New Protocol for Twinning of Raman Devices Toward a Raman Intensity Harmonization.

The use of Raman spectroscopy has rapidly been on the rise across a great number of industries where comparability, reproducibility, and reliability of the data are of paramount importance. However, controlling the intensity of the Raman signal depends on a large number of factors such as the wavelength of the laser light, the optical components of each device, or the number of molecules in the illuminated volume. For this reason, in this study, a new protocol has been applied to twin Raman devices to achieve a conversion of the signal between them, by pairing the intensity response of the units using a reference sample. The new reference material is a homogenous dispersion of a 0.5 wt% anatase (titanium dioxide, or TiO2) in an epoxy resin matrix, with deviations <2.5% in Raman intensity across the reference material. The proposed protocol for Raman-twinned devices takes a well-defined approach that leads to obtaining a correction factor that relates the differences in the signal intensity between the two Raman devices, in order to obtain the same Raman intensity counts. The performance of the proposed method was evaluated based on the data from the devices, which presented the most common user cases: twinning Raman devices of the non-confocal same model for two different wavelengths; and twinning confocal and non-confocal devices. The results obtained show that the protocol has worked for both of the Raman twinning cases, allowing the Raman intensity harmonization of Raman spectra between two different devices.

International Map of Axial Spondyloarthritis (IMAS): results from the perspective of 5557 patients from 27 countries around the globe.

BACKGROUND: The International Map of Axial Spondyloarthritis (IMAS) is a global initiative aimed to assess the impact and burden of axial spondyloarthritis (axSpA) and identify the unmet needs from the patient's perspective. METHOD: IMAS is a collaboration between the Axial Spondyloarthritis International Federation (ASIF), the University of Seville, Novartis Pharma AG and steered by a scientific committee. IMAS collected information through an online cross-sectional survey (2017-2022) from unselected patients with axSpA from Europe, Asia, North America, Latin America and Africa who completed a comprehensive questionnaire containing over 120 items. RESULTS: 5557 patients with axSpA participated in IMAS. Mean age was 43.9 ±12.8 years, 55.4% were female, 46.2% had a university education and 51.0% were employed. The mean diagnostic delay was 7.4 ±9.0 years (median: 4.0), and the mean symptom duration was 17.1 ±13.3 years. 75.0% of patients had active disease (Bath Ankylosing Spondylitis Disease Activity Index ≥4), and 59.4% reported poor mental health (12-item General Health Questionnaire ≥3). In the year before the survey, patients had visited primary care physicians 4.6 times and the rheumatologist 3.6 times. 78.6% had taken non-steroidal anti-inflammatory drug ever, 48.8% biological disease-modifying antirheumatic drugs and 43.6% conventional synthetic disease-modifying antirheumatic drugs. Patients's greatest fear was disease progression (55.9%), while the greatest hope was to be able to relieve pain (54.2%). CONCLUSIONS: IMAS shows the global profile of patients with axSpA, highlighting unmet needs, lengthy delays in diagnosis and high burden of disease in patients with axSpA worldwide. This global information will enable more detailed investigations to obtain evidence on the critical issues that matter to patients around the world to improve their care and quality of life.

Factors Associated with Poor Mental Health in Patients with Axial Spondyloarthritis: Results from the International Map of Axial Spondyloarthritis (IMAS).

BACKGROUND: This study aims to assess the prevalence of poor mental health in axial spondyloarthritis (axSpA) and its associated factors in a large sample of patients from the International Map of Axial Spondyloarthritis (IMAS) study from around the globe. METHODS: IMAS is a cross-sectional online survey (2017-2022) that includes 5557 unselected patients with axSpA worldwide. Mental health was evaluated by the 12-item General Health Questionnaire (GHQ-12) and the cut-off point for poor mental health was set at 3. Logistic regression analysis was used to evaluate relationships between the investigated factors and poor mental health (GHQ-12≥3) in patients with axSpA (n=4335). RESULTS: Of 5351 patients, the mean of GHQ-12 was 4.7 and 59.4% were having poor mental health, being 69.9% in South Africa, 63.7% in Latin America, 60.8% in Europe, 54.3% in North America and 51.8% in Asia. Overall, 40.5% and 37.2% of patients experienced anxiety and depression. The factors associated with poor mental health were younger age (OR=0.99), female gender (OR=1.16), being on sick leave or unemployed (OR=1.63), non-physical activity (OR=1.22), smoking (OR=1.20), higher Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] (OR=1.42), functional limitation (OR=1.02) and shorter symptoms duration (OR=0.98). CONCLUSIONS: Globally, 6 in 10 patients with axSpA had poor mental health, with a higher proportion in South Africa and lower in Asia. The factors associated with poor mental health include domains such as younger age, female gender, employment difficulties, harmful habits, disease burden and symptom duration. A holistic management approach to axSpA should encompass both physical and mental health.

Disruption of the mitochondrial network in a mouse model of Huntington's disease visualized by in-tissue multiscale 3D electron microscopy.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the coding sequence of huntingtin protein. Initially, it predominantly affects medium-sized spiny neurons (MSSNs) of the corpus striatum. No effective treatment is still available, thus urging the identification of potential therapeutic targets. While evidence of mitochondrial structural alterations in HD exists, previous studies mainly employed 2D approaches and were performed outside the strictly native brain context. In this study, we adopted a novel multiscale approach to conduct a comprehensive 3D in situ structural analysis of mitochondrial disturbances in a mouse model of HD. We investigated MSSNs within brain tissue under optimal structural conditions utilizing state-of-the-art 3D imaging technologies, specifically FIB/SEM for the complete imaging of neuronal somas and Electron Tomography for detailed morphological examination, and image processing-based quantitative analysis. Our findings suggest a disruption of the mitochondrial network towards fragmentation in HD. The network of interlaced, slim and long mitochondria observed in healthy conditions transforms into isolated, swollen and short entities, with internal cristae disorganization, cavities and abnormally large matrix granules.

Synergistic impact of innate immunity hyper-activation and endothelial dysfunction on the magnitude of organ failure in the infection-sepsis continuum.

OBJECTIVES: identifying host response biomarkers implicated in the emergence of organ failure during infection is key to improving early detection of this complication. METHODS: twenty biomarkers of innate immunity, T-cell response, endothelial dysfunction, coagulation and immunosuppression were profiled in 180 surgical patients with infections of diverse severity (IDS) and 53 with no infection (nIDS). Those better differentiating IDS/nIDS in the area under the curve (AUC) were combined to test their association with the Sequential Organ Failure Assessment (SOFA) score by linear regression analysis in IDS. Results were validated in another IDS cohort of 174 patients. RESULTS: C-reactive protein, procalcitonin, pentraxin-3, lipocalin-2, TNF-α, angiopoietin-2, TREM-1 and IL-15 yielded AUCs ≥ 0.75 to differentiate IDS from nIDS. The combination of lipocalin-2, IL-15, TREM-1, angiopoietin-2 (Dys-4) showed the strongest association with SOFA in IDS (adjusted regression coefficient; standard error; p): Dys-4 (3.55;0.44; <0.001), Lipocalin-2 (2.24; 0.28; <0.001), angiopoietin-2 (1.92; 0.33; <0.001), IL-15 (1.78; 0.40; <0.001), TREM-1(1.74; 0.46; <0.001), TNF-α (1.60; 0.31; <0.001), pentraxin-3 (1.12; 0.18; <0.001), procalcitonin (0.85; 0.12; <0.001). Dys-4 provided similar results in the validation cohort. CONCLUSIONS: there is a synergistic impact of innate immunity hyper-activation (lipocalin-2, IL-15, TREM-1) and endothelial dysfunction (angiopoietin-2) on the magnitude of organ failure during infection.

Lipid signature associated with chronic colon inflammation reveals a dysregulation in colonocyte differentiation process.

Inflammatory Bowel Disease (IBD) comprises a heterogeneous group of chronic inflammatory conditions of the gastrointestinal tract that include ulcerative colitis (UC) and Crohn's disease. Although the etiology is not well understood, IBD is characterized by a loss of the normal epithelium homeostasis that disrupts the intestinal barrier of these patients. Previous work by our group demonstrated that epithelial homeostasis along the colonic crypts involves a tight regulation of lipid profiles. To evaluate whether lipidomic profiles conveyed the functional alterations observed in the colonic epithelium of IBD, we performed matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) analyses of endoscopic biopsies from inflamed and non-inflamed segments obtained from UC patients. Our results indicated that lipid profiling of epithelial cells discriminated between healthy and UC patients. We also demonstrated that epithelial cells of the inflamed mucosa were characterized by a decrease in mono- and di-unsaturated fatty acid-containing phospholipids and higher levels of arachidonic acid-containing species, suggesting an alteration of the lipid gradients occurring concomitantly to the epithelial differentiation. This result was reinforced by the immunofluorescence analysis of EPHB2 and HPGD, markers of epithelial cell differentiation, sustaining that altered lipid profiles were at least partially due to a faulty differentiation process. Overall, our results showed that lipid profiling by MALDI-MSI faithfully conveys molecular and functional alterations associated with the inflamed epithelium, providing the foundation for a novel molecular characterization of UC patients.

Markerauto2: A fast and robust fully automatic fiducial marker-based tilt series alignment software for electron tomography.

Cryoelectron tomography (cryo-ET) has become an indispensable technology for visualizing in situ biological ultrastructures, where the tilt series alignment is the key step to obtain a high-resolution three-dimensional reconstruction. Specifically, with the advent of high-throughput cryo-ET data collection, there is an increasing demand for high-accuracy and fully automatic tilt series alignment, to enable efficient data processing. Here, we propose Markerauto2, a fast and robust fully automatic software that enables accurate fiducial marker-based tilt series alignment. Markerauto2 implements the following novel pipelines: (1) an accelerated high-precision fiducial marker detection with wavelet multiscale template, (2) an ultra-fast and robust fiducial marker tracking supported by hashed geometric features, (3) a high-angle fiducial marker supplementation strategy to produce more complete tracks, and (4) a precise and robust calibration of projection parameters with group-weighted parameter optimization. Comprehensive experiments conducted on both simulated and real-world datasets demonstrate the robustness, efficiency, and effectiveness of the proposed software.

Differences in Volatile Organic Compounds Between Concussed and Non-concussed Division I Athletes.

Introduction Diagnosing a concussion is challenging because of complex and variable symptoms. Establishing a viable biomarker of injury may rely on physiologic measurements rather than symptomology. Volatile organic compounds (VOCs) such as breath acetone have been identified as potential physiological markers that can capture changes in the utilization of energy substrates post-concussion. Here, we aimed to explore whether differences in VOCs exist between concussed and non-concussed athletes at the initial and later stages of injury recovery. Methods Six (N=6) non-concussed athletes were enrolled as control participants prior to the competitive season. Control participants' breath acetone, heart rate, and anthropometric measures were obtained at rest and throughout a single exercise challenge by breathalyzer. Six (N=6) athletes diagnosed with concussion during the competitive season had breath acetone measured daily until cleared to return to activity or approximately four weeks following enrollment where they participated in an exit exercise challenge having breath acetone, heart rate, and anthropometric measures obtained. Comparisons were made between at-rest measures of concussed and non-concussed participants at multiple time points during the recovery period. Paired t-test comparisons with individuals serving as their own control were used to determine individual differences in recovery. Visual graphs were used to demonstrate differences in obtained measures amongst individuals and between groups during the exercise challenges. Results Results demonstrated statistically significant differences in breath acetone between concussed and control participants when the highest day measured during the first week of concussion was compared to the control participant's resting values (P=0.017). Additionally, when the concussed participants served as their own control and their highest measured day of the first week post-concussion was compared to values when cleared to return to activity or at 26 days post-concussion, there was a significant difference in breath acetone (P=0.028). Comparing breath acetone during exercise between non-concussed and cleared concussed participants or four weeks post-injury, demonstrated no significant differences throughout the challenge or at rest prior. Visual graph comparisons in a single participant before and after concussion suggest differences may appear following exercise during the recovery period. Discussion These results suggest VOCs, particularly breath acetone, have the potential to serve as diagnostic markers of concussion. However, longitudinal research within larger cohorts and with equipment able to expel VOCs other than acetone from measures are needed to make informed recommendations.

EXPRESS: Landmark Publications in Analytical Atomic Spectrometry: Fundamentals and Instrumentation Development.

The almost-two-centuries history of spectrochemical analysis has generated a body of literature so vast that it has become nearly intractable for experts, much less for those wishing to enter the field. Authoritative, focused reviews help to address this problem but become so granular that the overall directions of the field are lost. This broader perspective can be provided partially by general overviews but then the thinking, experimental details, theoretical underpinnings and instrumental innovations of the original work must be sacrificed. In the present compilation, this dilemma is overcome by assembling the most impactful publications in the area of analytical atomic spectrometry. Each entry was proposed by at least one current expert in the field and supported by a narrative that justifies its inclusion. The entries were then assembled into a coherent sequence and returned to contributors for a round-robin review.

Regional Differences in Diagnosis Journey and Healthcare Utilization: Results from the International Map of Axial Spondyloarthritis (IMAS).

INTRODUCTION: To assess differences in the diagnosis journey and access to care in a large sample of patients with axial spondyloarthritis (axSpA) from around the world, included in the International Map of Axial Spondyloarthritis (IMAS). METHODS: IMAS was a cross-sectional online survey (2017-2022) of 5557 unselected patients with axSpA from 27 countries. Across five worldwide geographic regions, the patient journey until diagnosis and healthcare utilization in the last 12 months prior to survey were evaluated. Univariable and multivariable linear regression was used to analyze factors associated with higher healthcare utilization. RESULTS: Of 5557 participants in IMAS, the diagnosis took an average of 7.4 years, requiring more than two visits to HCPs (77.7% general practitioner and 51.3% rheumatologist), and more than two diagnostic tests [67.5% performed human leukocyte antigen B27 (HLA-B27), 64.2% x-ray, and 59.1% magnetic resonance imaging (MRI) scans]. North America and Europe were the regions with the highest number of healthcare professional (HCP) visits for diagnosis, while the lowest number of visits was in the Asian region. In the previous 12 months, 94.9% (n = 5272) used at least one healthcare resource, with an average of 29 uses per year. The regions with the highest healthcare utilization were Latin America, Europe, and North America. In the multiple linear regression, factors associated with higher number of healthcare utilization were younger age (b =  - 0.311), female gender (b = 7.736), higher disease activity (b = 1.461), poorer mental health (b = 0.624), greater functional limitation (b = 0.300), greater spinal stiffness (b = 1.527), and longer diagnostic delay (b = 0.104). CONCLUSION: The diagnosis of axSpA usually takes more than two visits to HCPs and at least 7 years. After diagnosis, axSpA is associated with frequent healthcare resource use. Younger age, female gender, higher disease activity, poorer mental health, greater functional limitation, greater spinal stiffness, and longer diagnostic delay are associated with higher healthcare utilization. Europe and North America use more HCP visits and diagnostic tests before and after diagnosis than the other regions.

The effect of sociodemographic characteristics, academic factors, and individual health behaviors on psychological well-being among college students.

Objective: This study aimed to measure the potential relationships between sociodemographic characteristics, academic factors, body mass index (BMI), financial challenges, individual health behaviors, impact of COVID-19, and psychological well-being (PWB) among students. Participants: Undergraduate college students. Methods: Data from the National College Health Assessment III (American College Health Association [ACHA]) were used (n = 1,439). Differences in absolute values among PWB groups were analyzed using analysis of variance (ANOVA). To measure the influence of all factors combined on PWB, multiple regression analyses were performed. Results: Significant differences were observed in age, GPA, financial challenges, and individual health behaviors by PWB groups (p < .05). Being older, being female, having a higher GPA, being a full-time student, having a higher intake of vegetables, taking less time to fall asleep, and having lower stress levels were significantly positively associated with higher PWB scores (p < .05). Conclusions: Multiple considerations related to the academic environment and individual behaviors seem to influence PWB among college students.

sp2-Iminosugar azobenzene O-glycosides: Light-sensitive glycosidase inhibitors with unprecedented tunability and switching factors.

The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and ß-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human ß-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and ß-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.

Chloroplast envelope K+/H+ antiporters are involved in cytosol pH regulation.

Variations in light intensity induce cytosol pH changes in photosynthetic tissues, providing a possible signal to adjust a variety of biochemical, physiological and developmental processes to the energy status of the cells. It was shown that these pH changes are partially due to the transport of protons in or out of the thylakoid lumen. However, the ion transporters in the chloroplast that transmit these pH changes to the cytosol are not known. KEA1 and KEA2 are K+/H+ antiporters in the chloroplast inner envelope that adjust stromal pH in light-to-dark transitions. We previously determined that stromal pH is higher in kea1kea2 mutant cells. In this study, we now show that KEA1 and KEA2 are required to attenuate cytosol pH variations upon sudden light intensity changes in leaf mesophyll cells, showing they are important components of the light-modulated pH signalling module. The kea1kea2 mutant mesophyll cells also have a considerably less negative membrane potential. Membrane potential is dependent on the activity of the plasma membrane proton ATPase and is regulated by secondary ion transporters, mainly potassium channels in the plasma membrane. We did not find significant differences in the activity of the plasma membrane proton pump but found a strongly increased membrane permeability to protons, especially potassium, of the double mutant plasma membranes. Our results indicate that chloroplast envelope K+/H+ antiporters not only affect chloroplast pH but also have a strong impact on cellular ion homeostasis and energization of the plasma membrane.

Crystal Nucleation in Supercooled Atomic Liquids.

The liquid-to-solid phase transition is a complex process that is difficult to investigate experimentally with sufficient spatial and temporal resolution. A key aspect of the transition is the formation of a critical seed of the crystalline phase in a supercooled liquid, that is, a liquid in a metastable state below the melting temperature. This stochastic process is commonly described within the framework of classical nucleation theory, but accurate tests of the theory in atomic and molecular liquids are challenging. Here, we employ femtosecond x-ray diffraction from microscopic liquid jets to study crystal nucleation in supercooled liquids of the rare gases argon and krypton. Our results provide stringent limits to the validity of classical nucleation theory in atomic liquids, and offer the long-sought possibility of testing nonclassical extensions of the theory.

Competition between O-H and S-H Intermolecular Interactions in Conformationally Complex Systems: The 2-Phenylethanethiol and 2-Phenylethanol Dimers.

Noncovalent interactions involving sulfur centers play a relevant role in biological and chemical environments. Yet, detailed molecular descriptions are scarce and limited to very simple model systems. Here we explore the formation of the elusive S-H···S hydrogen bond and the competition between S-H···O and O-H···S interactions in pure and mixed dimers of the conformationally flexible molecules 2-phenylethanethiol (PET) and 2-phenylethanol (PEAL), using the isolated and size-controlled environment of a jet expansion. The structure of both PET-PET and PET-PEAL dimers was unraveled through a comprehensive methodology that combined rotationally resolved microwave spectroscopy, mass-resolved isomer-specific infrared laser spectroscopy, and quantum chemical calculations. This synergic experimental-computational approach offered unique insights into the potential energy surface, conformational equilibria, molecular structure, and intermolecular interactions of the dimers. The results show a preferential order for establishing hydrogen bonds following the sequence S-H···S < S-H···O ≲ O-H···S < O-H···O, despite the hydrogen bond only accounting for a fraction of the total interaction energy.

Activity of propyl-propane-thiosulfinate and propyl-propane-thiosulfonate against carbapenem-resistant Gram-negative bacteria.

Organosulfur compounds derived from plants of the Allium genus, such as propyl-propane-thiosulfinate (PTS) and propyl-propane-thiosulfonate (PTSO), have been proposed as an alternative in antibiotic resistance. The aim of this study was to compare the activity of these substances with other antibiotics against clinical isolates of carbapenem-resistant (CAR-R) and carbapenem-susceptible (CAR-S) Gram-negative bacteria. A total of 126 clinical isolates of CAR-R and 155 CAR-S bacteria were selected, including Enterobacterales, A. baumannii and P. aeruginosa. The antibiotic susceptibility of all isolates was assessed using the microdilution and Kirby-Bauer methods for PTS, PTSO, amoxicillin/clavulanate, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, imipenem, ciprofloxacin, and amikacin. Both PTS and PTSO demonstrated in vitro bactericidal activity against CAR-R Enterobacteriaceae and A. baumannii, with no significant difference in activity compared to their response against CAR-S isolates. However, both compounds were less active against P. aeruginosa than against any of the other bacteria, regardless of their resistance to carbapenems. In all cases, the minimum inhibitory concentration values of PTSO were significantly lower than those of PTS. These findings offer valuable information about the potential antibacterial use of these substances, particularly against infections that currently have limited therapeutic options.

Topical Insulin Eye Drops: Stability and Safety of Two Compounded Formulations for Treating Persistent Corneal Epithelial Defects.

Compounded insulin eye drops were prepared at 1 IU/mL from commercially available subcutaneous insulin by dilution in saline solution or artificial tears. Physicochemical characterization and in vitro tolerance testing in human and conjunctival cells were followed by a 28-day short-term stability study under various conditions. The formulations were isotonic (280-300 mOsm/L), had a pH close to neutral (7-8), medium surface-tension values (<56 MN/m-1), and low (≈1 mPa·s) and medium (≈5 mPa·s) viscosities (compounded normal saline solution and artificial tear-based preparation, respectively). These values remained stable for 28 days under refrigeration. Microbiological stability was also excellent. Insulin potency remained in the 90-110% range in the compounded formulations containing normal saline solution when stored at 2-8 °C for 28 days, while it decreased in those based on artificial tears. Although both formulations were well tolerated in vitro, the compounded insulin diluted in a normal saline solution exhibited better cell tolerance. Preliminary data in humans showed that insulin in saline solution was an effective and safe treatment for persistent corneal epithelial defects. Compounded insulin eye drops diluted in normal saline solution could, therefore, constitute an emergent therapy for the treatment of persistent corneal epithelial defects.

Genetic Upregulation of Activated Protein C Mitigates Delayed Effects of Acute Radiation Exposure in the Mouse Plasma.

Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems, including the kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE in APCHi mice. The APCHi mouse model used in the study was developed in a C57BL/6N background, expressing the D168F/N173K mouse analog of the hyper-activatable human D167F/D172K protein C variant. This modification enables increased circulating APC levels throughout the mouse's lifetime. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS-based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TriCarboxylic Acid (TCA) and urea cycles, and arginine metabolism. We also observed gender- and genotype-modulated metabolic perturbations post radiation exposure. The APCHi mice showed near-normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute γ-radiation exposure in a gender-specific manner can be established for the first time.

Efficacy and Safety of Amenamevir, a Helicase-Primase Inhibitor for the Treatment of Acyclovir-Resistant Herpes Simplex Virus 1 Keratitis.

PURPOSE: The purpose of this study was to describe the efficacy and tolerance of amenamevir (AMNV), an inhibitor of the viral helicase-primase, for the treatment of recalcitrant herpes simplex keratitis (HSK) caused by acyclovir-resistant (ACVR) herpes simplex virus 1 strains. METHODS: In this retrospective case series, 6 consecutive patients with HSK caused by an ACVR herpes simplex virus 1 strain with a failure of conventional antiviral therapy were included after having been treated with AMNV (there was no control group of comparable patients for whom previous treatment would have been continued despite its inefficacy). Medical files were assessed for clinical data including reason(s) for AMNV introduction (frequent recurrences despite appropriate preventive antiviral treatment and/or clinical resistance to suppressive antiviral treatment of an ongoing clinical relapse), genotypical resistance to herpes simplex virus 1 documentation, immune status, clinical types and number of HSK episodes before and during AMNV treatment, adverse effects observed during AMNV treatment, and best corrected visual acuity. RESULTS: Of 6 patients, 4 (66%) did not experience a single recurrence during AMNV therapy while 2 others had recurrences (1 over 24 months of treatment and 2 over 23 months, ie two-fold less frequently than with conventional preventive treatment). On the overall history of these 6 patients, AMNV appeared to be associated with a reduction in HSK recurrences, with a mean of only 0.02 ± 0.04 episodes/month during follow-up under AMNV as compared to 0.14 ± 0.04 episodes/month in the year preceding AMNV introduction (P = 0.03). Improvement in vision acuity was also observed (mean best corrected visual acuity 0.17 ± 0.12 logarithm of the minimum angle of resolution at the end of follow-up vs. 0.30 ± 0.35 before AMNV onset), albeit nonsignificant probably due to the limited number of patients (P = 0.38). Neither clinical nor biological adverse effects were observed while under AMNV during the follow-up (16.5 ± 5.8 months). CONCLUSIONS: Although there was no control group, AMNV may be a valuable option to reduce ACVR HSK recurrences.