Differential Antimicrobial Efficacy of Multipurpose Solutions against Acanthamoeba Trophozoites.

SIGNIFICANCE: This investigation examines the effectiveness of several common contact lens solutions in the disinfection of Acanthamoeba, which causes a serious eye infection most often resulting from dysfunctional or improper use of contact lens products. PURPOSE: Acanthamoeba keratitis is an eye infection caused by a free-living amoeba, which can lead to extensive corneal damage and frequently blindness. Acanthamoeba keratitis is linked with contact lens use combined with noncompliance with contact lens care cleaning regimens. The patient's choice and use of multipurpose solutions (MPSs) continue to be a risk factor for Acanthamoeba keratitis. Thus, it is critical that the Acanthamoeba disinfection efficacy of the popular MPSs be determined. Here we compare the efficacy of seven major MPSs on the global market. METHODS: Using standard methods of Acanthamoeba disinfection and quantification, Acanthamoeba ATCC 30461, 30868, 50370, and 50676 trophozoites were inoculated into each MPS and held for the manufacturer's recommended disinfection time. Acanthamoeba recovery plates were incubated for 14 days, after which positive wells were identified and cell concentrations determined using the 50% endpoint method. RESULTS: Members of the OPTI-FREE products (Express, Replenish, and Puremoist [Alcon, Fort Worth, TX]) demonstrated significantly higher percentages of antimicrobial activity compared with the renu Advanced Formula (Bausch + Lomb, Rochester, NY), Biotrue (Bausch + Lomb), Acuvue RevitaLens (Johnson & Johnson, Santa Ana, CA), and Lite products (Cooper Vision, Scottsville, NY) for four of the trophozoite strains tested. CONCLUSIONS: Many of the popular MPS biocides maintain little or no antimicrobial activity against Acanthamoeba trophozoites, and the number of biocides in an MPS does not necessarily indicate its antimicrobial activity.

Double-read of skeletal surveys in suspected non-accidental trauma: what we learned.

BACKGROUND: Missing a fracture in a child on skeletal surveys for suspected non-accidental trauma can have devastating results. Double-read has the potential to improve fracture detection. However the yield of double-read is unknown. OBJECTIVE: To determine the advantage of double-read versus single-read of radiographic skeletal surveys for suspected non-accidental trauma. MATERIALS AND METHODS: The study was performed in two phases. In the first phase (April 2013 to September 2013), double-read was performed for all skeletal surveys obtained during weekday working hours. Because we had no new double-read findings in studies initially read as negative, we conducted a second phase (January 2014 to March 2014). In the second phase we limited double-reads to skeletal surveys found positive on the first read. At the end of this period, we retrospectively performed double-read for all initially negative skeletal surveys. We excluded follow-up skeletal surveys. The difference in discrepancy (new fracture or false diagnosis of a fracture) ratio between negative and positive skeletal surveys was evaluated using the Fisher exact test, and change in discrepancy ratio between the first and second study phases was evaluated using the stratified Cochran-Mantel-Haenszel test. RESULTS: Overall in the two phases, 178 skeletal surveys were performed in 178 children (67 girls) with mean age of 9 months (range 3 days to 3.7 years). Double-read found 16 discrepancies in 8/178 (4.5%) skeletal surveys. Seven of these studies showed additional fractures (n=15). In one study, an initial read of a skull fracture was read as a variant on the second read. There was a significant (P=0.01) difference between rate of disagreement in negative skeletal surveys (1/104, 1.0%) and positive skeletal surveys (7/74, 9.5%). No significant change in disagreement rate was demonstrated between the two phases of the study (P=0.59). CONCLUSION: Double-read of skeletal survey for suspected non-accidental trauma found false-negative fractures in a few cases and rarely found false-positive diagnosis of a fracture. Double-read uncommonly found discrepancies in an initially normal skeletal survey. Limiting double-read to initially positive studies improves the yield of the double-read.

The cortisol awakening response in a 3 month clinical trial of service dogs for veterans with posttraumatic stress disorder.

Recent literature suggests that service dogs may be a valuable complementary intervention option for posttraumatic stress disorder (PTSD) among military veterans due to the potential influence on stress response dysregulation. The aim of this short-term longitudinal study was to quantify the impact of service dogs in US military veterans with PTSD with particular attention to the cortisol awakening response. A sub aim of the study was to empirically evaluate the physiological effects of PTSD service dogs on veteran partners. We conducted a clinical trial (ID: NCT03245814) that assessed the cortisol awakening response for 245 participants at baseline and 3 months follow-up across an intervention group (service dog: veterans n = 88, partners n = 46) and control group (usual care: n = 73, partners n = 38). A total of N = 161 veterans and N = 84 partners collected whole saliva samples via a passive drool collection immediately upon waking, 30 min after waking, and 45 min after waking on three consecutive weekdays at baseline and again at follow-up. Mixed model repeated measures (MMRM) with a fixed effect of the intervention group (service dog or control) were utilized. Covariates considered for the model included time of awakening, sleep duration, sleep efficiency, prior day experiences (measured via ecological momentary assessment), traumatic brain injury, age, gender, race, ethnicity, socioeconomic status, smoking status, alcohol use, physical health, and body mass index. A total of 3951 salivary samples were collected (veterans: 2613, partners: 1338). MMRM results demonstrated that veterans with a service dog had a statistically significant higher cortisol awakening response, including the area under the curve with respect to both increase (AUCi, ß = 1.46, p = 0.046) and absolute increase (AINC, ß = 0.05, p = 0.035). Results were not statistically significant for partners. Findings suggest that veterans with service dogs have a higher, less blunted CAR in comparison to veterans receiving usual care alone. In veterans with a blunted morning cortisol response, service dog placement could help boost their morning cortisol response.

Differential drug response in pulmonary arterial hypertension: The potential for precision medicine.

Pulmonary arterial hypertension (PAH) is a rare, complex, and deadly cardiopulmonary disease. It is characterized by changes in endothelial cell function and smooth muscle cell proliferation in the pulmonary arteries, causing persistent vasoconstriction, resulting in right heart hypertrophy and failure. There are multiple drug classes specific to PAH treatment, but variation between patients may impact treatment response. A small subset of patients is responsive to pulmonary vasodilators and can be treated with calcium channel blockers, which would be deleterious if prescribed to a typical PAH patient. Little is known about the underlying cause of this important difference in vasoresponsive PAH patients. Sex, race/ethnicity, and pharmacogenomics may also factor into efficacy and safety of PAH-specific drugs. Research has indicated that endothelin receptor antagonists may be more effective in women and there have been some minor differences found in certain races and ethnicities, but these findings are muddled by the impact of socioeconomic factors and a lack of representation of non-White patients in clinical trials. Genetic variants in genes such as CYP3A5, CYP2C9, PTGIS, PTGIR, GNG2, CHST3, and CHST13 may influence the efficacy and safety of certain PAH-specific drugs. PAH research faces many challenges, but there is potential for new methodologies to glean new insights into PAH development and treatment.

Psychiatric service dog placements are associated with better daily psychosocial functioning for military veterans with posttraumatic stress disorder.

OBJECTIVE: Psychiatric service dog placements may benefit psychosocial functioning for veterans with posttraumatic stress disorder (PTSD), however, these effects have never been examined directly in daily life. This nonrandomized longitudinal clinical trial quantified the efficacy of psychiatric service dogs for daily psychosocial functioning among N = 168 veterans with PTSD using ecological momentary assessment (EMA). METHOD: EMA data were collected twice daily for 2 weeks at each assessment period (0 and 3 months), totaling 9,408 survey responses (2 Assessments × 14 Days × 2 Prompts × 168 Participants). RESULTS: At follow-up, regression analysis identified associations between service dog placement and better perceived social interaction quality (ß = 0.42, p < .05), better affect (negative affect: ß = -2.64, p < .001; positive affect: ß = 2.44, p < .001), and lower odds of panic attacks (OR = 0.68, p < .05). Social participation results were mixed: placements were associated with greater activity participation (ß = 3.21, p < .001) but lower odds of being away from home (OR = 0.77, p < .05), indicating possible support for anecdotes that public stigma is an obstacle to community participation. CONCLUSIONS: Results further revealed that the service dog's trained tasks may be particularly important for social functioning outcomes, and the service dog's presence for emotional functioning outcomes. Findings highlight a need for education surrounding service dog etiquette and reveal potential mechanisms underlying psychiatric service dog placements. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Posttraumatic stress disorder service dogs and the wellbeing of veteran families.

Background: Benefits and challenges associated with service dogs for veterans with posttraumatic stress disorder (PTSD) may extend beyond veterans to their families. Objective: The purpose of the current study is to evaluate the impact of veterans' PTSD service dogs on spouses and families in a parallel-group, longitudinal design with assessments at baseline and three months follow-up. Method: A total of 88 United States military veteran spouses completed a survey composed of multiple standardized measures at baseline and three months later. In the intervention group (n = 48), veterans received service dogs shortly after baseline while the waitlist control group (n = 40) did not. Results: Linear regression analyses demonstrated significantly lower caregiver satisfaction, higher caregiver burden and higher participation in life activities among spouses who had service dogs in their homes compared to those on the waitlist. Though not significant, small effect sizes were present among additional measures. Conclusion: Results suggest that although previous literature demonstrates service dogs may offer significant improvements for veterans, spouses and children may not experience those same benefits. Clinicians should consider how to prepare veteran spouses and families for integrating service dogs into their home. Future studies should explore family-focused approaches for service dog integration, defining an optimal strategy for the benefit of the entire family. HIGHLIGHTS: Though service dogs may improve wellbeing for veterans with posttraumatic disorder, families of veterans may not experience those same benefits. Researchers and clinicians should consider how to best prepare veteran families for integrating service dogs into their homes.Though posttraumatic stress disorder (PTSD) service dogs are trained specifically for veterans, recent studies have demonstrated that their impact may go beyond veterans themselves (McCall, Rodriguez, Wadsworth, Meis, & O'Haire, 2020; Nieforth, Craig, Behmer, MacDermid Wadsworth, & O'Haire, 2021). PTSD service dogs may provide both benefits and challenges for veteran families.

Antecedentes: Los beneficios y desafíos asociados con los perros de asistencia para veteranos con trastorno de estrés postraumático (TEPT) pueden extenderse más allá de los veteranos a sus familias. Objetivo: El propósito del estudio actual es evaluar el impacto de los perros de asistencia en el TEPT de cónyuges y familias de veteranos en un diseño longitudinal de grupos paralelos con evaluaciones al inicio y a los tres meses de seguimiento. Método: Un total de 88 cónyuges de veteranos militares de los Estados Unidos completaron una encuesta compuesta por múltiples medidas estandarizadas al inicio y tres meses después. En el grupo de intervención (n = 48), los veteranos recibieron perros de asistencia poco después del inicio, mientras que el grupo de control en lista de espera (n = 40) no lo hizo. Resultados: Los análisis de regresión lineal demostraron una satisfacción del cuidador significativamente menor, una mayor carga del cuidador y una mayor participación en las actividades de la vida entre los cónyuges que tenían perros de asistencia en sus hogares, comparado con los que estaban en la lista de espera. Aunque no significativos, pequeños tamaños de efecto estuvieron presentes entre las medidas adicionales. Conclusión: Los resultados sugieren que aunque la literatura previa demuestra que los perros de asistencia pueden ofrecer mejorías significativas para los veteranos, es posible que las cónyuges y sus hijos no experimenten los mismos beneficios. Los clínicos deben considerar cómo preparar a las cónyuges y familias de veteranos para integrar perros de asistencia en sus hogares. Los estudios futuros deberían explorar enfoques centrados en las familias para la integración del perro de asistencia, definiendo una estrategia óptima para el beneficio de toda la familia.

Differential Antimicrobial Efficacy of Preservative-Free Contact Lens Disinfection Systems against Common Ocular Pathogens.

Microbial keratitis is a devastating disease that can cause eye damage and blindness and can be the result of infections by several common ocular pathogens. Importantly, some of these pathogens, such as Acanthamoeba, are particularly unsusceptible to biocides in common contact lens care solutions. Therefore, the disinfection efficacy of preservative-free (PF) disinfection systems against bacteria, fungi, and Acanthamoeba trophozoites and cysts should be assessed as products with the most potential to be efficacious against resistant organisms. PF disinfection systems were analyzed for antimicrobial efficacy. These were the one-step (hydrogen peroxide-based) Clear Care and Clear Care Plus systems and the two-step (povidone-iodine-based) Cleadew system. Stand-alone challenges using bacteria, fungi, and Acanthamoeba were prepared according to the International Standards Organization method 14729. These same challenges were also conducted in the presence of the following contact lenses: Boston RGP, Acuvue Oasys, Biofinity, Ultra, and 2-week PremiO. All challenges were performed at the manufacturer's recommended disinfection time. All preservative-free disinfection systems demonstrated similarly high rates of antimicrobial efficacy when challenged with bacteria or fungi, with or without lenses. However, both Clear Care and Clear Care Plus demonstrated significantly greater disinfection efficacy against Acanthamoeba trophozoites and cysts, with and without lenses (P < 0.05). Cleadew efficacy was impacted by the addition of contact lenses, whereas Clear Care/Clear Care Plus maintained similar efficacies in the absence or presence of lenses. While both hydrogen peroxide and povidone-iodine are highly effective against bacteria and fungi, hydrogen peroxide maintains significantly greater disinfection capabilities than povidone-iodine against all forms of Acanthamoeba. IMPORTANCE Understanding the most efficacious products will allow clinicians to best communicate to patients and consumers the safest products on the market to reduce adverse events, including microbial keratitis, during contact lens use.

Reduction of disinfection efficacy of contact lens care products on the global market in the presence of contact lenses and cases.

OBJECTIVE: Sight-threatening infections can be caused by pathogenic micro-organisms colonising the cornea, leading to microbial keratitis (MK). These micro-organisms can be introduced to the eye via improper contact lens use and care. MK can also result from ineffective contact lens care solutions (CLCs), even if the patient is following best practice guidelines. Therefore, it is critical to understand the differences between the effectiveness of popular CLCs on the global market. METHODS AND ANALYSIS: Following the International Standards Organisation standards 14 729 and 18259, bacteria (Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus), fungi (Candida albicans, Fusarium strains) and Acanthamoeba strains were inoculated into each CLC with and without contact lenses, and held for the manufacturer's stated disinfection time. Plate counts were conducted to determine the number of surviving micro-organisms. RESULTS: All CLCs examined met the primary log reduction criteria during stand-alone testing for Pseudomonas, Staphylococcus, Candida and Fusarium. renu Multiplus, All Clean Soft, and Kombilösung Super did not meet the primary criteria when challenged with Serratia. Only OPTI-FREE Express exceeded 4 log reduction for both strains of Acanthamoeba tested. We noted a substantial reduction in disinfection efficacy when CLCs were challenged with Fusarium in the presence of lenses and cases versus stand-alone testing. OPTI-FREE Express demonstrated significantly less net log reduction loss than the other four CLCs tested. CONCLUSION: Of the popular CLCs on the global market, the product which relies on dual biocides polyquaternium-1 and myristamidopropyl dimethylamine demonstrated the highest disinfection efficacy in microbial disinfection challenges in the absence and presence of contact lenses.

Survey of international academic centers and institutes focused on human-animal bond: Scope and landscape in 2021.

Routine surveying of academic centers focused on the human-animal bond is critical to understand the trajectory of the field and to create an environment where centers can learn from one another and build collaborations. The purpose of this manuscript was to report the findings of a survey of these human-animal bond centers, to summarize the status of the field, and to identify changes within the field since 2016. Survey questions concentrated on the demographic characteristics, engagement programs, educational opportunities, and research focuses of the centers. Findings suggest that the field continues to grow as one-third of human-animal bond centers are less than 10 years old. The number of centers that participated in this survey increased by 31% compared to the previous survey (O'Haire et al., 2018). Centers have developed a variety of engagement programs, including animal-assisted intervention and companion animal education programs. About half of the centers (48%) offer degree programs and about one quarter of the centers (24%) offer certificate programs. Most centers (95%) focus their research on companion animals with the most studied companion animal being dogs (95%). The most frequent data collection method was surveys (86%). Qualitative analyses, behavior measures, and physiological measures were also common. The most notable changes from the 2016 survey include overall growth of the field (indicated by the establishment of new centers) and a shift in the specialty area of directors, moving from 44% of directors being veterinarians in 2016 survey to 90% having a human-focused specialty in the 2021 survey. Most centers' research focused on animal-assisted interventions which is consistent with the previous survey. As the field of the human-animal bond continues to grow and more centers emerge, ongoing evaluation of offerings is important to track changes, identify needs, and foster success.

Acanthamoeba spp. aggregate and encyst on contact lens material increasing resistance to disinfection.

Introduction: Acanthamoeba keratitis is often caused when Acanthamoeba contaminate contact lenses and infect the cornea. Acanthamoeba is pervasive in the environment as a motile, foraging trophozoite or biocide-resistant and persistent cyst. As contact lens contamination is a potential first step in infection, we studied Acanthamoeba's behavior and interactions on different contact lens materials. We hypothesized that contact lenses may induce aggregation, which is a precursor to encystment, and that aggregated encystment would be more difficult to disinfect than motile trophozoites. Methods: Six clinically and/or scientifically relevant strains of Acanthamoeba (ATCC 30010, ATCC 30461, ATCC 50370, ATCC 50702, ATCC 50703, and ATCC PRA-115) were investigated on seven different common silicone hydrogel contact lenses, and a no-lens control, for aggregation and encystment for 72 h. Cell count and size were used to determine aggregation, and fluorescent staining was used to understand encystment. RNA seq was performed to describe the genome of Acanthamoeba which was individually motile or aggregated on different lens materials. Disinfection efficacy using three common multi-purpose solutions was calculated to describe the potential disinfection resistance of trophozoites, individual cysts, or spheroids. Results: Acanthamoeba trophozoites of all strains examined demonstrated significantly more aggregation on specific contact lens materials than others, or the no-lens control. Fluorescent staining demonstrated encystment in as little as 4 hours on contact lens materials, which is substantially faster than previously reported in natural or laboratory settings. Gene expression profiles corroborated encystment, with significantly differentially expressed pathways involving actin arrangement and membrane complexes. High disinfection resistance of cysts and spheroids with multi-purpose solutions was observed. Discussion: Aggregation/encystment is a protective mechanism which may enable Acanthamoeba to be more disinfection resistant than individual trophozoites. This study demonstrates that some contact lens materials promote Acanthamoeba aggregation and encystment, and Acanthamoeba spheroids obstruct multi-purpose solutions from disinfecting Acanthamoeba.

Genome-wide association study of platelet factor 4/heparin antibodies in heparin-induced thrombocytopenia.

Heparin, a widely used anticoagulant, carries the risk of an antibody-mediated adverse drug reaction, heparin-induced thrombocytopenia (HIT). A subset of heparin-treated patients produces detectable levels of antibodies against complexes of heparin bound to circulating platelet factor 4 (PF4). Using a genome-wide association study (GWAS) approach, we aimed to identify genetic variants associated with anti-PF4/heparin antibodies that account for the variable antibody response seen in HIT. We performed a GWAS on anti-PF4/heparin antibody levels determined via polyclonal enzyme-linked immunosorbent assays. Our discovery cohort (n = 4237) and replication cohort (n = 807) constituted patients with European ancestry and clinical suspicion of HIT, with cases confirmed via functional assay. Genome-wide significance was considered at α = 5 × 10-8. No variants were significantly associated with anti-PF4/heparin antibody levels in the discovery cohort at a genome-wide significant level. Secondary GWAS analyses included the identification of variants with suggestive associations in the discovery cohort (α = 1 × 10-4). The top variant in both cohorts was rs1555175145 (discovery ß = -0.112 [0.018], P = 2.50 × 10-5; replication ß = -0.104 [0.051], P = .041). In gene set enrichment analysis, 3 gene sets reached false discovery rate-adjusted significance (q < 0.05) in both discovery and replication cohorts: "Leukocyte Transendothelial Migration," "Innate Immune Response," and "Lyase Activity." Our results indicate that genomic variation is not significantly associated with anti-PF4/heparin antibody levels. Given our power to identify variants with moderate frequencies and effect sizes, this evidence suggests genetic variation is not a primary driver of variable antibody response in heparin-treated patients with European ancestry.

Continuous Real-Time Motility Analysis of Acanthamoeba Reveals Sustained Movement in Absence of Nutrients.

Acanthamoeba keratitis is a serious ocular infection which is challenging to treat and can lead to blindness. While this pathogen is ubiquitous and can contaminate contact lenses after contact with water, its habits remain elusive. Understanding this organism's natural behavior will better inform us on how Acanthamoeba colonize contact lens care systems. Acanthamoeba trophozoites were allowed to adhere to either a glass coverslip or non-nutrient agar (NNA) within a flow cell with nutrients (Escherichia coli or an axenic culture medium (AC6)) or without nutrients (Ringer's solution). Images were taken once every 24 s over 12 h and compiled, and videos were analyzed using ImageJ Trackmate software. Acanthamoeba maintained continuous movement for the entire 12 h period. ATCC 50370 had limited differences between conditions and surfaces throughout the experiment. Nutrient differences had a noticeable impact for ATCC 30461, where E. coli resulted in the highest total distance and speed during the early periods of the experiment but had the lowest total distance and speed by 12 h. The Ringer's and AC6 conditions were the most similar between strains, while Acanthamoeba in the E. coli and NNA conditions demonstrated significant differences between strains (p < 0.05). These results indicate that quantifiable visual tracking of Acanthamoeba may be a novel and robust method for identifying the movement of Acanthamoeba in relation to contact lens care products. The present study indicates that Acanthamoeba can undertake sustained movement for at least 12 h with and without nutrients, on both rough and smooth surfaces, and that different strains have divergent behavior.

Elucidation of Cellular Contributions to Heparin-Induced Thrombocytopenia Using Omic Approaches.

Heparin-induced thrombocytopenia (HIT) is an unpredictable, complex, immune-mediated adverse drug reaction associated with a high mortality. Despite decades of research into HIT, fundamental knowledge gaps persist regarding HIT likely due to the complex and unusual nature of the HIT immune response. Such knowledge gaps include the identity of a HIT immunogen, the intrinsic roles of various cell types and their interactions, and the molecular basis that distinguishes pathogenic and non-pathogenic PF4/heparin antibodies. While a key feature of HIT, thrombocytopenia, implicates platelets as a seminal cell fragment in HIT pathogenesis, strong evidence exists for critical roles of multiple cell types. The rise in omic technologies over the last decade has resulted in a number of agnostic, whole system approaches for biological research that may be especially informative for complex phenotypes. Applying multi-omics techniques to HIT has the potential to bring new insights into HIT pathophysiology and identify biomarkers with clinical utility. In this review, we review the clinical, immunological, and molecular features of HIT with emphasis on key cell types and their roles. We then address the applicability of several omic techniques underutilized in HIT, which have the potential to fill knowledge gaps related to HIT biology.

Scientific and policy statements on environmental agents associated with neurodevelopmental disorders.

Given established scientific knowledge, protecting children from neurotoxic exposures from the earliest stages of fetal development is clearly an essential public health measure. By reducing environmental factors that may lead to learning and developmental disorders, we will create a healthier environment in which all children can reach and maintain their full potential. (Gilbert, 2008 ).

Immunogenicity generated by mRNA vaccine encoding VZV gE antigen is comparable to adjuvanted subunit vaccine and better than live attenuated vaccine in nonhuman primates.

Shingles is a painful, blistering rash caused by reactivation of latent varicella-zoster virus (VZV) and most frequently occurs in elderly and immunocompromised individuals. Currently, two approved vaccines for the prevention of shingles are on the market, a live attenuated virus vaccine ZOSTAVAX® (Merck & Co., Inc., Kenilworth, NJ, USA) and an AS01B adjuvanted subunit protein vaccine Shingrix™ (Glaxo Smith Kline, Rockville, MD, USA). Human clinical immunogenicity and vaccine efficacy data is available for these two benchmark vaccines, offering a unique opportunity for comparative analyses with novel vaccine platforms and animal model translatability studies. The studies presented here utilized non-human primates (NHP) to evaluate humoral and cellular immune response by three vaccine modalities: the new platform of lipid nanoparticle (LNP) formulated mRNA encoding VZV gE antigen (VZV gE mRNA/LNP) as compared with well-established platforms of live attenuated VZV (VZV LAV) and adjuvanted VZV gE subunit protein (VZV gE protein/adjuvant). The magnitude of response to vaccination with a single 100-200 µg mRNA dose or two 50 µg mRNA doses of VZV gE mRNA/LNP were comparable to two 50 µg protein doses of VZV gE protein/adjuvant, suggesting the VZV gE mRNA/LNP platform has the potential to elicit a robust immune response, and both modalities generated markedly higher responses than VZV LAV. Additionally, the slopes of decay for VZV-specific antibody titers were roughly similar across all three vaccines, indicating the magnitude of peak immunogenicity was the driving force in determining immune response longevity. Finally, vaccine-induced immunogenicity with VZV LAV and VZV gE protein/adjuvant in NHP closely resembled human clinical trials immune response data for ZOSTAVAX® and Shingrix™, helping to validate NHP as an appropriate preclinical model for evaluating these vaccines.

The new tapestry of risk assessment.

Neurotoxicology is entering a new phase in how it views and practices risk assessment. Perhaps more than any of the other disciplines that comprise the science of toxicology, it has been compelled to consider a daunting array of factors other than those directly coupled to chemical and dose, and the age and sex of the subject population. In epidemiological investigations, researchers are increasingly cognizant of the problems introduced by allegedly controlling for variables classified as confounders or covariates. In essence, they reason, the consequence is blurring or even concealing interactions of exposure with modifiers such as the individual's social ecology. Other researchers question the traditional practice of relying on values such as NOAELs when they are abstracted from a biological entity that in reality represents a multiplicity of intertwined systems. Although neurotoxicologists have come to recognize the complexities of assessing risk in all its dimensions, they still face the challenge of communicating this view to the health professions at large.

MD-Miner: a network-based approach for personalized drug repositioning.

BACKGROUND: Due to advances in next generation sequencing technologies and corresponding reductions in cost, it is now attainable to investigate genome-wide gene expression and variants at a patient-level, so as to better understand and anticipate heterogeneous responses to therapy. Consequently, it is feasible to inform personalized drug treatment decisions using personal genomics data. However, these efforts are limited due to a lack of reliable computational approaches for predicting effective drugs for individual patients. The reverse gene set enrichment analysis (i.e., connectivity mapping) approach and its variants have been widely and successfully used for drug prediction. However, the performance of these methods is limited by undefined mechanism of action (MoA) of drugs and reliance on cohorts of patients rather than personalized predictions for individual patients. RESULTS: In this study, we have developed and evaluated a computational approach, known as Mechanism and Drug Miner (MD-Miner), using a network-based computational approach to predict effective drugs and reveal potential drug mechanisms of action at the level of signaling pathways. Specifically, the patient-specific signaling network is constructed by integrating known disease associated genes with patient-derived gene expression profiles. In parallel, a drug mechanism of action network is constructed by integrating drug targets and z-score profiles of drug-induced gene expression (pre vs. post-drug treatment). Potentially effective candidate drugs are prioritized according to the number of common genes between the patient-specific dysfunctional signaling network and drug MoA network. We evaluated the MD-Miner method on the PC-3 prostate cancer cell line, and showed that it significantly improved the success rate of discovering effective drugs compared with the random selection, and could provide insight into potential mechanisms of action. CONCLUSIONS: This work provides a signaling network-based drug repositioning approach. Compared with the reverse gene signature based drug repositioning approaches, the proposed method can provide clues of mechanism of action in terms of signaling transduction networks.

Second harmonic generation microscopy as a tool for the early detection of crystallization in spray dried dispersions.

Various techniques have been used to detect crystallization in amorphous solid dispersions (ASD). However, most of these techniques do not enable the detection of very low levels of crystallinity (<1%). The aim of the current study was to compare the sensitivity of second harmonic generation (SHG) microscopy with powder X-ray diffraction (XRPD) in detecting the presence of crystals in low drug loading amorphous solid dispersions. Amorphous solid dispersions of the poorly water soluble compounds, flutamide (FTM, 15wt.% drug loading) and ezetimibe (EZT, 30wt.% drug loading) with hydroxypropyl methylcellulose acetate succinate (HPMCAS) were prepared by spray drying. To induce crystallization, samples were subsequently stored at 75% or 82% relative humidity (RH) and 40°C. Crystallization was monitored by XRPD and by SHG microscopy. Solid state nuclear magnetic resonance spectroscopy (ssNMR) was used to further investigate crystallinity in selected samples. For flutamide, crystals were detected by SHG microscopy after 8days of storage at 40°C/82% RH, whereas no evidence of crystallinity could be observed by XRPD until 26days. Correspondingly, for FTM samples stored at 40°C/75% RH, crystals were detected after 11days by SHG microscopy and after 53days by XRPD. The evolution of crystals, that is an increase in the number and size of crystalline regions, with time could be readily monitored from the SHG images, and revealed the formation of needle-shaped crystals. Further investigation with scanning electron microscopy indicated an unexpected mechanism of crystallization, whereby flutamide crystals grew as needle-shaped projections from the surface of the spray dried particles. Similarly, EZT crystals could be detected at earlier time points (15days) with SHG microscopy relative to with XRPD (60days). Thus, SHG microscopy was found to be a highly sensitive method for detecting and monitoring the evolution of crystals formed from spray dried particles, providing much earlier detection of crystallinity than XRPD under comparable run times.

Dave Eggers's a heartbreaking work of staggering genius: memoir as a "pain-relief device".

Dave Eggers's memoir is an important addition to the tradition of autobiography in America, and offers significant contributions to our understanding of creativity, sublimation, and the psychology of the memoir-writing process. A Heartbreaking Work of Staggering Genius is really two books--an autobiographical narrative about unbearable suffering, and a book of psychoanalytic commentary on the challenges of writing a memoir about catastrophic loss and trauma. The main narrative suggests the psychological resilience it takes to contain unbearable suffering. The metanarrative renders transparent the mind of someone who is both remembering his losses and constantly reflecting upon the process of writing about them. Eggers's identification with authorship, rather than bereavement or traumatization, may have played an important role in containing his affect and his sense of self when the heartbreaking events were originally unfolding. But a price is paid when a son uses his art to construct a new identity as an author--unconscious conflicts, primitive affect, anxieties about failing, as well as guilt about succeeding--consequences often missed by readers. Heartbreaking is a palimpsest, a story about story-telling superimposed on tales of death and survival, but its messages will be missed unless all its parts are preserved when being read or studied.