Mid-term surgical success after transscleral ab interno glaucoma gel stent implantation.

PURPOSE: To investigate the surgical success and efficacy of XEN45 implantation (XEN45 µm, AbbVie Inc., USA) with and without combined cataract surgery up to the first 5 years. METHODS: In a prospective observational monocentric trial, 192 eyes of 157 patients with open-angle glaucoma received either XEN45 implants only (solo surgery group) or combined surgery/cataract surgeries (combined surgery group). Surgical success (qualified and full success; IOP-limit: ≤12, 15, 18, 21 mmHg), time to secondary IOP-lowering procedure, IOP and number of IOP-lowering medications were analysed for 1, 2, 3, 4 and 5 years. RESULTS: Compared to baseline, IOP (24.1 ± 8.1 to 12.6 ± 2.8 mmHg, -48%, p < 0.001) and the number of IOP-lowering medications (3.0 ± 1.0 to 1.5 ± 1.2, -50%, p < 0.001) decreased significantly at 5 years. Although no differences between IOP and the number of IOP-lowering medication courses between the groups were detected at 5 years (p > 0.11), the combined procedure (63%, 37%) showed better success rates compared to the solo procedure (36%, 13%) in the definition IOP ≤18 and ≤12 mmHg (p = 0.035, 0.028). Solo XEN45 procedures had a higher rate of secondary IOP-lowering procedures compared to combined XEN45 cataract procedures (hazard ratio: 2.02, 95%CI: 1.03-3.97, p = 0.04). Twenty per cent of the eyes, including both procedures, required a secondary IOP-lowering procedure within 5 years. CONCLUSIONS: The XEN45 implant is effective in lowering IOP and the number of IOP-lowering medications in patients with open-angle glaucoma in the mid-term. Comparing XEN45 implant results with the results of trabeculectomy available in current literature, we speculate that there might be a higher surgical success rate without medications in favour of trabeculectomy.

Structure-based molecular networking, molecular docking, dynamics simulation and pharmacokinetic studies of Olax subscorpioidea for identification of potential inhibitors against selected cancer targets.

The rationale at the basis of targeted approach in oncology is radically shifting-from development of highly specific agents aiming at a single target towards molecules interfering with multiple targets. This study was performed to isolate and characterize bioactive molecules from Olax subscorpioidea stem and investigate their potentials as multi-targeted inhibitors against selected non-small cell lung cancer, breast cancer and chronic myelogenous leukemia oncogenic targets. Three compounds: ß-sitosterol (1), α-amyrin (2) and stigmasterol (3) were isolated. The structures of 1 - 3 were elucidated by analysis of their spectroscopic data (NMR, MS and IR). To the best of our knowledge, this is the first time these compounds were isolated from O. subscorpioidea stems. Furthermore, integrated analysis of MS/MS data using the Global Natural Products Social Molecular Networking (GNPS) workflow enabled dereplication and identification of 26 compounds, including alkaloids (remerine, boldine), terpenoids (3-hydroxy-11-ursen-28,13-olide, oleanolic acid), flavonoids (kaempferitrin, olax chalcone A) and saponins in O. subscorpioidea stem. Molecular docking studies revealed that some of the compounds, including olax chalcone A (-9.2 to -10.9 kcal/mol), 3-Hydroxy-11-ursen-28,13-olide (-6.6 to -10.2 kcal/mol), α-amyrin (-6.6 to -10.2 kcal/mol), stigmasterol (-7.7 to -10.1 kcal/mol), ß-Sitosterol (-7 to -9.9 kcal/mol) and kaempferitrin (-7.7 to -9 kcal/mol) possessed good inhibitory potentials against selected cancer targets, when compared with reference inhibitors (-8.4 to -13.7 kcal/mol). A few of these compounds were shown to have considerable to favorable pharmacokinetic and drug-likeness properties. This study provides some rationale for the use of O. subscorpioidea in ethnomedicinal management of cancer and identifies some potential anticancer agents.Communicated by Ramaswamy H. Sarma.

Predicting fecal composition, intake, and nutrient digestibility in beef cattle consuming high forage diets using near infrared spectroscopy.

The objective of this study was to develop near infrared spectroscopy (NIRS) calibrations to predict fecal nutrient composition, intake, and diet digestibility from beef cattle fed high forage diets. Heifers were fed 12 different forage-based diets (>95% forage dry matter basis) in 3 total collection digestibility studies, resulting in individual fecal samples and related spectra (n = 135), corresponding nutrient intake, and apparent total tract digestibility (aTTD) data. Fecal samples were also collected from steers grazing two annual and two perennial forage mixtures over two growing seasons. Samples (n = 13/paddock) were composited by paddock resulting in 30 samples from year 1, and 24 from year 2. The grazing fecal spectra (n = 54) were added to the existing fecal composition spectral library. Dried and ground fecal samples were scanned using a FOSS DS2500 scanning monochromator (FOSS, Eden Prairie, MN). Spectra were mathematically treated for detrend and scatter correction and modified partial least squares (MPLS) regression was performed. The coefficient of determination for cross validation (R2cv) and standard error of cross validation (SECV) were used to evaluate the quality of calibrations. Prediction equations were developed for fecal composition [organic matter (OM), nitrogen (N), amylase-treated ash-corrected neutral detergent fiber (aNDFom), acid detergent fiber (ADF), acid detergent lignin (ADL), undigestible NDF after 240 h of in vitro incubation (uNDF), calcium (Ca), and phosphorus (P)], digestibility [DM, OM, aNDFom, N], and intake [DM, OM, aNDFom, N, uNDF]. The calibrations for fecal OM, N, aNDFom, ADF, ADL, uNDF, Ca, P resulted in R2cv between 0.86 and 0.97 and SECV of 1.88, 0.07, 1.70, 1.10, 0.61, 2.00, 0.18, and 0.06, respectively. Equations predicting intake of DM, OM, N, aNDFom, ADL, and uNDF resulted in R2cv values between 0.59 and 0.91, SECV values of 1.12, 1.10, 0.02, 0.69, 0.06, 0.24 kg·d-1, respectively, and SECV values between 0.00 and 0.16 when expressed as % body weight (BW). Digestibility calibrations for DM, OM, aNDFom, and N resulted in R2cv ranging from 0.65 to 0.74 and SECV values from 2.20 to 2.82. We confirm the potential of NIRS to predict fecal chemical composition, digestibility, and intake of cattle fed high forage diets. Future steps include validation of the intake calibration equations for grazing cattle using forage internal marker and modelling energetics of grazing growth performance.

Recent assessment and characterization of Tuta absoluta resistance to cartap hydrochloride.

Tuta absoluta can cause 100% loss in tomato yield in Brazil and chemical control, which uses cartap hydrochloride (nereistoxin derivative), is still the most used tactic against T. absoluta populations. Despite the long use of cartap hydrochloride, the genetic and physiological bases underlying the resistance are not known. Resistance to cartap hydrochloride among field populations varied from very low (RR = 2.3 fold) to very high (RR = 537 fold). The Gameleira 2 (GML 2-Res) population was exposed to cartap hydrochloride (up to 500 mg L-1) for few rounds of selection to clean extrinsic factors before used in downstream experiments after 2.5 years without selection in laboratory. Resistance to cartap hydrochloride was autosomal, incompletely recessive, and polyfactorial. The effective dominance (dominance level of survival at a given insecticide dose) at 60 mg of cartap hydrochloride L-1 (which killed 100% of heterozygous individuals) discriminated resistant from susceptible phenotypes. Hydrolases and glutathione S-transferase appear to detoxify cartap hydrochloride as TPP and DEM synergized its toxicity, but CYP450-dependent monooxygenases are as well implicated. Cross-resistance was significant between cartap hydrochloride and methoxyfenozide (RR = 6.99 fold), deltamethrin (RR = 3.57 fold), chlorfenapyr (RR = 3.21 fold), or chlorantraniliprole (RR = 2.83 fold). The characterization of T. absoluta resistance to cartap hydrochloride provides valuable information to refine the management of resistance to insecticides (MRI) program in Brazil with cross resistance pattern very favorable to the rotation of active ingredients that will impair survival of this pest to that insecticide in the field.

Distribution of the cysteinyl leukotriene system components in the human, rat and mouse eye.

The cysteinyl leukotrienes (CysLTs) have important functions in the regulation of inflammation and cellular stress. Blocking the CysLT receptors (CysLTRs) with specific antagonists is beneficial against progression of retinopathies (e.g. diabetic retinopathy, wet AMD). However, the exact cellular localization of the CysLTRs and their endogenous ligands in the eye have not been elucidated in detail yet. It is also not known whether the expression patterns differ between humans and animal models. Therefore, the present study aimed to describe and compare the distribution of two important enzymes in CysLT biosynthesis, 5-lipoxygenase (5-LOX) and 5-lipoxygenase-activating protein (FLAP), and of CysLTR1 and CysLTR2 in healthy human, rat and mouse eyes. Human donor eyes (n = 10) and eyes from adult Sprague Dawley rats (n = 5) and CD1 mice (n = 8) of both sexes were collected. The eyes were fixed in 4% paraformaldehyde and cross-sections were investigated by immunofluorescence with specific antibodies against 5-LOX, FLAP (human tissue only), CysLTR1 and CysLTR2. Flat-mounts of the human choroid were prepared and processed similarly. Expression patterns were assessed and semiquantitatively evaluated using a confocal fluorescence microscope (LSM710, Zeiss). We observed so far unreported expression sites for CysLT system components in various ocular tissues. Overall, we detected expression of 5-LOX, CysLTR1 and CysLTR2 in the human, rat and mouse cornea, conjunctiva, iris, lens, ciliary body, retina and choroid. Importantly, expression profiles of CysLTR1 and CysLTR2 were highly similar between human and rodent eyes. FLAP was expressed in all human ocular tissues except the lens. Largely weak immunoreactivity of FLAP and 5-LOX was observed in a few, yet unidentified, cells of diverse ocular tissues, indicating low levels of CysLT biosynthesis in healthy eyes. CysLTR1 was predominantly detected in ocular epithelial cells, supporting the involvement of CysLTR1 in stress and immune responses. CysLTR2 was predominantly expressed in neuronal structures, suggesting neuromodulatory roles of CysLTR2 in the eye and revealing disparate functions of CysLTRs in ocular tissues. Taken together, we provide a comprehensive protein expression atlas of CysLT system components in the human and rodent eye. While the current study is purely descriptive and therefore does not allow significant functional conclusions yet, it represents an important basis for future studies in diseased ocular tissues in which distribution patterns or expression levels of the CysLT system might be altered. Furthermore, this is the first comprehensive study to elucidate expression patterns of CysLT system components in human and animal models that will help to identify and understand functions of the system as well as mechanisms of action of potential CysLTR ligands in the eye.

Pericyte-derived cells participate in optic nerve scar formation.

Introduction: Pericytes (PCs) are specialized cells located abluminal of endothelial cells on capillaries, fulfilling numerous important functions. Their potential involvement in wound healing and scar formation is achieving increasing attention since years. Thus, many studies investigated the participation of PCs following brain and spinal cord (SC) injury, however, lacking in-depth analysis of lesioned optic nerve (ON) tissue. Further, due to the lack of a unique PC marker and uniform definition of PCs, contradicting results are published. Methods: In the present study the inducible PDGFRß-P2A-CreERT2-tdTomato lineage tracing reporter mouse was used to investigate the participation and trans-differentiation of endogenous PC-derived cells in an ON crush (ONC) injury model, analyzing five different post lesion time points up to 8 weeks post lesion. Results: PC-specific labeling of the reporter was evaluated and confirmed in the unlesioned ON of the reporter mouse. After ONC, we detected PC-derived tdTomato+ cells in the lesion, whereof the majority is not associated with vascular structures. The number of PC-derived tdTomato+ cells within the lesion increased over time, accounting for 60-90% of all PDGFRß+ cells in the lesion. The presence of PDGFRß+tdTomato- cells in the ON scar suggests the existence of fibrotic cell subpopulations of different origins. Discussion: Our results clearly demonstrate the presence of non-vascular associated tdTomato+ cells in the lesion core, indicating the participation of PC-derived cells in fibrotic scar formation following ONC. Thus, these PC-derived cells represent promising target cells for therapeutic treatment strategies to modulate fibrotic scar formation to improve axonal regeneration.

Development of an icIEF assay for monitoring AAV capsid proteins and application to gene therapy products.

Adeno-associated virus (AAV) gene therapy vectors, which contain a DNA transgene packaged into a protein capsid, have shown tremendous therapeutic potential in recent years. Methods traditionally used in quality control labs, such as high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE), do not provide a complete understanding of capsid viral protein (VP) charge heterogeneity. In the present study, we developed simple, one-step sample preparation and charge-based VP separation using imaged capillary isoelectric focusing (icIEF) for monitoring AAV products. The robustness of the method was confirmed through a design of experiments (DoE) exercise. An orthogonal reverse-phase (RP) HPLC method coupled with mass spectrometry was developed to separate and identify charge species. Additionally, capsid point mutants demonstrate the capability of the method to resolve deamidation at a single site on the viral proteins. Finally, case studies using two different AAV serotype vectors establish the icIEF method as stability indicating and demonstrate that increases in acidic species measured by icIEF correlate with increased deamidation, which, we show, results in decreased transduction efficiency. The addition of a rapid and robust icIEF method to the AAV capsid analytical toolkit enables development and consistent manufacturing of well-characterized gene therapy products.

Radius-Maumenee syndrome: A case series with a long-term follow-up.

The aim of the case series is to highlight the surgical challenges experienced like failed intervention, choroidal effusion, a postoperative cystoid macular oedema, and describe treatment options for Radius-Maumenee syndrome. Authors reported on 3 bilateral cases of Radius-Maumenee syndrome which underwent medical treatment, trabeculectomy with Mitomycin C, implantation with XEN45, Ahmed glaucoma valve, Baerveldt glaucoma implant, and cyclophotocoagulation.

Corrigendum: Phenotypic and genetic parameters of circadian rhythms from core body temperature profiles and their relationships with beef steers' production efficiency profiles during successive winter feeding periods.

[This corrects the article DOI: 10.3389/fgene.2023.1026601.].

A reflex testing protocol using two multivariate index assays improves the risk assessment for ovarian cancer in patients with an adnexal mass.

OBJECTIVES: Patients with adnexal masses suspicious for malignancy benefit from referral to oncology specialists during presurgical assessment of the mass. OVA1 is a multivariate assay using a five-biomarker panel which offers high overall and early-stage sensitivity. However, OVA1 has a high false-positive rate for benign masses. Overa, a second-generation multivariate index assay was developed to reduce the false-positive rate. The aim of the present study was to use Overa as a reflex for OVA1 and increase specificity. METHODS: OVA1 cut-off scores were established to place patients into three categories: low, intermediate, and high cancer risk. Samples with intermediate-risk OVA1 scores were reflexed to the Overa and defined as high or low risk. This protocol was tested with 1035 prospectively collected serum samples and validated with an independent prospectively collected sample set (N = 207). RESULTS: Thirty-five per cent (359) of samples had intermediate OVA1 scores. Reflexing these to Overa eliminated 58% of the false-positives and improved the overall specificity from 50% to 72%. This finding was confirmed in the independent dataset, in which the specificity increased from 56% to 73%. CONCLUSIONS: Reflexing samples with intermediate OVA1 scores significantly decreases the false-positive rate, thereby reducing unnecessary surgical referrals.

Phenotypic and genetic parameters of circadian rhythms from core body temperature profiles and their relationships with beef steers' production efficiency profiles during successive winter feeding periods.

This 2-year study evaluated differences in circadian parameters obtained from measures of core body temperatures using telemetric reticulo-rumen and rectal devices during two winter feeding regimes in western Canada. The study also estimated phenotypic correlations and genetic parameters associated with circadian parameters and other production traits in each feeding regime. Each year, 80 weaned steer calves (initial age: 209 ± 11 days; BW: 264 ± 20 kg) from the same cohort were tested over two successive regimes, Fall-Winter (FW) and Winter-Spring (WS) at Lanigan, Saskatchewan, Canada. The steers received forage-based rations in both regimes where the individual feed intake was measured with automatic feeding units. During the trial, the reticulo-rumen (RTMP) and rectal (RCT) temperatures were simultaneously measured every 5 min using telemetric devices. These were used to calculate the circadian parameters (Midline Estimating Statistic Of Rhythms, amplitude, and acrophase/peak time) for both temperature measures. Growth and efficiency performance traits were also determined for all steers. Each steer was assigned into inefficient, neutral, and efficient classes based on the SD of the residual feed intake (RFI), residual gain (RG), and residual intake and gain (RIG) within each year and feeding regime. Higher (p < 0.0003) RTMP and rectal temperature MESORs were observed in the Fall-Winter compared to the Winter-Spring regime. While the two test regimes were different (p < 0.05) for the majority of the RTMP or RCT temperature parameters, they did not differ (p > 0.10) with the production efficiency profiles. The heritability estimates were higher in FW (0.78 ± 0.18 vs. 0.56 ± 0.26) than WS (0.50 ± 0.18 vs. 0.47 ± 0.22) for the rumen and rectal MESORs, respectively. There were positive genetic correlations between the two regimes for the RTMP (0.69 ± 0.21) and RCT (0.32 ± 0.59). There was a negative correlation (p < 0.001) between body temperature and ambient temperature. The high heritability estimates and genetic correlations for rumen and rectal temperature parameters demonstrate their potential as beef genetic improvement tools of economic traits associated with the parameters. However, there are limited practical implications of using only the core-body temperature as a proxy for production efficiency traits for beef steers during winter.

Evaluation of critical care burden following traumatic injury from two randomized controlled trials.

Trauma resuscitation practices have continued to improve with new advances targeting prehospital interventions. The critical care burden associated with severely injured patients at risk of hemorrhage has been poorly characterized. We aim to describe the individual and additive effects of multiorgan failure (MOF) and nosocomial infection (NI) on delayed mortality and resource utilization. A secondary analysis of harmonized data from two large prehospital randomized controlled trials (Prehospital Air Medical Plasma (PAMPer) Trial and Study of Tranexamic Acid during Air and Ground Medical Prehospital Transport (STAAMP) Trial) was conducted. Only those patients who survived beyond the first 24 hours post-injury and spent at least one day in the ICU were included. Patients were stratified by development of MOF only, NI only, both, or neither and diagnosis of early (≤ 3 days) versus late MOF (> 3 days). Risk factors of NI and MOF, time course of these ICU complications, associated mortality, and hospital resource utilization were evaluated. Of the 869 patients who were enrolled in PAMPer and STAAMP and who met study criteria, 27.4% developed MOF only (n = 238), 10.9% developed NI only (n = 95), and 15.3% were diagnosed with both MOF and NI (n = 133). Patients developing NI and/or MOF compared to those who had an uncomplicated ICU course had greater injury severity, lower GCS, and greater shock indexes. Early MOF occurred in isolation, while late MOF more often followed NI. MOF was associated with 65% higher independent risk of 30-day mortality when adjusting for cofounders (OR 1.65; 95% CI 1.04-2.6; p = 0.03), however NI did not significantly affect odds of mortality. NI was individually associated with longer mechanical ventilation, ICU stay, hospital stay, and rehabilitation requirements, and the addition of MOF further increased the burden of inpatient and post-discharge care. MOF and NI remain common complications for those who survive traumatic injury. MOF is a robust independent predictor of mortality following injury in this cohort, and NI is associated with higher resource utilization. Timing of these ICU complications may reveal differences in pathophysiology and offer targets for continued advancements in treatment.

Enhanced Electron Correlation and Significantly Suppressed Thermal Conductivity in Dirac Nodal-Line Metal Nanowires by Chemical Doping.

Enhancing electron correlation in a weakly interacting topological system has great potential to promote correlated topological states of matter with extraordinary quantum properties. Here, the enhancement of electron correlation in a prototypical topological metal, namely iridium dioxide (IrO2 ), via doping with 3d transition metal vanadium is demonstrated. Single-crystalline vanadium-doped IrO2 nanowires are synthesized through chemical vapor deposition where the nanowire yield and morphology are improved by creating rough surfaces on substrates. Vanadium doping leads to a dramatic decrease in Raman intensity without notable peak broadening, signifying the enhancement of electron correlation. The enhanced electron correlation is further evidenced by transport studies where the electrical resistivity is greatly increased and follows an unusual T $\sqrt T $ dependence on the temperature (T). The lattice thermal conductivity is suppressed by an order of magnitude via doping even at room temperature where phonon-impurity scattering becomes less important. Density functional theory calculations suggest that the remarkable reduction of thermal conductivity arises from the complex phonon dispersion and reduced energy gap between phonon branches, which greatly enhances phase space for phonon-phonon Umklapp scattering. This work demonstrates a unique system combining 3d and 5d transition metals in isostructural materials to enrich the system with various types of interactions.

Five-year follow-up of corneal endothelial cell density after transscleral ab interno glaucoma gel stent implantation.

PURPOSE: This study investigates the course of the endothelial cell density over a period of 5 years after XEN45 implantation (XEN45µm, Allergan Plc., USA) with or without combined cataract surgery. METHODS: This is a prospective, cross-sectional, monocentric, non-randomized clinical trial with the intention to treat a population of the University Eye Clinic Glaucoma Service Salzburg. One hundred and fifty-five eyes with preoperative central corneal endothelial cell counts were subjected to XEN45 implantation with (combined surgery group) or without (solo surgery group) combined cataract surgery. Endothelial cell density was measured at 3 corneal positions. XEN45 location parameters were determined with anterior segment OCT and gonioscopy. RESULTS: In the combined surgery group, a significant reduction of central endothelial cell count was found at years 2 and 4 when compared to baseline (p = 0.001 and p = 0.02, n = 86), whereas at years 1, 3, and 5, no change was detected (all p > 0.09). The median reduction of endothelial cell count was - 79 (95% CI: - 183 to - 9) and - 93 (95% CI: - 220 to 23) cells at years 2 and 4, respectively. In the solo surgery group (n = 69), no significant change in endothelial cell counts was detected at any time during the 5-year evaluation period (all p > 0.07). Explorative data analyses revealed that XEN45 location parameters did not significantly influence the course of endothelial cell count over time. CONCLUSIONS: Endothelial cell loss after XEN45 implantation seems to be low. The present data suggest no impact on the position of the implant with regard to central endothelial cell counts in this study.

Report on the GHPP-BloodTrain online workshop on "Authorisation and Licensing of Blood Establishments - Review of quality documentation of blood and blood components", 5th-8th of July 2021.

The GHPP BloodTrain team developed an e-learning concept in response to the COVID-19 travel restrictions, providing training formats with virtual stages that can be completed during the pandemic (and beyond) and on-site stages, where practical exercises and case reports in smaller groups can lead to a deeper understanding of the content. The virtual training workshop on "Authorisation and Licensing of Blood Establishments", hosted by the PEI GHPP BloodTrain from the 5th to the 8th of July 2021, was the first application of this concept. The number of participants could be substantially increased compared to an on-site event thanks to the virtual setting. Participants came mainly from national regulatory authorities and national blood transfusion services. There were also some Ministry of Health representatives from 19 countries from the WHO regions of AFRO, EMRO, and from Indonesia in attendance. The virtual workshop focused on reviewing and evaluating the quality documentation required for approval of processes used by blood establishments to prepare blood components. Presentations were given by members of the GHPP BloodTrain team as well as by representatives of the German Red Cross. The program was complemented by contributions from the WHO HQ and presentations on country-specific experiences from Ghana and Zimbabwe.

Congress report: Online workshop on assessment of technical files for blood screening in vitro diagnostics for sub-Sahara African countries.

OBJECTIVES: The online workshop on IVD regulation was performed to broaden the understanding of the technical documentation needed for IVD licensing and the strategies to asses it. BACKGROUND: Testing of blood donors and donations significantly reduces the risk of transmitting transfusion-transmissible infections. Many test systems are commercially available, but not all meet the recommended sensitivity and specificity standards. Many African countries either lack functional structures for the regulation of IVDs this poses a threat to the quality of the blood supply. MATERIALSAND METHODS: The Paul-Ehrlich-Institut BloodTrain organised an online workshop in September 2021 to introduce staff from several National Regulatory Authorities (NRAs) in Africa to the regulation of IVD and the technical information that need to be provided by the manufacturers of blood screening IVD. Their evaluation was trained in practical exercises. RESULTS: This online workshop brought together over hundred participants from NRAs of 12 African countries. Speakers from PEI, Blood Train, WHO and academia, with experience in IVD regulation trained participants in the various topics addressed during this workshop. CONCLUSIONS: This workshop presented a great starting point for most participating NRAs to set up and/or strengthen their regulatory structures for IVDs.

Advantages and Disadvantages of Using St. John's Wort as a Treatment for Depression.

BACKGROUND AND OBJECTIVES: St. John's wort (SJW) extracts are currently being used to treat depression of various degrees of severity. While many studies have shown it to be superior to placebo, data regarding the effectiveness of using SJW as a stand-alone treatment compared with standard antidepressants has yet to be proven conclusively. This study aims to understand the advantages and disadvantages of SJW as a treatment modality for depression. METHODS:  The authors searched PubMed, JAMA network, Springer Link, Elsevier, Google Scholar, and Scientific Progress databases, from 2011 through August 2021, using the following keywords: St John's wort, Hypericum perforatum, depression, antidepressant, complementary alternative medicine, economic evaluation depression St. wort, St John's wort and depression, antidepressant interactions. This yielded a total of 27 papers following a thorough removal of irrelevant content and dissemination in languages other than English. RESULTS:  In patients with mild and moderate depression, SJW proved superior to placebo. Certain studies comparing the efficacy of SJW versus selective serotonin reuptake inhibitors (SSRIs), especially fluoxetine, reported SJW to be more efficacious, while the majority reported no significant difference. Tricyclic antidepressants were also found to have similar efficacy as SJW. Moreover, treatment with SJW was also found to reduce postmenopausal depression. Regarding the safety profile, although SJW is better tolerated with fewer adverse effects when compared to standardized antidepressants, its predisposition to causing fatal serotonin syndrome, when used in conjunction with other serotonergic agents and drug interactions noted with CYP 450 drugs, raises a question in the safety profile. CONCLUSION:  It is essential to acknowledge that SJW has been used as a treatment measure in Germany. Despite being only listed as a dietary supplement by the FDA and not a drug, SJW has shown to be comparable, if not more efficacious, than most standard treatment options for depression. SJW does prove to be an exciting piece of pharmacotherapy in the realm of mental health and post-menopausal treatment. More prospective studies will help us better understand its efficacy in mild and moderate depression and its ability to serve as a long-term agent. Considering its mechanism of action, its role in relieving patients suffering from an anxiety disorder is also worth considering.

High Dimensional Multiomics Reveals Unique Characteristics of Early Plasma Administration in Polytrauma Patients With TBI.

OBJECTIVES: The authors sought to identify causal factors that explain the selective benefit of prehospital administration of thawed plasma (TP) in traumatic brain injury (TBI) patients using mediation analysis of a multiomic database. BACKGROUND: The Prehospital Air Medical Plasma (PAMPer) Trial showed that patients with TBI and a pronounced systemic response to injury [defined as endotype 2 (E2)], have a survival benefit from prehospital administration of TP. An interrogation of high dimensional proteomics, lipidomics and metabolomics previously demonstrated unique patterns in circulating biomarkers in patients receiving prehospital TP, suggesting that a deeper analysis could reveal causal features specific to TBI patients. METHODS: A novel proteomic database (SomaLogic Inc., aptamer-based assay, 7K platform) was generated using admission blood samples from a subset of patients (n=149) from the PAMPer Trial. This proteomic dataset was combined with previously reported metabolomic and lipidomic datasets from these same patients. A 2-step analysis was performed to identify factors that promote survival in E2-TBI patients who had received early TP. First, features were selected using both linear and multivariate-latent-factor regression analyses. Then, the selected features were entered into the causal mediation analysis. RESULTS: Causal mediation analysis of observable features identified 16 proteins and 41 lipids with a high proportion of mediated effect (>50%) to explain the survival benefit of early TP in E2-TBI patients. The multivariate latent-factor regression analyses also uncovered 5 latent clusters of features with a proportion effect >30%, many in common with the observable features. Among the observable and latent features were protease inhibitors known to inhibit activated protein C and block fibrinolysis (SERPINA5 and CPB2), a clotting factor (factor XI), as well as proteins involved in lipid transport and metabolism (APOE3 and sPLA(2)-XIIA). CONCLUSIONS: These findings suggest that severely injured patients with TBI process exogenous plasma differently than those without TBI. The beneficial effects of early TP in E2-TBI patients may be the result of improved blood clotting and the effect of brain protective factors independent of coagulation.

Identification of Recombinant Chimpanzee Adenovirus C68 Degradation Products Detected by AEX-HPLC.

Physicochemical tests represent important tools for the analytical control strategy of biotherapeutics. For adenoviral modalities, anion-exchange high performance liquid chromatography (AEX-HPLC) represents an important methodology, as it is able to simultaneously provide information on viral particle concentration, product purity and surface charge in a high-throughput manner. During product development of an adenoviral-based therapeutic, an accelerated stability study was performed and showed changes in each of the AEX-HPLC reportable attributes. These changes also correlated with a decrease in product infectivity prompting a detailed characterization of the impurity and mechanism of the surface charge change. Characterization experiments identified the impurity to be free hexon trimer, suggesting that capsid degradation could be contributing to both the impurity and reduced particle concentration. Additional mass spectrometry characterization identified deamidation of specific hexon residues to be associated with the external surface charge modification observed upon thermal stress conditions. To demonstrate a causal relationship between deamidation and surface charge changes observed by AEX-HPLC, site-directed mutagenesis experiments were performed. Through this effort, it was concluded that deamidation of asparagine 414 was responsible for the surface charge alteration observed in the AEX-HPLC profile but was not associated with the reduction in infectivity. Overall, this manuscript details critical characterization efforts conducted to enable understanding of a pivotal physicochemical test for adenoviral based therapeutics.