Orbital preservation in the treatment of acute invasive fungal sinusitis.

Acute invasive fungal sinusitis (AIFS) is an aggressive disease with significant mortality and morbidity. Surgical debridement is a mainstay of treatment. However, orbital involvement may limit its efficacy and is an independent risk factor for mortality. Traditionally, orbital exenteration has been utilized in cases with orbital invasion and ophthalmoplegia or vision loss. Retrobulbar liposomal amphotericin B injection may improve disease control and has the potential to spare the morbidity associated with exenteration. In this video article, we document the use of serial endonasal debridement with retrobulbar injections to salvage the eye in a patient with significant orbital involvement. A 28-year-old immunocompromised female patient presented with acute onset restricted right extraocular movement, progressive orbital pain, V2 trigeminal numbness, and 20/40 vision. The patient underwent recurrent debridement and retrobulbar injections of liposomal amphotericin B. Her serial exams, including changes in extraocular muscle appearance and gradual improvement in extraocular movement, were documented. The exam six months after initial presentation demonstrated 20/20 vision, minimal extraocular movement restriction, and proper healing of the orbit and ethmoid. The salvage of the patient's orbit suggests that liposomal amphotericin B injections with debridement may be a viable treatment alternative in patients with acute invasive fungal sinusitis and orbital involvement.

Texture perception at the foot sole: Comparison between walking, sitting, and to the hand.

We frequently interact with textured surfaces with both our feet and hands. Like texture's importance for grasping, texture perception via the foot sole might provide important signals about the stability of a surface, aiding in maintaining balance. However, how textures are perceived by the foot, and especially under the high forces experienced during walking, is unknown. The current study builds on extensive research investigating texture perception at the hand by presenting everyday textures to the foot while stepping onto them, exploring them with the foot while sitting, and exploring them with the hand. Participants rated each texture along three perceptual dimensions: roughness, hardness, and stickiness. Participants also rated how stable their posture felt when standing upon each texture. Results show that perceptual ratings of each textural dimension were highly correlated across conditions. Hardness exhibited the greatest consistency and stickiness the weakest. Moreover, correlations between stepping and exploration with the foot were lower than those between exploration with the foot and exploration with the hand, suggesting that mode of interaction (high vs low force) impacts perception more than body region used (foot vs hand). On an individual level, correlations between conditions were higher than those between participants, suggesting that differences are greater between individuals than between mode of interaction or body region. When investigating the relationship to perceived stability, only hardness contributed significantly, with harder surfaces rated as more stable. Overall, tactile perception appears consistent across body regions and interaction modes, although differences in perception are greater during walking.

Charcot-Marie-Tooth Disease and Hearing Loss: A Systematic Review With Meta-Analysis.

OBJECTIVE: To characterize the pattern of hearing loss in Charcot-Marie-Tooth (CMT) disease to help guide clinical management. DATABASES REVIEWED: CINAHL, PubMed, and Scopus. METHODS: Two independent investigators selected studies on CMT patients with pure-tone average (PTA) and auditory brainstem response (ABR) data. Case reports, case series <5 patients, and data that overlapped with another study were excluded. Investigators performed data extraction, quality rating, and risk-of-bias assessment using the Newcastle-Ottawa Scale. Meta-analysis of mean difference using fixed/random effects models was used. Also, data were analyzed using a weighted one-way analysis of variance, with post-hoc Tukey's test for comparison. RESULTS: Ultimately, 6 prospective studies (N = 197) were included. The most common demyelinating subtype (CMT1A) had significantly prolonged ABR latency values across wave III (0.20 ms, 95% confidence interval [CI]: 0.05-0.35), wave V (0.20 ms, 95% CI: 0.01-0.39), waves I-III (0.20 ms, 95% CI: 0.01-0.39), and waves I-V (0.20 ms, 95% CI: 0.01-0.39) when compared to matched controls. The autosomal recessive demyelinating subtype (CMT4C) had significantly worse PTA when compared to the most common subtype (CMT1A) (Δ 28.93 dB, 95% CI 18.34-39.52) and nondemyelinating subtype (CMT2A) (Δ 28.3 dB, 95% CI: 15.98-40.62). CONCLUSIONS: Patients with CMT can present with a variety of phenotypes depending on the causative mutation. The ABR interpeak latency values for the most common demyelinating form of CMT are delayed when compared to matched controls. Most subtypes have normal hearing thresholds, apart from CMT4C, which presents with mild hearing loss on average.

Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.

Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.

The Utility of Sentinel Lymph Node Biopsy in Elderly Patients with Melanoma.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is performed less often for older patients with melanoma. We investigated the association of SLNB and melanoma-specific survival (MSS) in the elderly. METHODS: We retrospectively reviewed the Surveillance, Epidemiology, and End Results (SEER: 2010-2019) for patients ≥ 70 years with cT2-4N0M0 melanoma. We used multivariable Cox proportional hazard models to evaluate the impact of SLNB performance and SLN status on MSS at increasing age cutoffs. In addition, we evaluated the association of different factors with SLNB performance using multivariable logistic regression. RESULTS: We identified 11,548 patients. Sentinel lymph node biopsy occurred in 6754 (58.5%) patients, 1050 (15.5%) of whom had a positive SLN. On adjusted SEER analysis, a negative SLN was independently associated with improved MSS (overall hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.63-0.67) for patients up to 87 years old. Positive SLNB was independently associated with inferior MSS (HR 1.71, 95% CI 1.93-1.98). Increasing age groups were significantly associated with decreased SLNB performance. CONCLUSIONS: Sentinel lymph node biopsy is associated with cancer-specific survival and adds prognostic information for elderly patients with melanoma. Sentinel lymph node biopsy performance should not be eliminated in elderly patients based on age alone, unless justified by poor performance status, patient preference, or other surgical contraindications. Decreased SLNB performance with increasing age in our cohort may indicate a missed therapeutic opportunity in the care of elderly patients with melanoma.

Update on Recommendations for Surveillance for Children with Predisposition to Hematopoietic Malignancy.

Children with certain germline gene variants have an increased risk of developing myelodysplastic syndrome (MDS) and other hematopoietic malignancies (HM), such as leukemias and lymphomas. Recent studies have identified an expanding number of these predisposition genes, with variants most prevalent in children with MDS but also found in other HM. For some hematopoietic malignancy predisposition (HMP) disorders, specifically those with a high risk of MDS, early intervention through hematopoietic stem cell transplantation (HSCT) can favorably impact overall survival, providing a rationale for rigorous surveillance. A multidisciplinary panel of experts at the 2023 AACR Childhood Cancer Predisposition Workshop reviewed the latest advances in the field and updated prior 2017 surveillance recommendations for children with HMP. In addition to general guidance for all children with HMP, which includes annual physical examination, education about the signs and symptoms of HM, consultation with experienced providers, and early assessment by an HSCT specialist, the panel provided specific recommendations for individuals with a higher risk of MDS based on the affected gene. These recommendations include periodic and comprehensive surveillance for individuals with those syndromes associated with higher risk of MDS, including serial bone marrow examinations to monitor for morphologic changes and deep sequencing for somatic changes in genes associated with HM progression. This approach enables close monitoring of disease evolution based on the individual's genetic profile. As more HMP-related genes are discovered and the disorders' natural histories are better defined, these personalized recommendations will serve as a foundation for future guidelines in managing these conditions.

Dynamic assemblies of parvalbumin interneurons in brain oscillations.

Brain oscillations are crucial for perception, memory, and behavior. Parvalbumin-expressing (PV) interneurons are critical for these oscillations, but their population dynamics remain unclear. Using voltage imaging, we simultaneously recorded membrane potentials in up to 26 PV interneurons in vivo during hippocampal ripple oscillations in mice. We found that PV cells generate ripple-frequency rhythms by forming highly dynamic cell assemblies. These assemblies exhibit rapid and significant changes from cycle to cycle, varying greatly in both size and membership. Importantly, this variability is not just random spiking failures of individual neurons. Rather, the activities of other PV cells contain significant information about whether a PV cell spikes or not in a given cycle. This coordination persists without network oscillations, and it exists in subthreshold potentials even when the cells are not spiking. Dynamic assemblies of interneurons may provide a new mechanism to modulate postsynaptic dynamics and impact cognitive functions flexibly and rapidly.

Elucidating and Optimizing the Photochemical Mechanism of Coumarin-Caged Tertiary Amines.

Photoactivatable or "caged" pharmacological agents combine the high spatiotemporal specificity of light application with the molecular specificity of drugs. A key factor in all optopharmacology experiments is the mechanism of uncaging, which dictates the photochemical quantum yield and determines the byproducts produced by the light-driven chemical reaction. In previous work, we demonstrated that coumarin-based photolabile groups could be used to cage tertiary amine drugs as quaternary ammonium salts. Although stable, water-soluble, and useful for experiments in brain tissue, these first-generation compounds exhibit relatively low uncaging quantum yield (Φu < 1%) and release the toxic byproduct formaldehyde upon photolysis. Here, we elucidate the photochemical mechanisms of coumarin-caged tertiary amines and then optimize the major pathway using chemical modification. We discovered that the combination of 3,3-dicarboxyazetidine and bromine substituents shift the mechanism of release to heterolysis, eliminating the formaldehyde byproduct and giving photolabile tertiary amine drugs with Φu > 20%─a 35-fold increase in uncaging efficiency. This new "ABC" cage allows synthesis of improved photoactivatable derivatives of escitalopram and nicotine along with a novel caged agonist of the oxytocin receptor.

Disparities in Receipt of Adjuvant Immunotherapy among Stage III Melanoma Patients.

OBJECTIVES: Melanoma survival has greatly improved with the advent of immunotherapy, but unequal access to these medications may exist due to nonmedical patient factors such as insurance status, educational background, and geographic proximity to treatment. METHODS: We used the National Cancer Database to assess patients with nonmetastatic cutaneous melanoma who underwent surgical resection and sentinel lymph node biopsy (SLNB) with tumor involvement from 2015 to 2020. We evaluated rates of adjuvant immunotherapy among this patient population based on patient, tumor, and facility variables, including insurance status, socioeconomic status, pathologic stage (IIIA-IIID), and treatment facility type and volume. RESULTS: Adjuvant immunotherapy was associated with improved survival for stage III melanoma, with a slight increase in 5-year OS for stage IIIA (87.9% vs. 85.9%, P=0.044) and a higher increase in stages IIIB-D disease (70.3% vs. 59.6%, P<0.001). Receipt of adjuvant immunotherapy was less likely for patients who were older, low socioeconomic status, or uninsured. Low-volume and community cancer centers had higher rates of adjuvant immunotherapy overall for all stage III patients, whereas high-volume and academic centers used adjuvant immunotherapy much less often for stage IIIA patients compared with those in stages IIIB-D. CONCLUSIONS: Our results demonstrate inconsistent use of adjuvant immunotherapy among patients with stage III melanoma despite a significant association with improved survival. Notably, there was a lower use of adjuvant immunotherapy in patients of lower SES and those treated at high-volume centers. Equity in access to novel standards of care represents an opportunity to improve outcomes for patients with melanoma.

Integrated organismal responses induced by projected levels of CO2 and temperature exposures in the early life stages of lake sturgeon.

Atmospheric CO2 and temperature are rising concurrently, and may have profound impacts on the transcriptional, physiological and behavioural responses of aquatic organisms. Further, spring snowmelt may cause transient increases of pCO2 in many freshwater systems. We examined the behavioural, physiological and transcriptomic responses of an ancient fish, the lake sturgeon (Acipenser fulvescens) to projected levels of warming and pCO2 during its most vulnerable period of life, the first year. Specifically, larval fish were raised in either low (16°C) or high (22°C) temperature, and/or low (1000 µatm) or high (2500 µatm) pCO2 in a crossed experimental design over approximately 8 months. Following overwintering, lake sturgeon were exposed to a transient increase in pCO2 of 10,000 µatm, simulating a spring melt based on data in freshwater systems. Transcriptional analyses revealed potential connections to otolith formation and reduced growth in fish exposed to high pCO2 and temperature in combination. Network analyses of differential gene expression revealed different biological processes among the different treatments on the edges of transcriptional networks. Na+/K+-ATPase activity increased in fish not exposed to elevated pCO2 during development, and mRNA abundance of the ß subunit was most strongly predictive of enzyme activity. Behavioural assays revealed a decrease in total activity following an acute CO2 exposure. These results demonstrate compensatory and compounding mechanisms of pCO2 and warming dependent on developmental conditions in lake sturgeon. Conserved elements of the cellular stress response across all organisms provide key information for how other freshwater organisms may respond to future climate change.

IDH1 inhibition potentiates chemotherapy efficacy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a five-year overall survival rate of just 13%, and development of chemotherapy resistance is nearly universal. PDAC cells overexpress wild-type IDH1 that can enable them to overcome metabolic stress, suggesting it could represent a therapeutic target in PDAC. Here, we found that anti-IDH1 therapy enhanced the efficacy of conventional chemotherapeutics. Chemotherapy treatment induced ROS and increased TCA cycle activity in PDAC cells, along with the induction of wild-type IDH1 expression as a key resistance factor. IDH1 facilitated PDAC survival following chemotherapy treatment by supporting mitochondrial function and antioxidant defense to neutralize reactive oxygen species through the generation of alpha-ketoglutarate and NADPH, respectively. Pharmacologic inhibition of wild-type IDH1 with ivosidenib synergized with conventional chemotherapeutics in vitro and potentiated the efficacy of sub-therapeutic doses of these drugs in vivo in murine PDAC models. This promising treatment approach is translatable through available and safe oral inhibitors and provides the basis of an open and accruing clinical trial testing this combination (NCT05209074).

Pharmacotherapy for older people with obesity.

Rates of obesity continue to rise, including in older adults. Use of medication for obesity in the elderly has been considered controversial, due to concerns around potential progression of age-related sarcopenia and a general lack of evidence for its use in this age group. Within this review, we describe the general considerations when prescribing obesity pharmacotherapy for older adults living with obesity. We evaluate in detail the anti-obesity medications currently licenced in Europe, with emphasis on the available efficacy, safety and cardiovascular outcome data gathered from study of older people. Finally, we discuss future directions and avenues of research.

Headache and Facial Pain/Pressure in the Chronic Rhinosinusitis Population: A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the severity and prevalence of headache and facial pain/pressurere in the chronic rhinosinusitis (CRS) population. DATA SOURCES: CINAHL, PubMed, Scopus. REVIEW METHODS: The literature was searched from inception through June 2023 for English language articles documenting "headache" or "facial pain/pressure" and "chronic rhinosinusitis." Data collected included Lund-MacKay computed tomography score, Lund-Kennedy endoscopy score, sinonasal outcome test, and visual analog scale. Meta-analyses were performed on continuous measures (mean), proportions (%), and regression. RESULTS: A total of 69 studies were included with 8643 CRS patients and 703 control patients. The CRS group had a mean age of 44.1 (range: 16-82; 95% confidence interval [CI]: 40.3-48) and 86.1% [95% CI: 76.4-93.5] with nasal polyposis. The control group had a mean age of 39.2 (range: 17-88; 95% CI: 28.7-49.8). All CRS subgroups had significantly more severe headache and facial pain/pressure when compared to the control (P < .0001). Patients without polyps had significantly more severe facial pain/pressure and headache when compared to patients with polyps (P < .0001). Facial pain/pressure is a moderate problem or worse in 29.8% of polypoid patients versus 56.4% of nonpolypoid patients; Δ26.6% [95% CI: 0.7-50; P = .045]. CONCLUSIONS: Across all outcome metrics, CRS patients experience significantly more severe headache and facial pain/pressure when compared to a control population. Nonpolypoid patients experience significantly more severe facial pain/pressure and headache when compared to polypoid patients. The majority of nonpolypoid patients experience facial pain/pressure that is moderate in severity or worse.

PCP auto count: a novel Fiji/ImageJ plug-in for automated quantification of planar cell polarity and cell counting.

Introdution: During development, planes of cells give rise to complex tissues and organs. The proper functioning of these tissues is critically dependent on proper inter- and intra-cellular spatial orientation, a feature known as planar cell polarity (PCP). To study the genetic and environmental factors affecting planar cell polarity, investigators must often manually measure cell orientations, which is a time-consuming endeavor. To automate cell counting and planar cell polarity data collection we developed a Fiji/ImageJ plug-in called PCP Auto Count (PCPA). Methods: PCPA analyzes binary images and identifies "chunks" of white pixels that contain "caves" of infiltrated black pixels. For validation, inner ear sensory epithelia including cochleae and utricles from mice were immunostained for ßII-spectrin and imaged with a confocal microscope. Images were preprocessed using existing Fiji functionality to enhance contrast, make binary, and reduce noise. An investigator rated PCPA cochlear hair cell angle measurements for accuracy using a one to five agreement scale. For utricle samples, PCPA derived measurements were directly compared against manually derived angle measurements and the concordance correlation coefficient (CCC) and Bland-Altman limits of agreement were calculated. PCPA was also tested against previously published images examining PCP in various tissues and across various species suggesting fairly broad utility. Results: PCPA was able to recognize and count 99.81% of cochlear hair cells, and was able to obtain ideally accurate planar cell polarity measurements for at least 96% of hair cells. When allowing for a <10° deviation from "perfect" measurements, PCPA's accuracy increased to 98%-100% for all users and across all samples. When PCPA's measurements were compared with manual angle measurements for E17.5 utricles there was negligible bias (<0.5°), and a CCC of 0.999. Qualitative examination of example images of Drosophila ommatidia, mouse ependymal cells, and mouse radial progenitors revealed a high level of accuracy for PCPA across a variety of stains, tissue types, and species. Discussion: Altogether, the data suggest that the PCPA plug-in suite is a robust and accurate tool for the automated collection of cell counts and PCP angle measurements.

Exploring Cr and molten salt interfacial interactions for molten salt applications.

Molten salts play an important role in various energy-related applications such as high-temperature heat transfer fluids and reaction media. However, the extreme molten salt environment causes the degradation of materials, raising safety and sustainability challenges. A fundamental understanding of material-molten salt interfacial evolution is needed. This work studies the transformation of metallic Cr in molten 50/50 mol% KCl-MgCl2via multi-modal in situ synchrotron X-ray nano-tomography, diffraction and spectroscopy combined with density functional theory (DFT) and ab initio molecular dynamics (AIMD) simulations. Notably, in addition to the dissolution of Cr in the molten salt to form porous structures, a δ-A15 Cr phase was found to gradually form as a result of the metal-salt interaction. This phase change of Cr is associated with a change in the coordination environment of Cr at the interface. DFT and AIMD simulations provide a basis for understanding the enhanced stability of δ-A15 Cr vs. bcc Cr, by revealing their competitive phase thermodynamics at elevated temperatures and probing the interfacial behavior of the molten salt at relevant facets. This study provides critical insights into the morphological and chemical evolution of metal-molten salt interfaces. The combination of multimodal synchrotron analysis and atomic simulation also offers an opportunity to explore a broader range of systems critical to energy applications.

An Age-Stratified Analysis of Early Postoperative Mortality Among Medicare-Eligible Patients With Common Gastrointestinal and Hepato-pancreato-biliary Malignancies.

Background: The frequency of major cancer surgery in the elderly (≥80 years) has increased concomitantly with the rise in average age of the population. We assessed early postoperative mortality following hepato-pancreato-biliary (HPB) and gastrointestinal (GI) procedures for common malignancies stratified by age. Methods: The National Cancer Database (2004-2017) was queried for patients who underwent resection for GI (gastroesophageal and colorectal) or HPB (pancreatic adenocarcinoma, biliary tract, and primary liver) cancers. We compared early postoperative mortality (30 d and 90 d) stratified by age (65-79 vs ≥80 years) and procedure, and compared survival outcomes by age and operative vs nonoperative management. Results: A total of 709,358 patients were included. The 30-day mortality ranged from 1.8% to 5.8% among patients 65-79 years and from 3.2% to 12.4% among patients ≥80 years depending on procedure. The 90-day mortality ranged from 3.6% to 10.6% in patients 65-79 years compared to 8.4%-21.0% among patients ≥80 years. The overall 90-day mortality was 5.2% for patients 65-79 years and 12.0% for patients ≥80 years (P < .001). Age ≥80 was associated with worse survival among operatively managed patients with each upper GI, HPB, and lower GI malignancy relative to younger patients on multivariable analysis. However, operative management of patients ≥80 years was associated with improved survival relative to nonoperative management. Discussion: Elderly patients suffer higher postoperative mortality after major GI and HPB cancer surgery, but operative management is associated with improved survival among patients ≥80 years as compared to nonoperative management. These data are important to contextualize when counseling elderly patients on their treatment options for localized GI and HPB cancers.

UCP1 expression in human brown adipose tissue is inversely associated with cardiometabolic risk factors.

OBJECTIVE: Brown adipose tissue (BAT) is a therapeutic target for obesity. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) is commonly used to quantify human BAT mass and activity. Detectable 18F-FDG uptake by BAT is associated with reduced prevalence of cardiometabolic disease. However, 18F-FDG uptake may not always be a reliable marker of BAT thermogenesis, for example, insulin resistance may reduce glucose uptake. Uncoupling protein 1 (UCP1) is the key thermogenic protein in BAT. Therefore, we hypothesised that UCP1 expression may be altered in individuals with cardiometabolic risk factors. METHODS: We quantified UCP1 expression as an alternative marker of thermogenic capacity in BAT and white adipose tissue (WAT) samples (n = 53) and in differentiated brown and white pre-adipocytes (n = 85). RESULTS: UCP1 expression in BAT, but not in WAT or brown/white differentiated pre-adipocytes, was reduced with increasing age, obesity, and adverse cardiometabolic risk factors such as fasting glucose, insulin, and blood pressure. However, UCP1 expression in BAT was preserved in obese subjects of <40 years of age. To determine if BAT activity was also preserved in vivo, we undertook a case-control study, performing 18F-FDG scanning during mild cold exposure in young (mean age ∼22 years) normal weight and obese volunteers. 18F-FDG uptake by BAT and BAT volume were similar between groups, despite increased insulin resistance. CONCLUSION: 18F-FDG uptake by BAT and UCP1 expression are preserved in young obese adults. Older subjects retain precursor cells with the capacity to form new thermogenic adipocytes. These data highlight the therapeutic potential of BAT mass expansion and activation in obesity.