Deep Neck Cellulitis, Myositis, and Reactive Lymphadenitis Secondary to Rothia dentocariosa in an Immunocompetent Female: A Case Report.

Rothia dentocariosa is a commensal organism that is typically found in the oropharyngeal and respiratory tracts, and it typically possesses a low virulence profile, especially for immunocompetent patients. The case presented here represents an extremely rare case of deep neck cellulitis, myositis, and reactive lymphadenitis secondary to R. dentocariosa in an immunocompetent female. A 35-year-old female with no significant past medical history presented to the emergency department with neck pain with reduced range of motion, fever, chills, sinus congestion, and headache for one day. After a thorough workup, blood cultures grew R. dentocariosa in the days following admission. The patient subsequently recovered without any notable sequelae after proper antibiotic treatment. Since Rothia species are currently considered a low-virulence organism that typically causes endocarditis in immunocompromised hosts, this case should serve as a reference for its possible virulence level in immunocompetent hosts. In spite of this organism's pathological rarity, this case highlights the importance of understanding the microbiology, historical context, and treatment for R. dentocariosa as a cause for deep neck cellulitis, myositis, and reactive lymphadenitis.

Serratia Sacroiliitis Secondary to Intravenous Drug Use: A Case Report.

Serratia spp. are ubiquitous, opportunistic, and infectious organisms that have historically been known to infect the upper respiratory, urinary, and circulatory systems. This manuscript presents the case of a 35-year-old White female with a past medical history of polysubstance abuse, intravenous drug use (IVDU), and poor dentition who was admitted to a community hospital with complaints of lower back pain for 10 days following the recent completion of treatment for a suspected epidural abscess. Per her report, her last IVDU with fentanyl was 11 days prior, and she admitted to using various sources of water to inject her drugs. Magnetic resonance imaging with contrast was significant for possible infectious sacroiliitis, and blood cultures grew Serratia marcescens. Due to this patient's extensive IVDU history, in-patient ceftriaxone was chosen over discharging the patient with a peripherally inserted central catheter line. Serratia spp.bacteremia with concomitant septic sacroiliitis in the setting of IVDU is an extremely rare presentation. Due to the nonspecific presentation of sacroiliitis, multidrug resistance profile of Serratia spp., and high mortality rate associated with S. marcescens sepsis, early detection and diagnosis is paramount in similar patients with extensive risk factors.

Peptide-MHC-targeted retroviruses enable in vivo expansion and gene delivery to tumor-specific T cells.

Tumor-infiltrating-lymphocyte (TIL) therapy has demonstrated that endogenous T cells can be harnessed to initiate an effective anti-tumor response. Despite clinical promise, current TIL production protocols involve weeks-long ex vivo expansions which can affect treatment efficacy. Therefore, additional tools are needed to engineer endogenous tumor-specific T cells to have increased potency while mitigating challenges of manufacturing. Here, we present a strategy for pseudotyping retroviral vectors with peptide-major histocompatibility complexes (pMHC) for antigen-specific gene delivery to CD8 T cells and examine the efficacy of these transduced cells in immunocompetent mouse models. We demonstrate that pMHC-targeted viruses are able to specifically deliver function-enhancing cargoes while simultaneously activating and expanding anti-tumor T cells. The specificity of these viral vectors enables in vivo engineering of tumor-specific T cells, circumventing ex vivo manufacturing processes and improving overall survival in B16F10-bearing mice. Altogether, we have established that pMHC-targeted viruses are efficient vectors for reprogramming and expanding tumor-specific populations of T cells directly in vivo , with the potential to substantially streamline engineered cell therapy production for a variety of applications.

Left Pubic Symphysis Fracture With Undiagnosed Ipsilateral Femoral Neck Fracture in an Elderly Female With Osteoporosis: A Case Report.

Femoral neck fractures are a common complication of falls, particularly in the osteoporotic elderly female population. This case highlights the significance of properly radiologically evaluating elderly patients with falls. A 68-year-old White female with paroxysmal atrial fibrillation on anticoagulation, nicotine use disorder, chronic hyponatremia, hypertension, and hyperlipidemia presented to the emergency department (ED) in considerable pain four days after a previously diagnosed left pubic symphysis fracture. Repeat imaging (X-ray and computed tomography (CT)) was significant for a left femoral neck fracture concurrent with the aforementioned pelvic fracture. Within 48 hours of admission, the patient underwent a hemiarthroplasty of the left hip. The postoperative course was unremarkable, except for immensely decreased pain and a remarkable ability to ambulate, and on postoperative day three, the patient was discharged. In patients with an overall high risk of hip fracture, CT imaging should be considered after X-ray in an effort to eliminate the frequency of undiagnosed fractures. It is essential to thoroughly evaluate the entire film, even after one fracture is found. This is crucial to a patient's overall well-being and can contribute to many unwanted phenomena.

Concussion Reduction in Division I and II Athletes: Effects of Simple Cervical Spine Exercise Regimen.

INTRODUCTION:  Primary preventative medicine lacks a consensus on effective concussion prevention strategies for collegiate athletes. Cervical strength has been identified as a potential factor in concussion risk reduction. This study evaluates the impact of a commercially available, portable cervical muscle stretching and strengthening device, NeckX®, on cervical strength, range of motion (ROM), and concussion incidence in collegiate athletes participating in high-concussion-risk sports. METHODS:  A single-arm prospective cohort study was conducted with 162 collegiate athletes from various sports. Participants underwent a 12-week neck exercise protocol using the NeckX® device. Clinical data, including neck strength and ROM, were collected at weeks 0, 6, and 12. Concussion incidence was self-reported by participants and cross-referenced with records from the athletic department. Data were analyzed for significant neck strength and ROM changes throughout the 12-week study. A two-way analysis of variance multiple comparisons with the Tukey-Kramer significant difference test was utilized, using the Holm-Sidak method, with an alpha of 0.05. RESULTS:  All athletic teams experienced a significant increase in cervical strength during the 12-week intervention (α = 0.05, p < 0.05). Increases in cervical flexion and extension force were most consistent between teams. Cervical ROM increased significantly in male and female soccer players (α = 0.05, p < 0.05). The overall incidence of head and neck injuries, including concussions, was reduced to 6.60% during the study period, the lowest recorded value in the university's athletic department history. CONCLUSION:  The use of the NeckX® device for 12 weeks was effective in enhancing pericervical muscle strength and ROM while reducing concussion incidence in collegiate athletes participating in high-concussion-risk sports. Interestingly, the positive outcomes were consistent for both males and females, indicating the universal advantages of neck training among collegiate athletes. These findings support existing research on the benefits of cervical strengthening exercises for reducing concussions in collegiate athletes and highlight the convenience and affordability of using this device.

Recurrent Left Periprosthetic Posterior Knee Dislocation in an Elderly Woman With Dementia and Altered Mental Status: A Case Report.

The case presented in this article is one of recurrent left posterior periprosthetic knee dislocation (PPKD) in a patient with altered mental status (AMS). The patient, a 69-year-old female with a complex medical history including dementia, Ménière's syndrome, and left total knee arthroplasty, presented to the emergency department with AMS whereupon a left PPKD was discovered. Less than three weeks before this presentation, she sustained a left PPKD during a previous admission. During her current admission, she sustained yet another left PPKD after trials of closed reduction and immobilization. The patient eventually underwent a left cemented revision total knee arthroplasty with a hinged prosthesis. The implant was noted to be stable, and the patient had minimal pain postoperatively with no vascular or neurological injury. Upon outpatient follow-up, the patient reported doing well. There have been few documented cases of recurrent or chronic PPKD in individuals with AMS or restricted intellect. These comorbidities create a complex approach to diagnosing and treating the aforementioned orthopedic injury, and as this injury can have devastating consequences, quickly and effectively delivering diagnosis and treatment is vital. This case highlights the importance of early identification, risk factors, preoperative management, and appropriate operative course for patients with AMS and recurrent PPKDs.

Long-term experience with AMS-700 CXR inflatable penile prosthesis in high-risk patients with corporal fibrosis.

Despite the widespread use of narrow diameter inflatable penile prosthesis (IPP) cylinders in patients with corporal fibrosis, outcomes data is sparse. We evaluated patients who underwent IPP placement with AMS™ 700 Controlled Expansion Restricted (CXR) cylinders from 2007-2021. Patient characteristics, device details, and surgical outcomes were assessed. A non-validated questionnaire was also distributed to patients to assess satisfaction. Among 982 IPPs placed over the study period at our institution, 49 (5.0%) used CXR cylinders. Indications for narrow cylinders: prior explant for infection (67.3%), ischemic priapism (16.3%), and idiopathic fibrosis (16.3%). Median corporal length was 19 cm (IQR 17-21 cm). Discordant intraoperative corporal measurements (24.5%) and RTE lengths (26.5%) were common. Post-operative complications occurred in 8 patients (16.3%) and included 3 infections (6.1%), 2 cylinder herniations (4.1%), 2 mechanical failures (4.1%), and one case of glans necrosis (2.0%). Five of these (10.2%) required explantation, while 4 (8.2%) were managed with revision. Over the follow-up period, 73.5% of patients reported satisfaction with rigidity. Primary drivers of dissatisfaction were perceived loss of penile length and girth. The AMS™ 700 CXR is a useful tool for challenging corporal fibrosis cases and shows acceptable surgical outcomes with moderate patient acceptability.

Emboldened in the rap "game": How severely stigmatized video models navigate disrespect and vulnerability to workplace mistreatment.

Moral stigma attached to an occupation can scar workers through discrediting, shaming, and denying respect. It can also open the door to interpersonal mistreatment, but little is known about how morally stigmatized workers navigate anticipated disrespect to potentially avoid harm. We explore this issue in a study of an occupation carrying severe moral stigma and where disrespect and workplace mistreatment are pervasive: models in hip-hop and rap music videos. Through analyses of 71 interviews with 48 video models and 19 industry informants, field observations, and archival data, we show how severe moral stigma and industry constraints promote generalized disrespect of video models (i.e., denial of worth to all role occupants) and, thus, each model's personal vulnerability to mistreatment. Two distinct groups of models emerged from our analysis-those who viewed themselves as emboldened in their role identity and those who did not-and this emboldened role identity was associated with differing perceptions of their personal vulnerability to mistreatment and their behaviors to mitigate it. The first group of models, those reporting an emboldened role identity, perceived their vulnerability to mistreatment as controllable. They strategically used both assertive behaviors (that earned respect from others) and passive behaviors (that avoided disrespect from others) to mitigate mistreatment. By contrast, the second group perceived their vulnerability to mistreatment as uncontrollable and reported using only passive behaviors (to avoid disrespect) when mistreatment was imminent. We discuss theoretical and practical implications of our findings, advancing knowledge of dirty work, workplace mistreatment, respect dynamics, and identity. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Analytical solution for acoustic radiation force and torque on a spheroid near a rigid or free planar boundary.

An analytical solution is developed for the acoustic radiation force and torque caused by an arbitrary sound field that is incident on a compressible spheroid of any size near a planar boundary that is either rigid or pressure release. The analysis is an extension of a recent solution for a compressible sphere near a planar boundary [Simon and Hamilton, J. Acoust. Soc. Am. 153, 627-642 (2023)]. Approximations that account for a boundary formed by a two-fluid interface may be incorporated as in the previous analysis for a sphere. The present solution is based on expansions of the total acoustic pressure field in spheroidal wave functions and the use of addition theorems. Verification of the solution is accomplished by comparison with a finite element model. Examples are presented for incident fields that are either plane or spherical waves. Effects resulting from the presence of the boundary are studied by comparing the full theory with a simplified model in which multiple scattering is neglected. Numerical implementation of the proposed solution is also discussed.

PARE: A framework for removal of confounding effects from any distance-based dimension reduction method.

Dimension reduction tools preserving similarity and graph structure such as t-SNE and UMAP can capture complex biological patterns in high-dimensional data. However, these tools typically are not designed to separate effects of interest from unwanted effects due to confounders. We introduce the partial embedding (PARE) framework, which enables removal of confounders from any distance-based dimension reduction method. We then develop partial t-SNE and partial UMAP and apply these methods to genomic and neuroimaging data. For lower-dimensional visualization, our results show that the PARE framework can remove batch effects in single-cell sequencing data as well as separate clinical and technical variability in neuroimaging measures. We demonstrate that the PARE framework extends dimension reduction methods to highlight biological patterns of interest while effectively removing confounding effects.

Quantifying myelin density in the feline auditory cortex.

The cerebral cortex comprises many distinct regions that differ in structure, function, and patterns of connectivity. Current approaches to parcellating these regions often take advantage of functional neuroimaging approaches that can identify regions involved in a particular process with reasonable spatial resolution. However, neuroanatomical biomarkers are also very useful in identifying distinct cortical regions either in addition to, or in place of functional measures. For example, differences in myelin density are thought to relate to functional differences between regions, are sensitive to individual patterns of experience, and have been shown to vary across functional hierarchies in a predictable manner. Accordingly, the current study provides quantitative stereological estimates of myelin density for each of the 13 regions that make up the feline auditory cortex. We demonstrate that significant differences can be observed between auditory cortical regions, with the highest myelin density observed in the regions that comprise the auditory core (i.e., the primary auditory cortex and anterior auditory field). Moreover, our myeloarchitectonic map suggests that myelin density varies in a hierarchical fashion that conforms to the traditional model of spatial organization in auditory cortex. Taken together, these results establish myelin as a useful biomarker for parcellating auditory cortical regions, and provide detailed estimates against which other, less invasive methods of quantifying cortical myelination may be compared.

Efficacy of Osteopathic Manipulative Treatment for Pain Reduction in Patients With Patellofemoral Pain Syndrome: A Meta-Analysis of Randomized Controlled Trials.

Patellofemoral pain syndrome (PFPS) is among the most common causes of musculoskeletal pain in the United States. It is defined as retropatellar or peripatellar pain that is reproduced with functional activities that load the patellofemoral joint in a flexed position, such as stair climbing or squatting. While it presents in both adolescents and adults, it is commonly found in physically active individuals, such as athletes and military recruits. Exploring the role of osteopathic manipulative treatment (OMT) in PFPS is of particular interest given the absence of a definitive treatment and the poor long-term prognosis associated with PFPS. This meta-analysis includes three studies exploring the use of OMT to reduce pain in patients suffering from PFPS and exploring the efficacy of OMT as a primary intervention. In these studies, pain assessments, pre-treatment, and post-treatment follow-up of at least 30 days were performed using a 10-cm visual analog scale (VAS). The mean difference in pain between OMT and no treatment (NT) groups using the random effects model was -3.95 (-6.39; -1.50) with a p<0.01, suggesting OMT resulted in significant knee pain reduction in those with PFPS. A measure of heterogeneity, known as I2, was found to be high at 97%, which suggests caution should be taken when interpreting the overall results. Given the lack of definitive treatment and the poor long-term prognosis for PFPS, the authors suggest OMT provides an effective option for pain relief in patients with PFPS. Further research is needed to provide results that may be more clinically applicable or valuably interpreted.

Management of a Traumatic Collapse of the First Carpometacarpal Joint After Trapeziectomy With Suture Suspensionplasty: A Case Report.

Arthritis of the first carpometacarpal (CMC) joint is a common pathology hand surgeons encounter. Treatment begins with conservative measures, but when they fail, surgery is a viable option for providing relief to patients. The most widely used surgical technique is CMC arthroplasty with ligament reconstruction and tendon interposition (LRTI). However, more novel techniques such as trapeziectomy with suspensionplasty are gaining popularity. When surgical measures fail, it is important to identify the mechanism of failure and proper treatment options. There are multiple options for revision surgery at the surgeon's disposal, with no consensus on a superior technique. This case illustrates a patient with painful subsidence secondary to a traumatic collapse of the first CMC joint eight months status post suspensionplasty with trapeziectomy. After conservative measures failed to provide relief, it was decided that a surgical revision was appropriate. The surgeon chose to move forward with suture button suspensionplasty, as it has multiple advantages over LRTI. In the short-term follow-up after revision, the patient experienced improvements in pain and range of motion, along with radiographic evidence of proper alignment of the first metacarpal without subsidence. Regarding the treatment of a case such as this, the authors believe this case should serve as a reference that may be used by future physicians when deciding which surgical technique to employ for the revision of a traumatically collapsed first CMC joint after trapeziectomy with CMC joint suspensionplasty.

Salvage Treatment for a Periprosthetic Humeral Nonunion: A Case Report.

The patient, a 69-year-old female, presented one year after receiving a total elbow arthroplasty with a nonunion periprosthetic fracture of the humerus. Due to the patient's severe osteoarthritis of the ipsilateral shoulder and significant humeral deformity, a procedure linking the total elbow arthroplasty to the reverse shoulder implant via a cemented allograft-composite linkage sleeve was performed. Previous literature suggests upper extremity salvage surgery using large-scale allografts is successful in treating large tumor or infection-derived defects, though data is lacking as to whether this treatment is effective in periprosthetic fractures in patients with significant comorbidities. This patient's success in the postoperative year supports the use of allograft-composite reconstruction followed by linkage to a reverse shoulder implant as a salvage treatment for periprosthetic fractures under certain conditions, such as multiple adjacent implants, bone deformity, and severe osteoarthritis.

Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence.

The anti-tumor function of engineered T cells expressing chimeric antigen receptors (CARs) is dependent on signals transduced through intracellular signaling domains (ICDs). Different ICDs are known to drive distinct phenotypes, but systematic investigations into how ICD architectures direct T cell function-particularly at the molecular level-are lacking. Here, we use single-cell sequencing to map diverse signaling inputs to transcriptional outputs, focusing on a defined library of clinically relevant ICD architectures. Informed by these observations, we functionally characterize transcriptionally distinct ICD variants across various contexts to build comprehensive maps from ICD composition to phenotypic output. We identify a unique tonic signaling signature associated with a subset of ICD architectures that drives durable in vivo persistence and efficacy in liquid, but not solid, tumors. Our findings work toward decoding CAR signaling design principles, with implications for the rational design of next-generation ICD architectures optimized for in vivo function.

Synaptic Protein Loss in Extracellular Vesicles Reflects Brain and Retinal Atrophy in People With Multiple Sclerosis.

OBJECTIVES: To assess whether the rate of change in synaptic proteins isolated from neuronally enriched extracellular vesicles (NEVs) is associated with brain and retinal atrophy in people with multiple sclerosis (MS). METHODS: People with MS were followed with serial blood draws, MRI (MRI), and optical coherence tomography (OCT) scans. NEVs were immunocaptured from plasma, and synaptopodin and synaptophysin proteins were measured using ELISA. Subject-specific rates of change in synaptic proteins, as well as brain and retinal atrophy, were determined and correlated. RESULTS: A total of 50 people with MS were included, 46 of whom had MRI and 45 had OCT serially. The rate of change in NEV synaptopodin was associated with whole brain (rho = 0.31; p = 0.04), cortical gray matter (rho = 0.34; p = 0.03), peripapillary retinal nerve fiber layer (rho = 0.37; p = 0.01), and ganglion cell/inner plexiform layer (rho = 0.41; p = 0.006) atrophy. The rate of change in NEV synaptophysin was also correlated with whole brain (rho = 0.31; p = 0.04) and cortical gray matter (rho = 0.31; p = 0.049) atrophy. DISCUSSION: NEV-derived synaptic proteins likely reflect neurodegeneration and may provide additional circulating biomarkers for disease progression in MS.

Natural selection on feralization genes contributed to the invasive spread of wild pigs throughout the United States.

Despite a long presence in the contiguous United States (US), the distribution of invasive wild pigs (Sus scrofa × domesticus) has expanded rapidly since the 1980s, suggesting a more recent evolutionary shift towards greater invasiveness. Contemporary populations of wild pigs represent exoferal hybrid descendants of domestic pigs and European wild boar, with such hybridization expected to enrich genetic diversity and increase the adaptive potential of populations. Our objective was to characterize how genetic enrichment through hybridization increases the invasiveness of populations by identifying signals of selection and the ancestral origins of selected loci. Our study focused on invasive wild pigs within Great Smoky Mountains National Park, which represents a hybrid population descendent from the admixture of established populations of feral pigs and an introduction of European wild boar to North America. Accordingly, we genotyped 881 wild pigs with multiple high-density single-nucleotide polymorphism (SNP) arrays. We found 233 markers under putative selection spread over 79 regions across 16 out of 18 autosomes, which contained genes involved in traits affecting feralization. Among these, genes were found to be related to skull formation and neurogenesis, with two genes, TYRP1 and TYR, also encoding for crucial melanogenesis enzymes. The most common haplotypes associated with regions under selection for the Great Smoky Mountains population were also common among other populations throughout the region, indicating a key role of putatively selective variants in the fitness of invasive populations. Interestingly, many of these haplotypes were absent among European wild boar reference genotypes, indicating feralization through genetic adaptation.

Coagulation activity and thrombotic risk following high-volume endurance exercise in recreationally active cyclists.

Despite the prognostic effect of physical activity, acute bouts of high-volume endurance exercise can induce cardiac stress and postexercise hypercoagulation associated with increased thrombotic risk. The aim of this study was to explore the effect of high-volume endurance exercise on coagulation and thrombotic activity in recreational cyclists. Thirty-four recreational cyclists completed 4.8 ± 0.3 h of cycling at 45 ± 5% of maximal power output on a bicycle ergometer. Intravenous blood samples were collected preexercise, immediately postexercise, 24 and 48 h postexercise, and analyzed for brain natriuretic peptide (BNP), cardiac troponin (cTn), C-reactive protein (CRP), D-dimer, thrombin-antithrombin (TAT) complex, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and TF-to-TFPI ratio (TF:TFPI). An increase in cTn was observed postexercise (P < 0.001). CRP concentrations were increased at 24 and 48 h postexercise compared with preexercise concentrations (P ≤ 0.001). TF was elevated at 24 h postexercise (P < 0.031) and TFPI was higher immediately postexercise (P < 0.044) compared with all other time points. TF:TFPI was increased at 24 and 48 h postexercise compared with preexercise (P < 0.025). TAT complex was reduced at 48 h postexercise compared with preexercise (P = 0.015), D-dimer was higher immediately postexercise compared with all other time points (P ≤ 0.013). No significant differences were observed in BNP (P > 0.05). High-volume endurance cycling induced markers of cardiac stress among recreational cyclists. However, plasma coagulation and fibrinolytic activity suggest no increase in thrombotic risk after high-volume endurance exercise.NEW & NOTEWORTHY In this study, a high-volume endurance exercise protocol induced markers of cardiac stress and altered plasma coagulation and fibrinolytic activity for up to 48 h in recreationally active cyclists. However, analysis of coagulation biomarkers indicates no increase in thrombotic risk when appropriate hydration and rest protocols are implemented.

A ketogenic diet enhances fluconazole efficacy in murine models of systemic fungal infection.

Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log10 reduction) and lung (mean 1.72 ± 0.399 log10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log10-reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity.