Next generation 3D-printed intravaginal ring for prevention of HIV and unintended pregnancy.

Globally, there are 20 million adolescent girls and young women living with HIV who have limited access to long-acting, effective, women-controlled preventative methods. Additionally, although there are many contraceptive methods available, globally, half of all pregnancies remain unintended. Here we report the first 3D-printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for HIV prevention and contraception. We utilized continuous liquid interface production (CLIP™) to fabricate MPT IVRs in a biocompatible silicone-based resin. Etonogestrel (ENG), ethinyl estradiol (EE), and islatravir (ISL) were loaded into the silicone poly(urethane) IVR in a controlled single step drug loading process driven by absorption. ENG/EE/ISL IVR promoted sustained release of drugs for 150 days in vitro and 14 days in sheep. There were no adverse MPT IVR-related findings of cervicovaginal toxicity or changes in vaginal biopsies or microbiome community profiles evaluated in sheep. Furthermore, ISL IVR in macaques promoted sustained release for 28 days with ISL-triphosphate levels above the established pharmacokinetic benchmark of 50-100 fmol/106 PBMCs. The ISL IVR was found to be safe and well tolerated in the macaques with no observed mucosal cytokine changes or alterations in peripheral CD4 T-cell populations. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls.

CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma.

Introduction: The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. Methods: To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. Results: The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. Discussion: This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.

Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

Immunotherapy is a key modality in the treatment of cancer, but many tumors remain immune resistant. The classic mouse model of B16-F10 melanoma is immune resistant even in the face of checkpoint inhibition. Apolipoprotein E (apoE), a known immune suppressant is strikingly elevated in many human tumors, but its role in cancer immunology is not defined. We investigated the role of apoE in the immune micro-environment using a mouse melanoma model. We demonstrate that ApoE is -highly expressed in wild-type B16-F10 melanoma and serum levels progressively increase as tumors grow. The conditioned media from wild type ApoE secreting melanoma cells suppress T-cell activation in vitro while this suppressive effect is absent in conditioned media from ApoE knock out tumor cells. Mechanistically, apoE induces IL-10 secreting dendritic cells and stimulates T-cell apoptosis and arrest partially via the lrp8 receptor. Ablating ApoE in mice inoculated with tumor cells enabled tumor cell rejection and was associated with induction of immune pathway activation and immune cell infiltration. Tumor secreted apoE appears to be a potent immune cell checkpoint and targeting apoE is associated with enhanced tumor immunity in the mouse melanoma model.

Biodegradable, Tissue Adhesive Polyester Blends for Safe, Complete Wound Healing.

Pressure-sensitive adhesives typically used for bandages are nonbiodegradable, inhibiting healing, and may cause an allergic reaction. Here, we investigated the effect of biodegradable copolymers with promising thermomechanical properties on wound healing for their eventual use as biodegradable, biocompatible adhesives. Blends of low molecular weight (LMW) and high molecular weight (HMW) poly(lactide-co-caprolactone) (PLCL) are investigated as tissue adhesives in comparison to a clinical control. Wounds treated with PLCL blend adhesives heal completely with similar vascularization, scarring, and inflammation indicators, yet require fewer dressing changes due to integration of the PLCL adhesive into the wound. A blend of LMW and HMW PLCL produces an adhesive material with significantly higher adhesive strength than either neat polymer. Wound adhesion is comparable to a polyurethane bandage, utilizing conventional nonbiodegradable adhesives designed for extremely strong adhesion.

MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination.

BACKGROUND: MYC oncogene is deregulated in 70% of all human cancers and is associated with multiple oncogenic functions including immunosuppression in the tumor microenvironment. The role of MYC in the immune microenvironment of neuroblastoma and melanoma is investigated and the effect of targeting Myc on immunogenicity of cancer cells is evaluated. METHODS: Immune cell infiltrates and immunogenic pathway signatures in the context of MYCN amplification were analyzed in human neuroblastoma tumors and in metastatic melanoma. Dose response and cell susceptibility to MYC inhibitors (I-BET726 and JQ1) were determined in mouse cell lines. The influence of downregulating Myc in tumor cells was characterized by immunogenic pathway signatures and functional assays. Myc-suppressed tumor cells were used as whole cell vaccines in preclinical neuroblastoma and melanoma models. RESULTS: Analysis of immune phenotype in human neuroblastoma and melanoma tumors revealed that MYCN or c-MYC amplified tumors respectively are associated with suppressed immune cell infiltrates and functional pathways. Targeting Myc in cancer cells with I-BET726 and JQ1 results in cell cycle arrest and induces cell immunogenicity. Combining vaccination of Myc-inhibited tumor cells with checkpoint inhibition induced robust antitumor immunity and resulted in therapeutic cancer vaccine therapy in mouse neuroblastoma tumors. Despite vigorous antitumor immunity in the mouse melanoma model, upregulation of immunosuppressive pathways enabled tumor escape. CONCLUSIONS: This study demonstrates that the Myc oncogene is an appropriate target for inducing tumor cell immunogenicity and suggests that Myc-suppressed whole tumor cells combined with checkpoint therapy could be used for formulating a personalized therapeutic tumor vaccine.

Post COVID-19 Ophthalmic Manifestations in an Asian Indian Male.

Introduction: The Ocular manifestations of coronavirus disease 2019 (COVID-19) reported include conjunctivitis, conjunctival hyperemia, chemosis, epiphora, episcleritis, retinal manifestations included cotton wool spots (CWS), micro-hemorrhages, papillophlebitis and neuro-ophthalmic manifestations.Purpose: To report post COVID-19 ophthalmic manifestations using multimodal imaging.Results: A 66-year-old Asian Indian male presented to us with bilateral blurring of vision, RE>LE, of 3 days following a diagnosis of COVID-19 disease. Corrected distance visual acuity were 20/2666 and 20/25 in the right (RE) and left (LE) eyes respectively. He had bilateral anterior chamber inflammation with a relative afferent pupillary defect in the RE. RE showed central retinal artery occlusion(CRAO) with CWS, few flame-shaped retinal hemorrhages and disc edema and hyperemia. LE had disc edema and hyperemia, few flame-shaped retinal hemorrhages, cystoid changes and CWS. A diagnosis of bilateral panuveitis and papillitis with CRAO in the RE was made.Conclusion: Our patient developed a vascular occlusion with panuveitis, which possibly represents an immune mediated event following COVID-19. Patients should be warned about possible ophthalmic sequelae even after recovery.

Pressure-Sensitive Tissue Adhesion and Biodegradation of Viscoelastic Polymer Blends.

Viscoelastic blends of biodegradable polyesters with low and high molecular weight distributions have remarkably strong adhesion (significantly greater than 1 N/cm2) to soft, wet tissue. Those that transition from viscous flow to elastic, solidlike behavior at approximately 1 Hz demonstrate pressure-sensitivity yet also have sufficient elasticity for durable bonding to soft, wet tissue. The pressure-sensitive tissue adhesive (PSTA) blends produce increasingly stronger pull-apart adhesion in response to compressive pressure application, from 10 to 300 s. By incorporating a stiffer high molecular weight component, the PSTA exhibits dramatically improved burst pressure (greater than 100 kPa) when used as a tissue sealant. The PSTA's biodegradation mechanism can be switched from erosion (occurring primarily over the first 10 days) to bulk chemical degradation (and minimal erosion) depending on the chemistry of the high molecular weight component. Interestingly, fibrosis toward the PSTA is reduced when fast-occurring erosion is the dominant biodegradation mechanism.

Sprayable and biodegradable, intrinsically adhesive wound dressing with antimicrobial properties.

Conventional wound dressings are difficult to apply to large total body surface area (TBSA) wounds, as they typically are prefabricated, require a layer of adhesive coating for fixation, and need frequent replacement for entrapped exudate. Large TBSA wounds as well as orthopedic trauma and low-resource surgery also have a high risk of infection. In this report, a sprayable and intrinsically adhesive wound dressing loaded with antimicrobial silver is investigated that provides personalized fabrication with minimal patient contact. The dressing is composed of adhesive and biodegradable poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA/PEG) blend fibers with or without silver salt (AgNO3). in vitro studies demonstrate that the PLGA/PEG/Ag dressing has antimicrobial properties and low cytotoxicity, with antimicrobial silver controllably released over 7-14 days. In a porcine partial-thickness wound model, the wounds treated with both antimicrobial and nonantimicrobial PLGA/PEG dressings heal at rates similar to those of the clinical, thin film polyurethane wound dressing, with similar scarring. However, PLGA/PEG adds a number of features beneficial for wound healing: greater exudate absorption, integration into the wound, a 25% reduction in dressing changes, and tissue regeneration with greater vascularization. There is also modest improvement in epidermis thickness compared to the control wound dressing.

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

PURPOSE: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors. EXPERIMENTAL DESIGN: We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival. RESULTS: Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment. CONCLUSIONS: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.

Multicolour imaging in central serous chorioretinopathy.

BACKGROUND: Multicolour imaging (MI) is a novel, non-invasive retinal imaging technology. Its sensitivity for detecting the clinical features in central serous chorioretinopathy (CSCR) has not been previously described. The aim of this study is to evaluate the accuracy of MI compared to fluorescein angiography and colour fundus photography in CSCR, and to describe the imaging features of MI. METHODS: In this retrospective study at a tertiary referral centre, 63 consecutive eyes with CSCR (both acute and chronic) were included after obtaining permission from the institutional review board. Multimodal imaging with colour fundus photography, optical coherence tomography, MI and fluorescein angiography/indocyanine green angiography and near-infrared and blue wavelength autofluorescence was analysed to identify the clinical findings in CSCR. Sensitivity and specificity values were computed for the different clinical features for each imaging modality. RESULTS: On comparison with fluorescein angiography, MI was found to be more effective in identifying the extent of subretinal fluid (78 per cent versus 13 per cent). MI was equally capable in identifying pigment epithelium detachment (100 per cent versus 100 per cent) and retinal pigment epithelial changes (100 per cent versus 100 per cent). Focal leaks were identified in 84 per cent and 97 per cent of eyes using MI and fluorescein angiography imaging, respectively. The sensitivity of MI in identifying focal retinal pigment epithelial leaks was higher compared to near-infrared autofluorescence (84 per cent versus 34 per cent) and blue wavelength autofluorescence (84 per cent versus 18 per cent) imaging. CONCLUSION: MI is a useful, non-invasive imaging modality for detecting clinical features in CSCR. In the future, MI has the potential to substitute for fluorescein angiography and colour fundus photography as the imaging modality of choice.

Retinal structural and vascular changes in posterior microphthalmos.

BACKGROUND: Posterior microphthalmos (PM) is a rare developmental disorder characterised by high hyperopia, short axial length, presence of retinal papillomacular fold and relatively normal anterior segment findings. The study objective is to describe the retinal structural and vascular changes in eyes with PM with spectral domain optical coherence tomography, optical coherence tomography angiography and multicolour imaging. METHODS: In this retrospective, comparative case series, 10 eyes of five patients with PM as cases and 10 eyes of five age- and sex-matched controls were included. Structural changes, namely inner and outer retinal layer thicknesses, were measured using optical coherence tomography. Multicolour imaging findings were noted. Perifoveal vascular changes with qualitative and quantitative assessments were analysed using optical coherence tomography angiography. RESULTS: The foveal dip was absent in all 10 eyes (100 per cent) with PM. There was an elevated retinal papillomacular fold in six eyes (60 per cent) and intraretinal cystoid spaces in two eyes (20 per cent) with PM. The inner retinal layers were thicker in PM. On multicolour imaging, foveal avascular zone and retinal wrinkles were identified in eyes with retinal papillomacular fold in blue and green reflectance images. Perifoveal vascular changes in optical coherence tomography angiography included foveal area size reduction in superficial and deep vascular networks. The foveal capillary vessel densities were higher in PM compared to the controls in both superficial (46.3 ± 3.7 per cent; p = 0.000) and deep (54.7 ± 3.5 per cent; p = 0.000) capillary plexuses. Flow areas in superficial (p = 0.693) and deep (p = 0.088) capillary plexuses were not statistically relevant. CONCLUSION: The study suggests that in PM, retinal foreshortening occurs in one meridian leading to secondary changes such as loss of foveal dip, posterior bowing of the outer layers of the eye, thickening of the inner retina and ultimately, retinal papillomacular fold formation. The findings of the study need further validation in a larger series of patients with PM.

Improving the adhesion, flexibility, and hemostatic efficacy of a sprayable polymer blend surgical sealant by incorporating silica particles.

Commercially available surgical sealants for internal use either lack sufficient adhesion or produce cytotoxicity. This work describes a surgical sealant based on a polymer blend of poly(lactic-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) that increases wet tissue adherence by incorporation of nano-to-microscale silica particles, without significantly affecting cell viability, biodegradation rate, or local inflammation. In functional studies, PLGA/PEG/silica composite sealants produce intestinal burst pressures that are comparable to cyanoacrylate glue (160 mmHg), ∼2 times greater than the non-composite sealant (59 mmHg), and ∼3 times greater than fibrin glue (49 mmHg). The addition of silica to PLGA/PEG is compatible with a sprayable in situ deposition method called solution blow spinning and decreases coagulation time in vitro and in vivo. These improvements are biocompatible and cause minimal additional inflammation, demonstrating the potential of a simple composite design to increase adhesion to wet tissue through physical, noncovalent mechanisms and enable use in procedures requiring simultaneous occlusion and hemostasis. STATEMENT OF SIGNIFICANCE: Incorporating silica particles increases the tissue adhesion of a polymer blend surgical sealant. The particles enable interfacial physical bonding with tissue and enhance the flexibility of the bulk of the sealant, without significantly affecting cytotoxicity, inflammation, or biodegradation. These studies also demonstrate how silica particles decrease blood coagulation time. This surgical sealant improves upon conventional devices because it can be easily deposited with accuracy directly onto the surgical site as a solid polymer fiber mat. The deposition method, solution blow spinning, allows for high loading in the composite fibers, which are sprayed from a polymer blend solution containing suspended silica particles. These findings could easily be translated to other implantable or wearable devices due to the versatility of silica particles.

Multicolor imaging in choroidal osteomas.

BACKGROUND: To describe the multicolour (MC) imaging characteristics associated with choroidal osteomas (CO) and their secondary complications. METHODS: Retrospective descriptive case series of eleven eyes of ten patients with CO. Findings of multicolour imaging were correlated with visual acuity, clinical features, lesion characteristics and findings from other imaging modalities. RESULTS: Infrared reflectance (IR) images showed calcified CO lesions as hyporeflectance (dark) areas while decalcified lesions were seen as iso reflectance (normal) areas. Overlying RPE atrophy on IR were seen as white areas. MC images showed color variations depending upon the reflectivity of the tumour material tumour and retinal pigment epithelial (RPE) atrophy. Green color was noted in calcified CO tumour while decalcified CO tumour showed no color change. RPE atrophy were seen as bright orange areas. Green and blue reflectance images were not able to pick the choroidal osteoma lesion. Other changes secondary to CO like presence of choroidal neovascular membrane, hemorrhage and/or fluid in the retinal layers were identified on green and blue reflectance images. CONCLUSION: MC imaging is a useful tool in our arsenal of existing imaging modalities in the assessment of CO and its secondary changes. Change in reflectance of the IR and MC images can be used as an indicator to assess the extent of tumour decalcification and its secondary changes and therefore, can aid in prognostication in the same. It has the potential to replace color fundus photography in documentation and follow up of patients with CO.

PD-L1 checkpoint inhibition and anti-CTLA-4 whole tumor cell vaccination counter adaptive immune resistance: A mouse neuroblastoma model that mimics human disease.

BACKGROUND: Adaptive immune resistance induces an immunosuppressive tumor environment that enables immune evasion. This phenomenon results in tumor escape with progression and metastasis. Programmed cell death-ligand 1 (PD-L1) expressed on tumors is thought to inhibit tumor-infiltrating lymphocytes (TILs) through programmed cell death 1 (PD1), enabling adaptive immune resistance. This study investigates the role of PD-L1 in both mouse and human neuroblastoma immunity. The consequence of PD-L1 inhibition is characterized in the context of an established whole tumor cell vaccine. METHODS AND FINDINGS: A mouse model of neuroblastoma was investigated using an Id2 knockdown whole cell vaccine in combination with checkpoint inhibition. We show that immunogenic mouse neuroblastoma acquires adaptive immune resistance by up-regulating PD-L1 expression, whereas PD-L1 is of lesser consequence in nonimmunogenic neuroblastoma tumors. Combining PD-L1 checkpoint inhibition with whole tumor cell/anti-CTLA-4 vaccination enhanced tumor cell killing, cured mice with established tumors, and induced long-term immune memory (6 months). From an evaluation of patient neuroblastoma tumors, we found that the inflammatory environment of the mouse neuroblastoma mimicked human disease in which PD-L1 expression was associated directly with TILs and lower-risk tumors. High-risk patient tumors were lacking both TILs and PD-L1 expression. Although a correlation in immunity seems to exist between the mouse model and human findings, the mouse tumor model is induced and not spontaneously occurring, and furthermore, the number of both mouse and human correlates is limited. CONCLUSIONS: This study demonstrates the role PD-L1 plays in neuroblastoma's resistance to immunity and defines the nonredundant effect of combination checkpoint inhibition with vaccine therapy in a mouse model. High-risk, nonimmunogenic human tumors display both diminished PD-L1 expression and adaptive immune resistance. Paradoxically, high-risk tumors may be more responsive to effective vaccine therapy because of their apparent lack of adaptive immune resistance.

UNREPORTED SIDE EFFECT OF INTRAVITREAL DICLOFENAC IN CHRONIC DIABETIC MACULAR EDEMA.

PURPOSE: To evaluate the safety and efficacy of intravitreal diclofenac sodium. METHODS: A 61-year-old male with persistent diabetic macular edema was treated with 450 µg of intravitreal diclofenac sodium (systemic preparation). RESULTS: Postinjection Day 1, the spectral domain optical coherence tomography showed irregular vitreoretinal interface with wrinkling and separation of the internal limiting membrane from the nerve fiber layer with homogeneity of the inner layers. At 1 month, the compactness of the retinal layers was restored. Complete resolution of the cystoid macular edema was seen. At 1 year, there was mild flattening of the foveal depression with epiretinal membrane. CONCLUSION: Various studies have shown the safety and efficacy of intravitreal diclofenac without any reported side effect. We report the inner retinal toxicity in the form of cystic spaces and splitting of internal limiting membrane from nerve fiber layer on the first follow-up day, postinjection, which resolved over a period of 1 month. Further studies are needed to assess the safety of intravitreal diclofenac sodium.

The ARMOUR Study: Anti-VEGF in Neovascular AMD--Our Understanding in a Real-World Indian Setting.

PURPOSE: The aim of our study was to share our experience with anti-vascular endothelial growth factor (anti-VEGF) injections in the treatment of neovascular age-related macular degeneration (nAMD) in a real-world setting. DESIGN: A retrospective, observational study. METHODS: Patients of Indian origin with nAMD receiving anti-VEGF with a minimum follow-up of 12 months were enrolled in this study. In group 1, patients were treated on a pro re nata (PRN) basis; in group 2, patients received a loading dose (3 injecti Results: Overall, we observed that 77.31% (92/119 eyes) of patients either maintained or had improved visual acuity at 12 months' follow-up. Similar visual outcome was observed in both groups. The average number of injections given in group 1 was 4.98 and in group 2 was 3.7. CDVA at 12 months was significantly correlated with type of drug molecule, CSFT at 3 and 12 months, baseline visual acuity, and CDVA at 3 months. CONCLUSIONS: PRN treatment with significantly fewer injections achieved similar anatomical and functional outcomes when compared with the loading dose group. The results of this study need to be validated with a larger study group and a longer follow-up.

Novel multipurpose pod-intravaginal ring for the prevention of HIV, HSV, and unintended pregnancy: Pharmacokinetic evaluation in a macaque model.

Globally, women bear an uneven burden for sexual HIV acquisition. Results from two clinical trials evaluating intravaginal rings (IVRs) delivering the antiretroviral agent dapivirine have shown that protection from HIV infection can be achieved with this modality, but high adherence is essential. Multipurpose prevention technologies (MPTs) can potentially increase product adherence by offering protection against multiple vaginally transmitted infections and unintended pregnancy. Here we describe a coitally independent, long-acting pod-IVR MPT that could potentially prevent HIV and HSV infection as well as unintended pregnancy. The pharmacokinetics of MPT pod-IVRs delivering tenofovir alafenamide hemifumarate (TAF2) to prevent HIV, acyclovir (ACV) to prevent HSV, and etonogestrel (ENG) in combination with ethinyl estradiol (EE), FDA-approved hormonal contraceptives, were evaluated in pigtailed macaques (N = 6) over 35 days. Pod IVRs were exchanged at 14 days with the only modification being lower ENG release rates in the second IVR. Plasma progesterone was monitored weekly to determine the effect of ENG/EE on menstrual cycle. The mean in vivo release rates (mg d-1) for the two formulations over 30 days ranged as follows: TAF2 0.35-0.40; ACV 0.56-0.70; EE 0.03-0.08; ENG (high releasing) 0.63; and ENG (low releasing) 0.05. Mean peak progesterone levels were 4.4 ± 1.8 ng mL-1 prior to IVR insertion and 0.075 ± 0.064 ng mL-1 for 5 weeks after insertion, suggesting that systemic EE/ENG levels were sufficient to suppress menstruation. The TAF2 and ACV release rates and resulting vaginal tissue drug concentrations (medians: TFV, 2.4 ng mg-1; ACV, 0.2 ng mg-1) may be sufficient to protect against HIV and HSV infection, respectively. This proof of principle study demonstrates that MPT-pod IVRs could serve as a potent biomedical prevention tool to protect women's sexual and reproductive health and may increase adherence to HIV PrEP even among younger high-risk populations.

A Dose Ranging Pharmacokinetic Evaluation of IQP-0528 Released from Intravaginal Rings in Non-Human Primates.

PURPOSE: Design of intravaginal rings (IVRs) for delivery of antiretrovirals is often guided by in vitro release under sink conditions, based on the assumption that in vivo release will follow a similar release profile. METHODS: We conducted a dose-ranging study in the female reproductive tract of pigtail macaques using matrix IVRs containing IQP-0528, a poorly soluble but highly potent antiretroviral drug with an IC90 of 146 ng/mL. These IVRs consisted of drug-loaded segments, 15.6% IQP-0528 in Tecoflex 85A, comprising either all, half, or a quarter of the entire ring. RESULTS: In vitro release under sink conditions demonstrates loading-proportional release, with a cumulative 30-day release of 48.5 ± 2.2 mg for our 100% loaded ring, 24.8 ± .36 mg from our 50% loaded ring, and 13.99 ± 1.58 mg from our 25% loaded ring. In vivo, while drug concentration in vaginal fluid is well in excess of IQP-0528's EC90, we find no statistical difference between the different ring loadings in either swab drug levels or drug released from our rings. CONCLUSIONS: We show that in vitro release may not accurately reflect in vivo release, particularly for poorly soluble drugs. All tested loadings of our IVRs are capable of delivering IQP-0528 well in excess of the IC90.

The nomadic Ozurdex®: Anterior migration of the dexamethasone implant and back!

Dexamethasone intravitreal implantation has been used in various retinal and uveal pathologies. Common complications include cataract formation and raised intraocular pressure. Although uncommon, migration of the implant has also been well reported. We describe a case with migration of the implant into the anterior chamber in a patient with a scleral-fixated intraocular lens, which was managed noninvasively by pupillary dilatation and positioning of the patient.

Repeated administration of high-dose depot medroxyprogesterone acetate does not alter SHIVSF162p3 viral kinetics and tenofovir pharmacokinetics when delivered via intravaginal rings.

BACKGROUND: Intravaginal rings (IVR) for HIV prevention will likely be used by women on depot medroxyprogesterone acetate (DMPA) hormonal contraception. We used pigtailed macaques to evaluate the effects of DMPA on tenofovir disoproxil fumarate (TDF) IVR pharmacokinetics and viral shedding. METHODS: Mucosal tenofovir (TFV) levels were compared in SHIVSF162p3 -negative DMPA-treated (n=4) and normally cycling (n=6) macaques receiving TDF IVRs. Plasma viremia and vaginal shedding were determined in groups of SHIVSF162p3 -positive DMPA-treated (n=6) and normally cycling (n=5) macaques. RESULTS: Similar median vaginal fluid TFV concentrations were observed in the DMPA-treated and cycling macaques over 4 weeks (1.2×105 and 1.1.×105  ng/mL, respectively). Median plasma viremia and vaginal shedding AUC of the DMPA-treated (2.73×107 and 8.15×104 copies/mL, respectively) and cycling macaques (3.98×107 and 1.47×103 copies/mL, respectively) were statistically similar. CONCLUSIONS: DMPA does not affect TDF IVR pharmacokinetics or SHIV shedding.