parallel processes to reach a single explanation for a child to present unwell.