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Background: Most travelers experience Jet Lag Disorder (JLD) symptoms due to misalignment of their circadian rhythms with respect to the new time zone. We assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle (JET8 Study). We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness.Methods: We undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18–73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7 and 9 h each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20 mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov, NCT03373201.Results: Between October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon (n = 160) or placebo (n = 160). Tasimelteon treatment increased TST2/3 (primary endpoint) by 60.3 min (95%CI 44.0 to 76.7, P < 0.0001) and whole night TST by 85.5 min (95% CI 64.3 to 106.6, P < 0.0001), improved next day alertness, next day sleepiness, and shortened latency to persistent sleep by −15.1 min (95% CI −26.2 to −4.0, P = 0.0081).Conclusion: A single dose of tasimelteon improves the primary symptoms of JLD, including nighttime insomnia and next day functioning among participants in a laboratory model of JLD simulating eastward trans-meridian travel by inducing an 8-h phase advance of the sleep-wake cycle.

Background and AimsThere is a high unmet need for the treatment of gastroparesis and studies of NK1-R antagonists suggest potential benefit in reducing the symptoms of nausea and vomiting. We hypothesized that tradipitant, an NK1-R antagonist, would be effective in treating patients with idiopathic or diabetic gastroparesis.MethodsIn a randomized, double-blind, placebo-controlled study across 47 U.S. sites, 152 gastroparesis patients were randomized to receive oral 85mg BID tradipitant (n=77) or placebo (n=75) daily for four weeks. Symptoms were assessed using a daily symptom dairy, Gastroparesis Cardinal Symptom Index (GCSI), and other patient reported questionnaires.ResultsPatients receiving tradipitant had a significant decrease in nausea score at Week 4 compared to placebo (−1.2 improvement vs −0.7, respectively, p=0.0099), and a significant increase in nausea-free days (28.8% increase on tradipitant vs 15.0% on placebo p=0.0160). Patients with both nausea and vomiting at baseline (n=101) showed an even greater decrease in nausea score (−1.4 improvement on tradipitant vs −0.4 on placebo pConclusionsTradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. These robust efficacy results suggest tradipitant has the potential to become a useful pharmacological treatment for gastroparesis.

BackgroundTravelers frequently experience Jet Lag Disorder (JLD) symptoms due to misalignment of the circadian rhythm with respect to the new time zone. In the JET8 Study, we assessed the efficacy and safety of tasimelteon (HETLIOZ®) in healthy participants using a laboratory model of JLD induced by an 8-h phase advance of the sleep-wake cycle. We hypothesized that tasimelteon treatment in participants experiencing JLD would cause increased sleep time, increased next-day alertness, and reduced next-day sleepiness.MethodsWe undertook a randomized, double-blind, placebo-controlled trial in 12 US clinical research sleep centers. We screened healthy adults ages 18-73 years, who were eligible for the randomization phase of JET8 if they typically went to bed between 21:00 and 01:00, slept between 7-9 hours each night, and slept at a consistent bedtime. We used block randomization stratified by site to assign participants (1:1) to receive a single oral dose of tasimelteon (20mg) or placebo 30 min before their 8-h phase-advanced bedtime. The primary endpoint was Total Sleep Time in the first 2/3 of the night (TST2/3), which was measured by polysomnography during the 8-h sleep episode, and assessed in the intent-to-treat population. The trial is completed and registered with ClinicalTrials.gov,NCT03373201.ResultsBetween October 16, 2017 and January 17, 2018, we screened 607 healthy participants for JET8, of whom 320 (53%) were assigned to receive tasimelteon (n=160) or placebo (n=160). Tasimelteon treatment resulted in increased TST2/3by 60.3 min (95%CI 44.0 to 76.7,PConclusionA single dose of tasimelteon improves symptoms, including sleep and next day functioning in participants, following an 8-h phase advance of the sleep-wake cycle in a laboratory model of JLD simulating eastward trans-meridian travel.

Treatments are needed for gastroparesis; antagonists of tachykinin receptor 1 (TACR1, also called NK1R) can reduce symptoms of nausea and vomiting. We investigated the safety and efficacy of tradipitant, an antagonist of NK1R, in patients with idiopathic or diabetic gastroparesis.We performed a double-blind trial of 152 adults with gastroparesis at 47 sites in the United States from November 2016 through December 2018. Participants were randomly assigned to groups given oral tradipitant 85 mg (n = 77) or placebo (n = 75) twice daily for 4 weeks. Symptoms were assessed by a daily symptom dairy, Gastroparesis Cardinal Symptom Index scores, and other patient-reported questionnaires. The primary outcome from the intent-to-treat analysis was change from baseline to week 4 in average nausea severity, measured by the Gastroparesis Core Symptom Daily Diary.Patients receiving tradipitant had a significant decrease in nausea score (reduction of 1.2) at week 4 compared with placebo (reduction of 0.7) (P = .0099) and a significant increase in of nausea-free days at week 4 (28.8% increase on tradipitant vs 15.0% on placebo; P = .0160). Patients with nausea and vomiting at baseline (n = 101) had an even greater decrease in nausea in when given tradipitant (reduction of 1.4) compared with those given placebo (reduction of 0.4) (P.0001), as well as an increase in nausea-free days at week 4 (32.3% improvement on tradipitant vs 7.6% on placebo; P = .0003). The average nausea score was 1 or less at week 4 in 32.9% of patients given tradipitant compared with 11.8% of patients given placebo (P = .0013). A greater than 1-point improvement in Gastroparesis Cardinal Symptom Index score was observed in 46.6% of patients given tradipitant compared with 23.5% of patients given placebo (P = .0053).Tradipitant resulted in statistically and clinically meaningful improvements in nausea and reduced vomiting, compared with placebo, in patients with idiopathic or diabetic gastroparesis. ClinicalTrials.gov, Number: NCT02970968.

Background: Patients with diabetic and idiopathic gastroparesis with delayed gastric emptying and moderate to severe nausea were enrolled into a phase II multicenter, randomized, double-blind, placebo-controlled trial. Subjects were randomized to receive oral 85mg tradipitant bid or placebo (1:1) for 4 weeks. Of the 152 patients, 60% of patients had idiopathic and 40% had diabetic gastroparesis. Methods: The primary outcome was change in average nausea from baseline, measured using the 5-point Gastroparesis Core Symptom Daily Diary (GCSDD). Overall gastroparesis symptoms were evaluated using the Gastroparesis Cardinal Symptom Index (GCSI), and Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM). Results: A statistically significant and clinically meaningful improvement in nausea and overall gastroparesis symptoms was observed in patients on tradipitant. Subjects receiving tradipitant had a significant decrease in their average nausea score compared to placebo with LS mean difference (95% CI) of -0.53 (-0.92, -0.13, p=0.0099) as well as a significant increase in nausea free days (28.8% increase on tradipitant compared to 15.0% increase on placebo, p=0.0160). A clinically meaningful response of 1-point or more improvement on the GCSI total score was observed in 46.0% of patients on tradipitant compared to 24.2% of patients on placebo (p=0.0086). Conclusions: Tradipitant treatment resulted in statistically and clinically meaningful improvements in nausea and overall gastroparesis symptoms. Tradipitant was well tolerated with comparable rates of adverse events between tradipitant and placebo groups. These robust efficacy results suggest tradipitant has the potential to become a first line treatment for idiopathic and diabetic gastroparesis. Disclosure J.L. Carlin: Employee; Self; Vanda Pharmaceuticals, Inc. V.R. Lieberman: Employee; Self; Vanda Pharmaceuticals, Inc. Stock/Shareholder; Self; Vanda Pharmaceuticals, Inc. A. Dahal: Employee; Self; Vanda Pharmaceuticals, Inc. Stock/Shareholder; Self; Vanda Pharmaceuticals, Inc. M.S. Keefe: Employee; Self; Vanda Pharmaceuticals. Stock/Shareholder; Self; Vanda Pharmaceuticals. C. Xiao: Employee; Self; Vanda pharmaceutical inc. G. Birznieks: Employee; Self; Vanda Pharmaceuticals. M.H. Polymeropoulos: Employee; Self; Vanda Pharmaceuticals Inc.

Li[Ni0.5Mn0.3Co0.2]O2/graphite pouch cells were cycled using protocols that included 24 h spent at high voltage (≥ 4.3 V) under constant voltage or open circuit conditions to accelerate failure. Compared to traditional cycling, failure was reached up to 3.5 times faster. When this protocol was applied to cells containing low LiPF6 concentrations (≤ 0.4 M) failure was achieved up to 17.5 times faster than traditional cycling with normal LiPF6 concentrations. This represents a time improvement on the order of years and therefore can be used as a high-throughput screening method. Failure mechanisms for cells containing a range of LiPF6 concentrations undergoing these aggressive protocols were investigated using charge-discharge cycling, impedance spectroscopy (including symmetric cell analysis) and isothermal microcalorimetry. Long times at high voltage rapidly increase positive electrode impedance but do not seem to consume lithium inventory. The use of lower LiPF6 concentrations does not seem to introduce new failure mechanisms but makes cells less tolerant to positive electrode impedance growth. The utility of this method is demonstrated by screening cells with a variety of electrolyte additive combinations. Fewer than 3 months were required to distinguish cells containing 1% lithium difluorophospate as superior to cells with other additive combinations.

Li(Ni0.5Mn0.3Co0.2)O2/artificial graphite cells containing different electrolyte additives were studied using electrochemical impedance spectroscopy (EIS) and X-ray photoelectron spectroscopy (XPS) after formation and after long-term charge-discharge cycling. Positive and negative electrodes were examined separately in symmetric cells to study the solid electrolyte interphase (SEI) at each electrode. EIS measurements were taken vs temperature, and activation energies (Ea) related to Li+ transport through the SEI were calculated. After cycling, Ea differed depending on electrolyte additive, electrode type, and cycling voltage limits. Charge transfer resistance was also compared after formation and cycling and did not always correlate with Ea trends, suggesting that multiple factors influence SEI properties. XPS was used to study the chemical composition and thickness of the SEI. Electrolyte additives affected the quantity of inorganic materials in the SEI, and more inorganic material appeared to correlate with lower Ea values. Cells containing lithium difluorophosphate electrolyte additive had the best lifetime of the cells studied in this work. These cells also showed the lowest SEI activation energy values, lowest charge transfer resistance, and most inorganic SEI composition after cycling.

Impedance in lithium ion cells grows over the lifetime of the cell and can be a large contributing factor to cell failure. This study attempts to understand impedance growth by looking at the factors that contribute to cell impedance. Separating these factors and understanding the origins of impedance in cells provides insight into how and why cells fail and could lead to improvements in cell cycling and lifetime. The positive and negative electrode solid electrolyte interphase (SEI) layer, contact resistances, degradation of electrical conductivity in electrodes, and loss of ionic conductivity in electrolyte are all contributing factors to overall cell impedance. However, separating these factors can be difficult in impedance spectroscopy measurements. In this study, Li[Ni0.5Mn0.3Co0.2]O2/artificial graphite pouch cells were used with 1.2M LiPF6 in EC:DMC 3:7 (w:w) electrolyte containing 2 wt% vinylene carbonate (VC), 1 wt% lithium difluorophosphate (LiPF2O2 – called LFO here), or no additive as a control electrolyte. Cells were formed to 4.2 V or 4.4 V and were either left at top of charge or discharged to 3.8 V before disassembly. See Table 1 for a full list of electrolytes and voltages of the cells used in this study. Following pouch cell formation, symmetric cells were made from two positive electrodes or two negative electrodes harvested from the full lithium ion cell to study each electrode separately. Full coin cells were also made with one positive and one negative electrode. Electrochemical impedance spectroscopy (EIS) was performed at a range of temperatures to facilitate the separation of impedance factors. Measurements were taken at -10°C, 0°C, 10°C, 20°C, 30°C, and 40°C. Spectra were measured at 10°C at the beginning, middle, and end of the experiments to ensure repeatability. Figure 1 is an example of measurements taken from one disassembled pouch cell. Note that only -10°C, 10°C, 30°C, and 40°C are shown in this figure for simplicity. The left column in Figure 1 shows the Nyquist plots for negative symmetric cells at the various temperatures. The middle and right columns show the positive symmetric cells and the full cells respectively. The middle, positive symmetric cell column contains two spectra, one for a cell made with aluminum hardware and the other with steel hardware, labelled (A) and (S) respectively. Data from one symmetric cell is shown per type of symmetric cell, however several cells of each type were made from each pouch cell to ensure repeatability of the data. The low frequency (right side) semicircular feature in these Nyquist plots may be attributed to charge transfer resistance between the electrolyte and the electrodes. The charge transfer resistance used here lumps together ion desolvation, ion transfer through the SEI and combination with an electron at the inner SEI surface. The high frequency (left side) semicircular feature may be attributed to contact resistance. The steel and aluminum hardware positive symmetric cell data have very similarly sized low frequency features – representing charge transfer resistance, which should not change at all with hardware. However, the high frequency feature varies substantially between the two symmetric cells, indicating that this feature is in fact due to contact resistance. In general, for all spectra, charge transfer resistance increases dramatically in magnitude with decreasing temperature, while the contact resistance remains almost constant. Therefore, Figure 1 strongly suggests that researchers interested in studying charge transfer resistance with minimal confusion should make their measurements at low temperature. The full cells have three features, which represent a combination of charge transfer and contact resistances from the negative and positive electrodes in combination. This data shows that the majority of cell impedance growth as temperature decreases originates from the positive electrode SEI. Equivalent electric circuit models have been used to model the impedance behavior of the symmetric cells. Circuit models include resistance factors representing charge transfer resistance, contact resistance, and solution resistance, as well as imperfect capacitances (constant phase elements) representing electrochemical double layers. Impedance spectra have been fitted using these simple circuit models. Using this technique, charge transfer resistances, contact resistances, solution resistances, and double layer capacitance values can be obtained for positive and negative electrodes/SEI layers separately as a function of temperature. Activation energies for the charge transfer between SEI and electrolyte have been extracted from charge transfer resistance measurements as they follow an Arrhenius temperature dependence. Capacitance values associated with double layers at the SEI/electrolyte interface were also be obtained through these measurements and these will be discussed. Figure 1

Sometimes lithium-ion cells show a very insidious type of failure where they display close to 100% of their capacity for about 1000 charge-discharge cycles and then lose most of their capacity in only 100 cycles or so with very little warning to the user. This is called “rollover failure” [1]. Experimental observations show that the likelihood of rollover failure increases with upper cut-off potential of lithium-ion cells and decreases with LiPF6 concentration in a reasonable range. Since increasing the upper cut-off potential is essential to increase the energy density of lithium-ion cells, a full understanding of the causes of rollover failure is essential, but this is proving very difficult to attain. The phenomenon of rollover failure during long-term cycling will be discussed based on a comparison among Li(Ni0.5Mn0.3Co0.2)O2/graphite pouch cells with different electrolyte and electrode designs undergoing different testing protocols. A few facts can be gleaned from the data: For cells charged to the same upper cut-off potential, those showing the highest rates of electrolyte oxidation at the positive electrode (due to electrolyte or cell chemistry changes) are most prone to rollover failure. Any cell is more prone to rollover failure if charged to a higher potential. This increases the rate of electrolyte oxidation at the positive electrode. When rollover occurs, the impedance at the positive electrode always increases significantly while the impedance at the negative electrode side is relatively stable. Lithium metal plating at the negative graphite electrode surface is not always observed during the initial stages of rollover failure. Increasing the LiPF6 concentration properly can delay the occurrence of rollover failure. For example Figure 1 shows the impact of increasing salt concentration from 1.2 M to 1.5 M. Based on these and other observations, some simple models that integrate electrolyte oxidation, impedance growth and lithium ion diffusion can be postulated but further experimental studies using a variety of methods are required for full understanding. [1] J. C. Burns, A. Kassam, N. N. Sinha, L. E. Downie, L. Solnickova, B. M. Way, J. R. Dahn, J. Electrochem. Soc., 160, A1451-A1456 (2013). Figure 1. Capacity (top panels), normalized capacity (middle panels) and ΔV (bottom panels) versus cycles of Li[Ni0.5Mn0.3Co0.2]O2/graphite pouch cells filled with 1.2 M LiPF6 or 1.5 M LiPF6 in EC:EMC:DMC (25:5:70 vol.%) and 2 wt.%VC+1 wt.%DTD. Cycling was performed between 3V and 4.1V or 4.3V at 20 oC with charging/discharging rates at 1C/1C. Figure 1

Purpose The purpose of this study was to report a case of Vogt-Koyanagi-Harada disease causing large tears of the retinal pigment epithelium (RPE). Methods Case report and literature review. Results A 41-year-old woman presented with headache, tinnitus, and bilateral panuveitis with multiple serous retinal detachments. She was started on oral prednisone, and the inflammation and serous detachments subsided. However, 2 weeks later, she developed large RPE tears. Conclusion Vogt-Koyanagi-Harada disease is an inflammatory disorder of the choroid; however, irregularities in the RPE have been noted, most recently with the use of spectral domain ophthalmic coherence tomography. The finding of RPE tear with resolution of serous retinal detachment may further implicate involvement of the RPE in the disease process.

Introduction: The lifetime prevalence of post-traumatic stress disorder (PTSD) is estimated to be 7.3% in the U.S. population, 10-20% among active duty service members and 35-40% among veterans. Overall success rates of evidence-based therapies for PTSD are low, leading clinicians to explore new therapeutic options. This study evaluated all published articles on the use of stellate ganglion block (SGB) as an adjunctive therapy for treatmentrefractory PTSD. Methods: EMBASE, PubMed, PsychINFO and Cochrane databases were searched using keyword combinations including stellate ganglion block, SGB, post-traumatic stress disorder, and PTSD. Articles were restricted to English language with no date delimiter. Twelve publications were identified, seven of which were eliminated due to lack of case data, duplicate patient sample, or descriptive reports with no standardized PTSD symptom assessment. Twenty-four cases from five articles were examined further by two independent evaluators who extracted data on sociodemographic and clinical characteristics including PTSD symptoms, comorbidities, and treatment history. Interrater reliability showed complete agreement (κ=1.0). Results: Cases were predominantly male (n=21, 88%) and active duty military (n=14, 58%) or veterans (n=8, 33%) with combat-related PTSD. The average age was 40.5 years (±10.0 SD). All cases had received >1 year of psychotherapy and pharmacotherapy before SGB. Seventeen cases (71%) received one SGB, seven (29%) received multiple SGBs. Clinically meaningful improvements were observed in 75% (n=18) of cases after SGB, with significant differences in mean PTSD scores pre- (69.5 ± 26.6) and post-SGB (34.2 ± 32.5) across cases (p

To determine the efficacy of prinomastat (AG3340), a synthetic inhibitor of matrix metalloproteinase, in the treatment of experimental proliferative vitreoretinopathy (PVR) induced by intravitreal dispase injection.One eye each of 53 New Zealand white rabbits was injected in the vitreous cavity with 0.07 unit of dispase to induce PVR. One week after PVR induction, 53 rabbits were randomized (27:26) to receive 0.5 mg prinomastat or the vehicle of the drug (acidified water) intravitreally every two weeks. The scores of PVR severity (scale of 1-5) were graded to compare the prinomastat-treated animals with the control group.The average PVR scores in the treatment and control groups were 2.62 and 3.57 respectively (p = 0.038; Wilcoxon rank sum). Clinically significant PVR with retinal detachment (PVRor = grade 3) developed in 76% of rabbits in the control group versus 51% of rabbits treated with prinomastat.Intravitreally administered prinomastat decreased development of PVR in an experimental model which made use of dispase to induce PVR.

This study was conducted to evaluate the vitreous clarity and intraocular therapeutic index of three preparations of the carboxymethyl ester of 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zealand white rabbits were intravitreally injected with one of three preparations of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intraocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injection of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitreal compound aggregates in eyes with the middle and high doses. The intraocular therapeutic index was lower than 465:1. Intravitreal injection of liposomal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final int...

Purpose. To characterize the anterior segment effects of cidofovir, using an animal model.Methods. Cidofovir drops, at concentrations of 0.04%, 0.4% and 4%, were instilled in eyes of guinea pigs once daily for 10 days. Fellow eyes (controls) received normal saline. The corneal epithelium was debrided at day one and then at every other day for 10 days. Subconjunctival injections of 20 μl of 4% cidofovir were given in another group of animals. A micro-manometer was used to determine the intraocular pressure (IOP). Eyes were studied histopathologically at the conclusion of the study.Results. There was no significant drop in IOP after 10 days, using the 0.04% concentration of cidofovir drops. Histology revealed mild corneal edema and inflammatory infiltrate; iris, ciliary body and retina were normal. There was a statistically significant drop in IOP in the eyes treated with 0.4% and 4.0% cidofovir eye drops at 10 days (p = 0.005 and p < 0.0001, respectively) compared to baseline. Morphological changes include...

Purpose: This study was performed to determine the prognostic significance of the presence of loops defined as periodic acid-Schiff-positive fibrovascular septa that completely surround lobules of tumor cells in cases of uveal melanoma. Methods: The presence of loops was evaluated using an ordinary light microscope and routinely stained periodic acid-Schiff and hematoxylin sections from 496 posterior uveal melanomas without knowledge of the follow-up data on the patient. Results: At 15 years, survival decreased from 67.5% to 33.8% when complete loops were present. Univariate Cox regression analysis indicated that the presence of loops was an indicator of poor outcome, and was better than age but not as good as the mean diameter of the largest nucleoli, cell type, or tumor size. Conclusions: The presence of loops, as evaluated in this study, was not as strong an indicator of poor outcome as were loops assessed in a previous study of 234 cases from another laboratory. The authors suspect this difference may be due to their only using routinely stained sections without a green filter, as was used in previously reported studies. The authors' description of loops does not require any special equipment and gives sufficiently useful results to justify its inclusion by the pathologist in reports of such specimens. A description of vascular loops should be added to the use of the modified Callender cell type, tumor dimensions, mitotic count, extraocular extension, and lymphocytic infiltration in the final pathologic report.

Varicella zoster virus retinitis in patients with the acquired immunodeficiency syndrome is known to be a devastating disease. We studied a series of six consecutive patients that sheds new light on the clinical manifestations and treatment options of this disorder. All patients had episodes of cutaneous zoster, long-term exposure to oral acyclovir, and CD4+ T lymphocyte counts less than 50 cells/mm 3 . Two of the six patients had simultaneous radiographically demonstrable and histologically proven varicella zoster virus encephalitis; this is an important association. Histologic examination of autopsy specimens disclosed that the retinal infection by varicella zoster virus involves the retinal pigment epithelium more heavily than the inner retina, which is consistent with the characteristic clinical impression of an outer retinal necrosis.

Electrolysis was performed with a palladium cathode and an electrolyte containing both hydrogen and deuterium ions. The cathode bends toward the anode during this process. Examination of both the concave and the convex surfaces with the scanning electron microscope, scanning tunneling microscope, and atomic force microscope shows unusual surface characteristics. Rimmed craters with faceted crystals inside and multitextural surfaces were observed on an electrolyzed palladium cathode but not on palladium that has not been electrolyzed. 9 refs., 9 figs.

Purpose: To analyze a phenomenon seen in patients with acquired immune deficiency syndrome (AIDS) with cytomegalovirus (CMV) retinitis undergoing systemic antiviral treatment: a persistent white border opacification on the edge of healed CMV retinitis. Patients and Methods: The authors prospectively evaluated a population of 137 patients with AIDS and CMV retinitis during a 44-month period. Eleven patients (12 eyes) who were undergoing maintenance antiviral treatment were identified with an atypical healing response—the persistence of a white flat border opacification that did not advance for many weeks to months. Patient records and photographs were reviewed. Results of one autopsy were analyzed with histopathology and special stains. Results: The persistent white edge maintained (without advancement or smoldering) for an average of 11.6 weeks (range, 4 to 41 weeks). This border opacification was not affected by reinduction treatment in the six patients to whom reinduction was given. Results from histopathologic examination of one patient with a persistent white border are presented: these results show that dead cytomegalic cells formed stable structures within the retina, causing white opacification that could be confused with active lesions. Immunoperoxidase stains identified CMV antigens. Conclusion: This persistent white border opacification, which does not advance or smolder, represents an important clinical entity that should be recognized during antiviral treatment for CMV retinitis. It can often be observed. If it is not recognized as a stable configuration, patients may undergo unnecessary reinductions with potentially toxic doses of antiviral medications.

Reconstruction in the head and neck can be difficult owing to the size of the defect or characteristics of the tissue that needs to be replaced. Facial wounds or reconstruction sites can be subject to contamination, thereby risking infection of any implanted material even under ideal circumstances. Particular areas of concern are sites where minimizing the bacterial contamination prior to placing an implant is difficult (eg, the oral cavity and internal nose). Reconstruction involves the facial subcutaneous soft tissue and/or bone, and the ideal implant provides support and natural feel, as well as a low risk of infection. The biocompatibility of alloplastic implants depends on the tissue inertness of the implant and the porosity, allowing connective tissue ingrowth, which in turn decreases the susceptibility to infection. Scalafani et al demonstrated that alloplastic implants contaminated prior to fibrovascular ingrowth had a much higher incidence of infection and rejection.To examine the effectiveness of several techniques for infiltrating antibiotics into alloplastic implants of different porosity using 2 commonly used alloplastic implants, expanded polytetrafluoroethylene (e-PTFE, or GORE-TEX) and porous high-density polyethylene (Medpor).Using an in vitro bacterial growth inhibition model, we found that suction infiltration of the implant with antibiotics was the most effective technique, with a statistically significant advantage over other techniques used. The advantages of the suction impregnation were seen to be most effective using alloplasts with a smaller pore size (20-30 microm) (P.001), but there was a statistically significant difference even with implants with a larger pore size (150-200 microm) (P.001).Suction infiltration of antibiotics into porous implants seems to be the most effective method identified using an in vitro testing protocol. Further experiments will be needed to confirm the effectiveness in reducing the perioperative risk of infection in vivo.

We describe a case of focal cytomegalovirus iritis in a patient with acquired imunodeficiency syndrome (AIDS) who had CMV retinitis. The autopsy showed histologic evidence of focal iritis in the left eye. This iritis was characterized by infiltration of acute inflammatory cells mixed with cytomegalic cells, which was confirmed by CMV- specific immunohistochemical staining. The case suggested that cytomegalovirus could be a direct causative agent of infectious iritis in AIDS patients. [Ophthlamic Surg Lasers 1998;29:930-932.]

This cross-sectional study aimed to evaluate the interrelationships of psychiatric symptom severity, medical comorbidity, and psychosocial functioning in a sample of patients with schizophrenia by utilizing the baseline data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE).This study utilized baseline data from a multisite trial of antipsychotic pharmacotherapy, which collected data from 1,460 patients with schizophrenia at more than 50 sites in the United States between 2001 and 2003. Bivariate correlations were used to evaluate associations between schizophrenia symptoms and medical comorbidity, and multivariate regression models were used to determine the independent association between medical comorbidity and psychosocial functioning.Of the 1,424 participants in the study sample, 58 percent had at least one medical condition: 20 percent had hypertension, 11 percent had diabetes mellitus, and 9 percent had four or more medical conditions. Medical comorbidity was associated with poorer neurocognitive functioning and greater depressive symptoms. The number of medical conditions was not associated with more severe schizophrenia symptoms. Both the number of medical conditions and physical health status were only weak correlates of psychosocial functioning.In this sample of persons with schizophrenia, medical comorbidity was associated with depression and neurocognitive impairment but was a weaker correlate of psychosocial functioning or employment status than psychotic symptoms, depression, and neurocognitive impairment.

The conflict in the Middle East has led to an increase in the incidence and severity of facial trauma evaluated at tertiary military medical facilities. The Naval Medical Center San Diego, San Diego, Calif, has treated 5 patients with penetrating injuries to the orbit with associated comminuted fractures. We have used the technology of image-guided surgery to assist in reconstructing these injuries. Image-guided surgery has many applications in the head and neck. This review consists of a series of traumatic applications of the image-guided system with a focus on orbital and midfacial trauma. We will discuss the benefits and drawbacks of this technique compared with previously described techniques.

In a search for a pharmacologic adjuvant in the management of posttraumatic proliferative vitreoretinopathy (PVR), we investigated the effect of intravitreal injection of prinomastat (AG3340) on an experimental model. Posterior penetrating eye trauma was created in one eye each of 24 New Zealand white rabbits. One week after the surgery, all rabbits were randomized (1:1) to receive 0.5 mg prinomastat or the vehicle of the drug intravitreally every week for 6 weeks. The degree of PVR for each hemiretina was scored, and the two scores were summed to obtain a total eye score. The mean total eye score was 3.58 in the treatment group and 5.75 in the control group (p = 0.0307). The numbers of eyes with tractional retinal detachment in the prinomastat-treated (n = 12) and control (n = 12) groups were 3 and 9, respectively (p = 0.0391). These results suggest that intravitreally administered prinomastat has an inhibitory effect on posttraumatic PVR.

To evaluate the intraocular safety and antiviral treatment efficacy of the sustained lipid prodrug of ganciclovir, 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV), as an intravitreal injectable drug system for viral retinitis.HDP-P-GCV was synthesized by coupling 1-O-hexadecyl-propanediol-3-phosphate to either free hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as catalyst. The compound was formulated into liposomes. The antiviral activity was assessed by DNA reduction in vitro, and intraocular safety was assessed by ophthalmoscopy, electrophysiology, and histology after intravitreal injections, with resultant intravitreal concentrations of 0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by simultaneous intravitreal injection of HDP-P-GCV and herpes simplex virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at various times before HSV-1 intravitreal inoculation. Retinitis was scored with ophthalmoscopy and compared with controls.In vitro, the IC50 of HDP-P-GCV against HSV-1 and human cytomegalovirus (HCMV) infected cells was 0.02 and 0.6 microM, respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and maintained a good vitreous clarity at all doses except 2 mM final intravitreal concentration. Although cataracts were observed in some eyes at the higher doses, they were not observed in eyes with 0.2 mM final intravitreal concentration. No other indications of ocular toxicity were observed. Intravitreal injection of HDP-P-GCV with resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis rabbit model demonstrated a complete protection of the retina with the simultaneous treatment strategy and a 4 (P = 0.03) to 6-(P = 0.058) week significant protection of retina with the pretreatment strategies when compared with ganciclovir or blank liposome controls.In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting intravitreal injectable anti-CMV or anti-HSV compound. This self-assembling liposome system could be applicable for many compounds available for intraocular diseases.

This study was conducted to evaluate the vitreous clarity and intraocular therapeutic index of three preparations ofthe carboxymethyl ester of 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zealand white rabbits were intravitreally injected with one of three preparations of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intraocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injection of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitreal compound aggregates in eyes with the middle and high doses. The intraocular therapeutic index was lower than 465:1. Intravitreal injection of liposomal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final intravitreal concentrations. No retinal toxicity was confirmed for the 1.12 mM final intravitreal concentration at the eight week observation following injection. The intraocular therapeutic index was between 585-1037:1. ODG-PFA-O-Me possesses better vitreous compatibility than ODG-PFA. Liposomal ODG-PFA-O-Me can be intravitreally injected with a resulting clear vitreous and high intraocular therapeutic index. Liposomal ODG-PFA-O-Me could be a long acting nontoxic intravitreous injectable drug for CMV retinitis.

To determine intraocular toxicity and efficacy of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long-acting, nontoxic intravitreous injectable drug delivery system for cytomegalovirus (CMV) retinitis.ODG-PFA was synthesized by coupling the phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and formulated as micelles and liposomes at concentrations so that, after injection into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM, 0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63 mM for liposomal formulation. The compounds were injected, and toxicology evaluations were performed.Intravitreal injections of micellar ODG-PFA resulted in aggregation of the material in vitreous and variable local retinal damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion of the compounds and a clear vitreous, using final concentration in the vitreous of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was 0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal injection was estimated to be 1470:1.Lipid-derivatized foscarnet liposome formulations may be a useful long-acting delivery system for the therapy of CMV retinitis.

We describe a case of focal cytomegalovirus iritis in a patient with acquired immunodeficiency syndrome (AIDS) who had CMV retinitis. The autopsy showed histologic evidence of focal iritis in the left eye. This iritis was characterized by infiltration of acute inflammatory cells mixed with cytomegalic cells, which was confirmed by CMV-specific immunohistochemical staining. The case suggested that cytomegalovirus could be a direct causative agent of infectious iritis in AIDS patients.