Crystal and mol-ecular structure of 2-methyl-1,4-phenyl-ene bis-(3,5-di-bromo-benzoate).

The aryl diester compound, 2-methyl-1,4-phenyl-ene bis-(3,5-di-bromo-benzoate), C21H12Br4O4, was synthesized by esterification of methyl hydro-quinone with 3,5-di-bromo-benzoic acid. A crystalline sample was obtained by cooling a sample of the melt (m.p. = 502 K/DSC) to room temperature. The mol-ecular structure consists of a central benzene ring with anti-3,5-di-bromo-benzoate groups symmetrically attached at the 1 and 4 positions and a methyl group attached at the 2 position of the central ring. In the crystal structure (space group P), mol-ecules of the title aryl diester are located on inversion centers imposing disorder of the methyl group and H atom across the central benzene ring. The crystal structure is consolidated by a network of C-H⋯Br hydrogen bonds in addition to weaker and offset π-π inter-actions involving the central benzene rings as well as the rings of the attached 3,5-di-bromo-benzoate groups.

Operative Time, Cost, and Union Rate of Power Rasp Joint Preparation Versus Traditional Preparation in Arthrodesis of the Foot and Rearfoot.

Time spent in the operating room is valuable to both surgeons and patients. One of the biggest rate-limiting factors when it comes to arthrodesis procedures of the foot and ankle is cartilage removal and joint preparation. Power instrumentation in joint preparation provides an avenue to decrease joint preparation time, thus decreasing operating room time and costs. Arthrodesis of 47 joints (n) from 27 patients were included. Power rasp joint preparation in 26 joints was compared to traditional osteotome and curette joint preparation in 21 joints in both time (seconds), cost (total operating room time cost per minute), and union rate. The overall mean joint preparation time using power rasp for the subtalar joint was 268.3 seconds, talonavicular joint 212.3 seconds, calcaneocuboid joint 142.6 seconds, 1st TMT 107.2 seconds. Mean joint preparation time using traditional method for subtalar joint 509.8 seconds, talonavicular joint 393.0 seconds, calcaneocuboid joint 400.0 seconds, 1st TMT 319.6 seconds. Mean cost of joint preparation using power rasp for subtalar joint $165.47, talonavicular joint $130.89, calcaneocuboid joint $87.94, 1st TMT $66.11. Mean cost of joint preparation using traditional techniques for subtalar joint $314.34, talonavicular joint $242.35, calcaneocuboid joint $246.67, 1st TMT $197.33. Overall union rate was 98% (1 asymptomatic non-union). Increasing efficiency in the operating room is vital to every surgeon's practice. Power rasp joint preparation is a viable option to increase efficiency and decrease operative time, this study shows no statistically significant differences in union rate, with comparable rates to existing literature.

High species diversity of Phintella and Phintella-like spiders (Araneae: Salticidae) in Vietnam revealed by DNA-based species delimitation analyses.

Salticidae (jumping spiders) usually exhibit pronounced sexual dimorphism in adult morphology, particularly body coloration and size and shape of the first legs. Consequently, the male and female from the same species might be erroneously assigned to different species or even different genera, which could generate synonymies in classification if only morphological data were used. Phintella is a species-rich genus of Salticidae, which currently exhibits 76 named species. However, the male-female counterpart is unknown for nearly half of the species. In this study, we used a molecular approach to delineate the species boundaries for Phintella and Phintella-like specimens collected in Vietnam, using morphological information as supporting data. We used three gene fragments (mitochondrial COI, 16S-ND1, and nuclear 28S) and biogeographical considerations for species delimitation. A total of 22 putative species were recognized: 18 species of the genus Phintella, one species of the genus Lechia (L. squamata), and three species of the genus Phinteloides. Eleven undescribed species were discovered, of which seven have a male-female combination, two species have only males, and two species have only females. The crown age of Phintella was estimated at the Serravallian stage of the Miocene after the increase of species number around 16 MYA. The crown ages of most putative species recognized in this study were estimated in the Pleistocene, and the divergence among sister species likely occurred from the mid-Miocene to the Pliocene. Our ancestral range reconstruction results showed that the diversification of our ingroup was governed by progressive dispersal events, i.e., Phintella and their related species in Vietnam diversified while expanding their range on the continent. Our results provide fundamental biodiversity data for a high-diversity genus in Vietnamese Phintella spiders.

Donor-Site Morbidity Analysis of Thenar and Hypothenar Flap.

Background For the small glabrous skin defect, Thenar and Hypothenar skin are useful donors and they have been used as a free flap. Because of similar skin characteristics, both flaps have same indications. We will conduct comparative study for the donor morbidity of the Free thenar flap and Hypothenar free flap. Methods From January 2011 to December 2021, demographic data, characteristics of each flap, and complications using retrospective chart review were obtained. Donor outcomes of the patient, who had been followed up for more than 6 months, were measured using photographic analysis and physical examination. General pain was assessed by Numeric Rating Scale (NRS) score, neuropathic pain was assessed by Douleur Neuropathique 4 Questions (DN4) score, scar appearance was assessed by modified Vancouver Scar Scale (mVSS), and patient satisfaction was assessed on a 3-point scale. Statistical analysis was performed on the outcomes. Results Out of the 39 survey respondents, 17 patients received Free thenar flaps, and 22 patients received Hypothenar free flaps. Thenar group had higher NRS, DN4, and mVSS ( p < 0.05). The average scores for the Thenar and Hypothenar groups were 1.35 and 0.27 for NRS, 2.41 and 0.55 for DN4, and 3.12 and 1.59 for mVSS, respectively. Despite the Hypothenar group showing greater satisfaction on the 3-point scale (1.82) compared with the Thenar group (1.47), the difference was not significant ( p = 0.085). Linear regression analysis indicated that flap width did not have a notable impact on the outcome measures, and multiple linear regression analysis revealed no significant interaction between flap width and each of the outcome measures. Conclusion Despite the limited number of participants, higher donor morbidity in general pain, neuropathic pain, and scar formation was noted in the Thenar free flap compared with the Hypothenar free flap. However, no difference in overall patient satisfaction was found between the two groups.

Holmium Laser Enucleation of the Prostate vs Robot-Assisted Simple Prostatectomy for Lower Urinary Tract Symptoms in Patients with Extremely Large Prostates ≥200 cc: A Comparative Analysis.

Introduction and Objectives: Robot-assisted simple prostatectomy (RASP) and holmium laser enucleation of the prostate (HoLEP) are both well-established, minimally invasive surgical treatment options for lower urinary tract symptoms caused by benign prostatic enlargement. We have reported the first comparative analysis of both techniques in patients with prostates of ≥200 cc. Materials and Methods: Between 2009 and 2020 a total of 53 patients with a prostate volume of ≥200 cc were surgically treated at OLV Hospital Aalst (Belgium): 31 underwent RASP and 22 underwent HoLEP. Preoperative and postoperative assessments included uroflowmetry with maximum urinary flow rate (Qmax) and postvoid residual volume (PVR), as well as the International Prostate Symptom Score (IPSS) and quality of life (IPSS-QoL). The complication rates were evaluated according to the Clavien-Dindo Classification. Results: Patients treated with RASP had significantly larger prostate volumes compared with HoLEP (median 226 cc vs 204.5 cc, p = 0.004). After a median follow-up of 14 months, both groups showed a significant improvement in the maximum flow rate (+10.60 mL/s vs +10.70 mL/s, p = 0.724) and a reduction of the IPSS score (-12.50 vs -9, p = 0.246) as well as improvement of the QoL (-3 vs -3, p = 0.880). Median operative time was similar in both groups (150 minutes vs 132.5 minutes, p = 0.665). The amount of resected tissue was lower in the RASP group (134.5 g vs 180 g, p = 0.029) and there was no significant difference in postoperative prostate-specific antigen (1.2 ng/mL vs 0.8 ng/mL, p = 0.112). Despite a similar median catheterization time (3 days vs 2 days, p = 0.748), the median hospitalization time was shorter in the HoLEP group (4 days vs 3 days, p = 0.052). Complication rates were similar in both groups (32% vs 36%, p = 0.987). Conclusion: Our results suggest similar outcomes for RASP and HoLEP in patients with very large prostates ≥200 cc. These findings will require external validation at other high-volume centers.

Comparison of Contemporary Surgical Outcomes Between Holmium Laser Enucleation of the Prostate and Robotic-Assisted Simple Prostatectomy.

PURPOSE OF REVIEW: This study reviews contemporary literature on RASP and HoLEP to evaluate perioperative outcomes, common complications, cost analytics, and future directions of both procedures. RECENT FINDINGS: RASP is indicated for prostates > 80 mL, while HoLEP is size-independent. No notable differences were found in operative time, PSA nadir (surrogate for enucleation volume), re-catheterization rates, or long-term durability. Prolonged incontinence and bladder neck contracture rates are low for both surgeries. Patients experience similar satisfaction outcomes and improvements in uroflowmetry and post-void residual volumes. HoLEP demonstrates shorter hospitalizations, lower transfusion rates, lower costs, and higher rates of same-day discharge. RASP offers a shorter learning curve and lower rates of early postoperative urinary incontinence. HoLEP is a size-independent surgery that offers advantages for patients seeking a minimally invasive procedure with the potential for catheter-free same-day discharge. Future directions with single-port simple prostatectomy may offer parity in same-day discharge, but further research is needed to determine broader feasibility.

Peptides That Block RAS-p21 Protein-Induced Cell Transformation.

This is a review of approaches to the design of peptides and small molecules that selectively block the oncogenic RAS-p21 protein in ras-induced cancers. Single amino acid substitutions in this protein, at critical positions such as at Gly 12 and Gln 61, cause the protein to become oncogenic. These mutant proteins cause over 90 percent of pancreatic cancers, 40-50 percent of colon cancers and about one third of non-small cell cancers of the lung (NSCCL). RAS-p21 is a G-protein that becomes activated when it exchanges GDP for GTP. Several promising approaches have been developed that target mutant (oncogenic) RAS-p21 proteins in these different cancers. These approaches comprise: molecular simulations of mutant and wild-type proteins to identify effector domains, for which peptides can be made that selectively inhibit the oncogenic protein that include PNC-1 (ras residues 115-126), PNC-2 (ras residues 96-110) and PNC7 (ras residues 35-47); the use of contiguous RAS-p21 peptide sequences that can block ras signaling; cyclic peptides from large peptide libraries and small molecule libraries that can be identified in high throughput assays that can selectively stabilize inactive forms of RAS-p21; informatic approaches to discover peptides and small molecules that dock to specific domains of RAS-p21 that can block mitogenic signal transduction by oncogenic RAS-p21; and the use of cell-penetrating peptides (CPPs) that are attached to the variable domains of the anti-RAS-p21 inactivating monoclonal antibody, Y13 259, that selectively enters oncogenic RAS-p21-containing cancer cells, causing these cells to undergo apoptosis. Several new anti-oncogenic RAS-p21 agents, i.e., Amgen's AMG510 and Mirati Therapeutics' MRTX849, polycyclic aromatic compounds, have recently been FDA-approved and are already being used clinically to treat RAS-p21-induced NSCCL and colorectal carcinomas. These new drugs target the inactive form of RAS-p21 bound to GDP with G12C substitution at the critical Gly 12 residue by binding to a groove bordered by specific domains in this mutant protein into which these compounds insert, resulting in the stabilization of the inactive GDP-bound form of RAS-p21. Other peptides and small molecules have been discovered that block the G12D-RAS-p21 oncogenic protein. These agents can treat specific mutant protein-induced cancers and are excellent examples of personalized medicine. However, many oncogenic RAS-p21-induced tumors are caused by other mutations at positions 12, 13 and 61, requiring other, more general anti-oncogenic agents that are being provided using alternate methods.

A novel reactive aldehyde species inhibitor prevents the deleterious effects of ethanol in an animal model of alcoholic liver disease.

BACKGROUND AND AIMS: Current treatment strategies for alcoholic liver disease (ALD) are limited by the lack of agents specifically targeting the metabolic breakdown products of ethanol. Reactive aldehyde species (RASP) inhibitors have been developed that have the capability to sequester these aldehyde byproducts, potentially limiting toxicity. The purpose of this study was to determine if the RASP inhibitor ADX-629 could target these metabolic breakdown products in a mouse model of ALD. METHODS AND RESULTS: A chronic/binge mouse model of ALD was used to determine the efficacy of ADX-629 treatment. Mice were fed an alcohol-containing (5 %) liquid or control diet for 10 days and treated by oral gavage with ADX-629 30 min prior to administering a bolus gavage of 31.5 % ethanol. Test groups included: Control - no ADX, Control + ADX, Ethanol - no ADX and Ethanol + ADX. Compared to ethanol-fed mice receiving sham treatment, ethanol mice treated with ADX-629 demonstrated significant decreases (p < 0.05) in liver acetaldehyde (AA), liver malondialdehyde-acetaldehyde (MAA), circulating anti-MAA antibody, liver/serum triglycerides (p < 0.01) levels, and overall fat accumulation in the liver as determined by Oil Red O and bodipy staining (p < 0.0001). Serum levels of pro-inflammatory cytokines IFN-γ and MCP-1 levels were decreased following ADX-629 treatment (p < 0.01). CONCLUSIONS: These findings demonstrate that the use of this unique RASP inhibitor (ADX-629) is effective in the treatment of ALD. Given the ubiquitous nature of aldehydes in the context of tissue inflammation and damage, ADX-629 and other RASP inhibitors may have additional applications in disease states.

The Th1/Tfh-like biased responses elicited by the rASP-1 innate adjuvant are dependent on TRIF and Type I IFN receptor pathways.

Ov-ASP-1 (rASP-1), a parasite-derived protein secreted by the helminth Onchocerca volvulus, is an adjuvant which enhances the potency of the influenza trivalent vaccine (IIV3), even when used with 40-fold less IIV3. This study is aimed to provide a deeper insight into the molecular networks that underline the adjuvanticity of rASP-1. Here we show that rASP-1 stimulates mouse CD11c+ bone marrow-derived dendritic (BMDCs) to secrete elevated levels of IL-12p40, TNF-α, IP-10 and IFN-ß in a TRIF-dependent but MyD88-independent manner. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th1 cells (IFN-γ+) that was TRIF- and type I interferon receptor (IFNAR)-dependent, and into Tfh-like cells (IL21+) and Tfh1 (IFN-γ+ IL21+) that were TRIF-, MyD88- and IFNAR-dependent. rASP-1-activated BMDCs promoted the differentiation of naïve CD4+ T cells into Th17 (IL-17+) cells only when the MyD88 pathway was inhibited. Importantly, rASP-1-activated human blood cDCs expressed upregulated genes that are associated with DC maturation, type I IFN and type II IFN signaling, as well as TLR4-TRIF dependent signaling. These activated cDCs promoted the differentiation of naïve human CD4+ T cells into Th1, Tfh-like and Th17 cells. Our data thus confirms that the rASP-1 is a potent innate adjuvant that polarizes the adaptive T cell responses to Th1/Tfh1 in both mouse and human DCs. Notably, the rASP-1-adjuvanted IIV3 vaccine elicited protection of mice from a lethal H1N1 infection that is also dependent on the TLR4-TRIF axis and IFNAR signaling pathway, as well as on its ability to induce anti-IIV3 antibody production.

Is "cellular senescence" a misnomer?

One of the most striking findings in biogerontology in the 2010s was the demonstration that elimination of senescent cells delays many late-life diseases and extends lifespan in mice. This implied that accumulation of senescent cells promotes late-life diseases, particularly through action of senescent cell secretions (the senescence-associated secretory phenotype, or SASP). But what exactly is a senescent cell? Subsequent to the initial characterization of cellular senescence, it became clear that, prior to aging, this phenomenon is in fact adaptive. It supports tissue remodeling functions in a variety of contexts, including embryogenesis, parturition, and acute inflammatory processes that restore normal tissue architecture and function, such as wound healing, tissue repair after infection, and amphibian limb regeneration. In these contexts, such cells are normal and healthy and not in any way senescent in the true sense of the word, as originally meant by Hayflick. Thus, it is misleading to refer to them as "senescent." Similarly, the common assertion that senescent cells accumulate with age due to stress and DNA damage is no longer safe, particularly given their role in inflammation-a process that becomes persistent in later life. We therefore suggest that it would be useful to update some terminology, to bring it into line with contemporary understanding, and to avoid future confusion. To open a discussion of this issue, we propose replacing the term cellular senescence with remodeling activation, and SASP with RASP (remodeling-associated secretory phenotype).

Facilitated harvesting of a radial artery superficial palmar branch flap for reconstruction of moderate finger skin defects.

Radial artery superficial palmar branch harvesting is technically challenging, especially for inexperienced hand surgeons. The short pedicle and a damaged recipient digital artery require proximal digital artery dissection and relatively long pedicles. Herein, we describe a facilitated flap elevation technique and its application in various cases. From 2013 to 2021, 10 patients with finger injuries received radial artery superficial palmar flaps. We assessed flap survival, sizes, complications, two-point discrimination, and the Semmes-Weinstein monofilament test results. The main shortcoming of a radial artery superficial palmar flap is its short pedicle. Therefore, we developed a long skin flap design in the long axis direction, and the accompanying vein was dissected proximally to the radial artery to obtain a long pedicle. All flaps survived. The median flap dimension was 5.0 × 2.2 cm (maximum size: 6.0 × 2.0 + 5.0 × 2.0 cm [for a bilobed flap]). While nerve reconstruction was performed in one patient, all patients had preserved sensation. A sufficiently long pedicle can be obtained by dissecting the accompanying vein proximally to the radial artery. Perforators found in the skin around the scaphoid tubercle in all cases suggest value in including this region in flap design. To obtain a longer pedicle, the flap was developed with the long-skin design in the long-axis direction. Although the accompanying vein is usually thin and difficult to anastomose with the finger vein, its proximal dissection led to the accompanying vein of the radial artery that facilitated the harvesting of a sufficiently long vein.

Reproxalap Activity and Estimation of Clinically Relevant Thresholds for Ocular Itching and Redness in a Randomized Allergic Conjunctivitis Field Trial.

INTRODUCTION: This clinical trial assessed the activity of reproxalap, a novel reactive aldehyde species modulator, and estimated clinically relevant thresholds for changes in ocular itching and redness in an allergic conjunctivitis field trial. METHODS: This was a randomized, double-masked, vehicle-controlled phase 2 trial. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days in an environmental setting with approximately four doses per day of either 0.25% reproxalap, 0.5% reproxalap, or vehicle. Patients recorded ocular itching, redness, tearing, and eyelid swelling scores (each with a 0-4 scale, except for a 0-3 scale for swelling), and completed the Allergic Conjunctivitis Quality of Life Questionnaire at the beginning and end of the trial. RESULTS: Mixed model of repeated measures analysis demonstrated statistically lower itching and tearing scores (pooled P = 0.026 and P < 0.001, respectively) and numerically lower redness and eyelid swelling scores than vehicle on days when pollen exceeded the 95th percentile value. Using three anchor-based and three distribution-based approaches, the meaningful within-patient change and the between-group meaningful difference for patient-reported ocular itching and redness was estimated to be approximately 0.5. The most common treatment-emergent adverse event associated with reproxalap was transient irritation upon instillation. CONCLUSION: In a field clinical trial, reproxalap was well tolerated and superior to vehicle in reducing ocular itching on high-pollen days. The clinical meaningfulness threshold estimates of 0.5 units are among the first such calculations generated for the standard ocular itching and redness scores, providing important context for the clinical interpretation of clinical trials in allergic conjunctivitis.

While allergic conjunctivitis affects millions of patients worldwide, treatments with new mechanisms have not been introduced in decades. Reproxalap, a medicine being investigated as a treatment for allergic conjunctivitis, works by regulating reactive aldehyde species­molecules that are increased in a variety of inflammatory diseases. This clinical trial assessed the activity of reproxalap and estimated what amount of change in ocular itching and redness should be considered clinically important. Patients with ragweed-associated allergic conjunctivitis were assessed over 28 days and were given one of three possible eye drops at approximately four doses per day: 0.25% reproxalap; 0.5% reproxalap; or vehicle, which was composed of the same ingredients but does not contain reproxalap. Patients recorded ocular itching, redness, tearing, and eyelid swelling (all scales ranged from 0 [none] to 4 [severe] except for eyelid swelling, which ranged from 0 to 3), and completed a quality-of-life questionnaire on allergic conjunctivitis at the beginning and end of the trial. The results indicated that reproxalap was significantly better than vehicle in reducing itching and tearing scores and was better than vehicle in reducing redness and eyelid swelling scores on days when pollen counts were high. The trial also suggested that a reduction in ocular itching and redness scores of approximately 0.5 or more (scale 0­4) is likely to be clinically important. Overall, reproxalap was well tolerated and no safety concerns were noted. The most common side effect was transient ocular discomfort after eye drop administration.

Therapeutic Targets in Allergic Conjunctivitis.

Allergic conjunctivitis (AC) is a common condition resulting from exposure to allergens such as pollen, animal dander, or mold. It is typically mediated by allergen-induced crosslinking of immunoglobulin E attached to receptors on primed conjunctival mast cells, which results in mast cell degranulation and histamine release, as well as the release of lipid mediators, cytokines, and chemokines. The clinical result is conjunctival hyperemia, tearing, intense itching, and chemosis. Refractory and chronic cases can result in ocular surface complications that may be vision threatening. Patients who experience even mild forms of this disease report an impact on their quality of life. Current treatment options range from non-pharmacologic therapies to ocular and systemic options. However, to adequately control AC, the use of multiple agents is often required. As such, a precise understanding of the immune mechanisms responsible for this ocular surface inflammation is needed to support ongoing research for potential therapeutic targets such as chemokine receptors, cytokine receptors, non-receptor tyrosine kinases, and integrins. This review utilized several published articles regarding the current therapeutic options to treat AC, as well as the pathological and immune mechanisms relevant to AC. This review will also focus on cellular and molecular targets in AC, with particular emphasis on potential therapeutic agents that can attenuate the pathology and immune mechanisms driven by cells, receptors, and molecules that participate in the immunopathogenesis and immunopathology of AC.

Endoscopic Enucleation of the Prostate Is Better than Robot-assisted Simple Prostatectomy.

In 2022, endoscopic enucleation of the prostate (EEP) is the treatment of choice for benign prostatic obstruction (BPO) for glands >80 ml and is a valid alternative for patients with bleeding disorders. Unlike robot-assisted radical prostatectomy, EEP has no additional access-related trauma and can be performed using the same instruments as for bipolar enucleoresection. With favorable costs, EEP can serve as a global solution for BPO treatment.

Reduced Incidence of Perioperative Periprosthetic Fractures Using Hybrid Rasp-Impaction Broaching Over Impaction Broaching When Using the Direct Anterior Approach for Total Hip Arthroplasty.

Background: A not infrequent complication encountered with the direct anterior approach is perioperative fracture. The purpose of this study was to compare the incidence of perioperative fractures using a hybrid rasp-impaction broach vs an impaction broach for a similarly designed stem. Methods: Retrospective study of 798 primary total hip replacements by 1 surgeon performed using noncollared dual tapered femoral stems, including 457 implanted using hybrid rasp-impaction broaching and 341 implanted using impaction broaching. Intraoperative and 90-day postoperative fractures were identified in each group. Bivariate tests and multivariate regression analysis were used to compare the 2 groups. Results: There were 33 (4.1%) fractures in the sample, 13 (2.8%) with hybrid rasp-impaction broaching and 20 (5.8%) with impaction broaching (P = .034). Three (0.7%) intraoperative fractures occurred with hybrid rasp-impaction broaching and 12 (3.5%) with impaction broaching (P = .003). Five (1.1%) total calcar fractures occurred with hybrid rasp-impaction broaching and 11 (3.2%) with impaction broaching (P = .034). Intraoperative calcar fractures occurred with 1 (0.2%) hybrid rasp-impaction broaching and 6 (1.8%) impaction broaching (P = .021). In multivariate analyses, hybrid rasp-impaction broaching had a statistically lower odds ratio (OR) for total fracture (OR 0.45 [0.22 to 0.93]); total intraoperative fracture (OR 0.17 [0.05 to 0.60]); total calcar fracture (OR 0.33 [0.11 to 0.97]); intraoperative calcar fracture (OR 0.11 [0.01 to 0.98]); and rate of readmission (OR 0.27 [0.10 to 0.78]). Conclusion: The use of a hybrid rasp-impaction broach compared with impaction broach led to a reduced incidence of periprosthetic fractures when using a dual tapered stem through the direct anterior approach.

Reproxalap Improves Signs and Symptoms of Allergic Conjunctivitis in an Allergen Chamber: A Real-World Model of Allergen Exposure.

PURPOSE: To assess the prophylactic and treatment activity of reproxalap, a novel reactive aldehyde species inhibitor, in a real-world model of allergen exposure. METHODS: In a randomized, double-masked, vehicle-controlled, crossover Phase 2 trial, 70 adult patients with ≥2 years of moderate to severe allergic conjunctivitis history, a positive skin test to ragweed pollen, and allergen chamber-induced ocular itching and redness scores of ≥2.5 and ≥2 (both scales range from 0 to 4), respectively, were randomized 1:1:1 to one of three sequences: 0.25% reproxalap, 0.5% reproxalap, and placebo; 0.5% reproxalap, placebo, and 0.25% reproxalap; or placebo, 0.25% reproxalap, and 0.5% reproxalap. Symptoms and conjunctival redness were assessed over 3.5 hours in an allergen chamber of aerosolized ragweed pollen (3500 grains/m3). Test article was administered bilaterally just before chamber entry and at 90 minutes after chamber entry. RESULTS: Reproxalap was safe and well tolerated; 66 of 70 enrolled patients completed all visits. Relative to vehicle, both concentrations of reproxalap demonstrated statistically significant and clinically relevant improvements in ocular itching, tearing, and redness over the duration of exposure in the chamber (P < 0.001 for all assessments). Prophylactic and treatment activity of drug were demonstrated. CONCLUSION: In an allergen chamber, reproxalap, a novel reactive aldehyde species inhibitor, was statistically superior to vehicle across the typical symptoms and signs of allergic conjunctivitis. These data are among the first rigorous clinical results demonstrating drug improvement in allergic conjunctivitis in an allergen chamber, a real-world model of allergen exposure.

Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers.

Despite increasingly thorough mechanistic understanding of the dominant genetic drivers of gastrointestinal (GI) tumorigenesis (e.g., Ras/Raf, TP53, etc.), only a small proportion of these molecular alterations are therapeutically actionable. In an attempt to address this therapeutic impasse, our group has proposed an innovative extreme outlier model to identify novel cooperative molecular vulnerabilities in high-risk GI cancers which dictate prognosis, correlate with distinct patterns of metastasis, and define therapeutic sensitivity or resistance. Our model also proposes comprehensive investigation of their downstream transcriptomic, immunomic, metabolic, or upstream epigenomic cellular consequences to reveal novel therapeutic targets in previously "undruggable" tumors with high-risk genomic features. Leveraging this methodology, our and others' data reveal that the genomic cooperativity between Ras and p53 alterations is not only prognostically relevant in GI malignancy, but may also represent the incipient molecular events that initiate and sustain innate immunoregulatory signaling networks within the GI tumor microenvironment, driving T-cell exclusion and therapeutic resistance in these cancers. As such, deciphering the unique transcriptional programs encoded by Ras-p53 cooperativity that promote innate immune trafficking and chronic inflammatory tumor-stromal-immune crosstalk may uncover immunologic vulnerabilities that could be exploited to develop novel therapeutic strategies for these difficult-to-treat malignancies.

A Post-Acute Ocular Tolerability Comparison of Topical Reproxalap 0.25% and Lifitegrast 5% in Patients with Dry Eye Disease.

PURPOSE: To assess the subjective eye drop experience of patients with dry eye disease (DED) over approximately 1 hour after a single dose of two formulations of reproxalap versus lifitegrast. METHODS: Two formulations of topical ocular reproxalap 0.25% were evaluated versus lifitegrast ophthalmic solution 5% in patients with DED in a single-center, double-masked, active-comparator, single-dose crossover clinical trial. Nineteen patients had test article topically administered to both eyes. Treatments were administered 2 to 4 days apart. Comfort assessments, including ocular discomfort, blurry vision, and dysgeusia assessments; ocular descriptive assessments; quality of life assessments; and overall experience questions were completed after each treatment over one hour, beginning at 90 seconds. RESULTS: Both reproxalap formulations scored better in ocular discomfort score (ODS), blurry vision, and dysgeusia assessments than lifitegrast at each timepoint and cumulatively over all time points after instillation. There were lower rates of negative responses for both reproxalap formulations compared to lifitegrast across ocular discomfort, blurry vision, and dysgeusia assessments, and the durations of negative responses were shorter with reproxalap than with lifitegrast. The reproxalap groups experienced fewer quality of life impacts. No significant safety findings were observed following reproxalap or lifitegrast administration. CONCLUSION: The reproxalap eye drop experience over 1 hour after instillation was superior to that of lifitegrast. There were no statistically significant differences between reproxalap groups for ODS, blurry vision, or dysgeusia. The improved performance of reproxalap with regard to the most commonly reported side effects of lifitegrast (ie, ocular discomfort, blurry vision, and dysgeusia) may result in greater patient adherence and lower discontinuation rates.

MR-guided blood-brain barrier opening induced by rapid short-pulse ultrasound in non-human primates.

BACKGROUND: Opening the blood-brain barrier (BBB) with focused ultrasound and microbubbles (MBs) has potential use in non-invasive targeted therapy for central nervous system (CNS) diseases. Rapid short-pulse (RaSP) ultrasound with a microsecond sequence has been proposed as a minimally disruptive and efficient method for opening the BBB. This work aimed to test the feasibility and safety of BBB opening in a non-human primate model using combined RaSP ultrasound sequence and MBs. METHODS: The BBB of 2 rhesus macaques were opened with RaSP and the commonly used 10 millisecond long pulse (LP), combined with microbubble (SonoVueTM, 0.2 µL/g) injection in a bolus. The transducer's central frequency was 300 kHz, and the acoustic pressure was set to 0.56 MPa calibrated in water. The BBB opening procedure was guided and evaluated with contrast-enhanced magnetic resonance imaging. The relative signal enhancement was compared between RaSP and LP sonication. T2-weighted fast-spin echo (FSE) and T2*-weighted gradient echo (GRE) sequences were scanned to evaluate edema and micro-bleeding at the end of the procedure. RESULTS: The relative signal enhancement was significantly higher (P<0.01) in the focal area compared to a similar area of the opposite hemisphere at all time points after sonication in each monkey, indicating the successful opening of the BBB. The relative signal enhancement in RaSP reached more than 60% of that with LP in our experiment, while the energy deposition was only 6% of LP. No edema or hemorrhage was found on magnetic resonance images after RaSP. CONCLUSIONS: Combined RaSP ultrasound and MBs for the BBB opening is a practical method in large animal models.

Rivermead assessment of somatosensory performance: Italian normative data.

The Rivermead assessment of somatosensory performance (RASP) provides a quantitative assessment of somatosensory processing, suitable for brain-damaged patients suffering from stroke. It consists of seven subcomponents: Subtest 1 (sharp/dull discrimination), Subtest 2 (surface pressure touch), Subtest 3 (surface localization), Subtest 4 (sensory extinction), Subtest 5 (2-point discrimination), Subtest 6 (temperature discrimination), and Subtest 7 (proprioception). Overall, the RASP assesses 5 bilateral body regions: face (cheek), hand (palm and back), and foot (sole and back). This study aimed at providing normative data and cut-off scores for RASP subtests, for each body region, in a large Italian population sample. We present results from 300 healthy Italian individuals aged 19 to 98 years. Data represent a comprehensive set of norms that cover each subtest and each body region tested. Performance in Subtests 1, 5, and 6 decreased, for some body regions, with increasing age. Based on these results, norms were stratified for age (seven groups), with the pathological/non-pathological cut-off coinciding with the 5th percentile. Conversely, other results were not influenced by age; in such cases, a single error, in each body region, has to be considered indicative of pathological performance. This independent investigation of all subcomponents of the somatosensory system, for each body region, further confirms RASP's potential in clinical practice, for neurological assessment, as well as in research settings.