An economic evaluation of chronic obstructive pulmonary disease clinical pathway in Saskatchewan, Canada: Data-driven techniques to identify cost-effectiveness among patient subgroups.

BACKGROUND: Saskatchewan has implemented care pathways for several common health conditions. To date, there has not been any cost-effectiveness evaluation of care pathways in the province. The objective of this study was to evaluate the real-world cost-effectiveness of a chronic obstructive pulmonary disease (COPD) care pathway program in Saskatchewan. METHODS: Using patient-level administrative health data, we identified adults (35+ years) with COPD diagnosis recruited into the care pathway program in Regina between April 1, 2018, and March 31, 2019 (N = 759). The control group comprised adults (35+ years) with COPD who lived in Saskatoon during the same period (N = 759). The control group was matched to the intervention group using propensity scores. Costs were calculated at the patient level. The outcome measure was the number of days patients remained without experiencing COPD exacerbation within 1-year follow-up. Both manual and data-driven policy learning approaches were used to assess heterogeneity in the cost-effectiveness by patient demographic and disease characteristics. Bootstrapping was used to quantify uncertainty in the results. RESULTS: In the overall sample, the estimates indicate that the COPD care pathway was not cost-effective using the willingness to pay (WTP) threshold values in the range of $1,000 and $5,000/exacerbation day averted. The manual subgroup analyses show the COPD care pathway was dominant among patients with comorbidities and among patients aged 65 years or younger at the WTP threshold of $2000/exacerbation day averted. Although similar profiles as those identified in the manual subgroup analyses were confirmed, the data-driven policy learning approach suggests more nuanced demographic and disease profiles that the care pathway would be most appropriate for. CONCLUSIONS: Both manual subgroup analysis and data-driven policy learning approach showed that the COPD care pathway consistently produced cost savings and better health outcomes among patients with comorbidities or among those relatively younger. The care pathway was not cost-effective in the entire sample.

The influence of health service interactions and local policies on vaccination decision-making in immigrant women: A multi-site Canadian qualitative study.

OBJECTIVES: Research on immigrant and refugee vaccination uptake in Canada shows that immunization decisions vary by vaccine type, location, age and migration status. Despite their diversity, these studies often treat immigrant and refugee populations as a single group relative to other Canadians. In this comparative study, we explored how previous risk communication and immunization experiences influence immunization decisions by immigrant and refugee women from three communities across Canada. METHODS: Participants included women from the Punjabi immigrant community located in Surrey and Abbotsford, British Columbia (n = 36), the Nigerian immigrant community located in Winnipeg, Manitoba (n = 43), and the Congolese refugee community in Edmonton, Alberta (n = 18). Using focus groups guided by focused ethnography methodology, we sought to understand immunization experiences in Canada and before arrival, and what information sources influenced the immunization decision-making process by the women in the three communities. RESULTS: Participants had differing past experiences in Canada and before their arrival that influenced how they used information in their vaccination decisions. Clear vaccination communications and dialogue with Canadian health care providers increased trust in Canadian health care and the likelihood of vaccine uptake. By contrast, weak vaccine recommendations and antivaccination information in the community prompted participants to decline future vaccines. CONCLUSION: Given our participants' different communication preferences and needs, we argue that a one-size-fits-all communication approach is inappropriate for immigrant and refugee populations. Instead, multi-pronged communication strategies are required to reach participants and respond to previous experiences and information that may lead to vaccination hesitancy.

Clinical Diagnosis and Laboratory Testing of Abnormal Appearing Toenails: A Retrospective Assessment of Confirmatory Testing for Onychomycosis in the United States, 2022-2023.

Onychomycosis is an under-recognized healthcare burden. Despite the risk of misdiagnosis, confirmatory laboratory testing is under-utilized. Histopathologic examination with polymerase chain reaction (PCR) is currently the most effective diagnostic method; it offers direct detection and identification of a fungal invasion. In this retrospective cohort study, we assessed confirmatory testing results, with matching clinical diagnoses, in 96,293 nail specimens submitted during a 9-month period from 2022 to 2023. Toenail specimens were examined using fungal culture, histopathology and/or PCR. Clinical diagnoses were identified using the International Classification of Diseases 10th Revision codes. For clinically diagnosed onychomycosis patients, the overall positivity rate was 59.4%; a similar positivity rate (59.5%) was found in patients with clinically diagnosed non-fungal nail dystrophy. Performing a histopathologic examination with PCR was more likely to provide pathogen identification results than using fungal culture. Male patients had a higher rate of onychomycosis overall; however, female patients had more non-dermatophyte mold onychomycosis caused by Aspergillus. Clinically diagnosed onychomycosis patients with a co-diagnosis of tinea pedis were more likely to test positive for onychomycosis by PCR (odds ratio [OR]: 4.2; 95% confidence interval [CI]: 2.7-6.4), histopathology (OR: 2.5; 95% CI: 2.0-3.1) and fungal culture (OR: 3.2; 95% CI: 1.5-6.6). Our results support the use of confirmatory laboratory testing when there is a clinical diagnosis of onychomycosis.

Real-World Cost-Consequence Analysis of an Integrated Chronic Disease Management Program in Saskatchewan, Canada.

An integrated disease management program otherwise called a clinical pathway was recently implemented in Saskatchewan, Canada for patients living with chronic obstructive pulmonary disease (COPD). This study compared the real-world costs and consequences of the COPD clinical pathway program with 2 control treatment programs. The study comprised adult COPD patients in Regina (clinical pathway group, N = 759) matched on propensity scores to 2 independent control groups of similar adults in (1) Regina (historical controls, N = 759) and (2) Saskatoon (contemporaneous controls, N = 759). The study measures included patient-level healthcare costs and acute COPD exacerbation outcomes, both tracked in population-based administrative health data over a one-year follow-up period. Analyses included Cox proportional hazards models and differences in means between groups. The bias-corrected and accelerated bootstrap method was used to calculate 95% confidence intervals (CI). The COPD pathway patients had lower risks of moderate (hazard ratio [HR] =0.57, 95% CI [0.40-0.83]) and severe (HR = 0.43, 95% CI [0.28-0.66]) exacerbations compared to the historical control group, but similar risks compared with the contemporaneous control group. The COPD pathway patients experienced fewer episodes of exacerbations compared with the historical control group (mean difference = -0.30, 95% CI [-0.40, -0.20]) and the contemporaneous control group (mean difference = -0.12, 95% CI [-0.20, -0.03]). Average annual healthcare costs in Canadian dollars were marginally higher among patients in the COPD clinical pathway (mean = $10 549, standard deviation [SD] =$18 149) than those in the contemporaneous control group ($8841, SD = $17 120), but comparable to the historical control group ($10 677, SD = $21 201). The COPD pathway provides better outcomes at about the same costs when compared to the historical controls, but only slightly better outcomes and at a marginally higher cost when compared to the contemporaneous controls.

Involvement of the tumour necrosis factor receptor system in glioblastoma cell death induced by palbociclib-heptamethine cyanine dye conjugate.

Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-brain cancer agents are challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery. We conjugated palbociclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, to an HMCD, MHI-148, and conducted drug activity analysis on primary patient-derived glioblastoma cell lines. In addition to the expected cytostatic activity, our in vitro studies revealed that palbociclib-MHI-148 conjugate resulted in an almost 100-fold increase in cytotoxicity compared to palbociclib alone. This shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI-148 was due to increased DNA damage, as indicated by an increase in γH2AX foci, followed by an increased expression of key extrinsic apoptosis genes, including TP53, TNFR1, TRAIL, FADD and caspase 8. In addition, we observed a time-dependent increase in the cell surface expression of TNFR1, consistent with an observed increase in the secretion TNFα, followed by TNFR1 endocytosis at 48 h. The treatment of patient GBM cells with the palbociclib-MHI-148 conjugate prevented TNFα-induced NFκB translocation, suggesting conjugate-induced TNFR1 signalling favoured the TNFR1-mediated apoptotic response rather than the pro-inflammatory response pathway. Notably, pharmacological inhibition of endocytosis of TNFR1, and siRNA-knockdown of TNFR1 reversed the palbociclib-MHI-148-induced cell death. These results show a novel susceptibility of glioblastoma cells to TNFR1-dependent apoptosis, dependent on inhibition of canonical NFκB signalling using our previously reported palbociclib-HMCD conjugate. Video Abstract.

A comprehensive review of nondermatophyte mould onychomycosis: Epidemiology, diagnosis and management.

Nondermatophyte moulds (NDMs) are widely distributed and can be detected in association with mycotic nails; however, sometimes it can be challenging to establish the role of NDMs in the pathogenesis of onychomycosis (i.e. causative vs. contaminant). In studies where the ongoing invasive presence of NDMs is confirmed through repeat cultures, the global prevalence of NDMs in onychomycosis patients is estimated at 6.9% with the 3 most common genus being: Aspergillus, Scopulariopsis and Fusarium. NDM onychomycosis can, in many cases, appear clinically indistinguishable from dermatophyte onychomycosis. Clinical features suggestive of NDMs include proximal subungual onychomycosis with paronychia associated with Aspergillus spp., Fusarium spp. and Scopulariopsis brevicaulis, as well as superficial white onychomycosis in a deep and diffused pattern associated with Aspergillus and Fusarium. Longitudinal streaks seen in patients with distal and lateral onychomycosis may serve as an additional indicator. For diagnosis, light microscopic examination should demonstrate fungal filaments consistent with an NDM with at least two independent isolations in the absence of a dermatophyte; the advent of molecular testing combined with histological assessment may serve as an alternative with improved sensitivity and turnover time. In most instances, antifungal susceptibility testing has limited value. Information on effective treatments for NDM onychomycosis is relatively scarce, unlike the situation in the study of dermatophyte onychomycosis. Terbinafine and itraconazole therapy (continuous and pulsed) appear effective to varying extents for treating onychomycosis caused by Aspergillus, Fusarium or Scopulariopsis. There is scant literature on oral treatments for Neoscytalidium.

Utility of devices for onychomycosis: a review.

Onychomycosis is difficult to treat due to long treatment durations, poor efficacy rates of treatments, high relapse rates, and safety issues when using systemic antifungal agents. Device-based treatments are targeted to specific regions of the nail, have favorable safely profiles, and do not interfere with systemic agents. They may be an effective alternative therapy for onychomycosis especially with increasing reports of squalene epoxidase gene mutations and potential resistance to terbinafine therapy. In this review, we discuss four devices used as antifungal treatments and three devices used as penetration enhancers for topical agents. Lasers, photodynamic therapy, microwaves, and non-thermal plasma have the capacity to inactivate fungal pathogens demonstrated through in vivo studies. Efficacy rates for these devices, however, remain relatively low pointing toward the need to further optimize device or usage parameters. Ultrasound, nail drilling, and iontophoresis aid in improving the permeability of topical agents through the nail and have been investigated as adjunctive therapies. Due to the paucity in clinical data, their efficacy in treating onychomycosis has not yet been established. While the results of clinical studies point toward the potential utility of devices for onychomycosis, further large-scale randomized clinical trials following regulatory guidelines are required to confirm current results.

RepBox: a toolbox for the identification of repetitive elements.

BACKGROUND: Transposable elements (TEs) are short, mobile DNA elements that are known to play important roles in the genomes of many eukaryotic species. The identification and categorization of these elements is a critical task for many genomic studies, and the continued increase in the number of de novo assembled genomes demands new tools to improve the efficiency of this process. For this reason, we developed RepBox, a suite of Python scripts that combine several pre-existing family-specific TE detection methods into a single user-friendly pipeline. RESULTS: Based on comparisons of RepBox with the standard TE detection software RepeatModeler, we find that RepBox consistently classifies more elements and is also able to identify a more diverse array of TE families than the existing methods in plant genomes. CONCLUSIONS: The performance of RepBox on two different plant genomes indicates that our toolbox represents a significant improvement over existing TE detection methods, and should facilitate future TE annotation efforts in additional species.

JGI Plant Gene Atlas: an updateable transcriptome resource to improve functional gene descriptions across the plant kingdom.

Gene functional descriptions offer a crucial line of evidence for candidate genes underlying trait variation. Conversely, plant responses to environmental cues represent important resources to decipher gene function and subsequently provide molecular targets for plant improvement through gene editing. However, biological roles of large proportions of genes across the plant phylogeny are poorly annotated. Here we describe the Joint Genome Institute (JGI) Plant Gene Atlas, an updateable data resource consisting of transcript abundance assays spanning 18 diverse species. To integrate across these diverse genotypes, we analyzed expression profiles, built gene clusters that exhibited tissue/condition specific expression, and tested for transcriptional response to environmental queues. We discovered extensive phylogenetically constrained and condition-specific expression profiles for genes without any previously documented functional annotation. Such conserved expression patterns and tightly co-expressed gene clusters let us assign expression derived additional biological information to 64 495 genes with otherwise unknown functions. The ever-expanding Gene Atlas resource is available at JGI Plant Gene Atlas (https://plantgeneatlas.jgi.doe.gov) and Phytozome (https://phytozome.jgi.doe.gov/), providing bulk access to data and user-specified queries of gene sets. Combined, these web interfaces let users access differentially expressed genes, track orthologs across the Gene Atlas plants, graphically represent co-expressed genes, and visualize gene ontology and pathway enrichments.

Antifungal Resistance, Susceptibility Testing and Treatment of Recalcitrant Dermatophytosis Caused by Trichophyton indotineae: A North American Perspective on Management.

There is an ongoing epidemic of chronic, relapsing dermatophytoses caused by Trichophyton indotineae that are unresponsive to one or multiple antifungal agents. Although this new species may have originated from the Indian subcontinent, there has been a notable increase of its reporting in other countries. Based on current literature, antifungal susceptibility testing (AFST) showed a large variation of terbinafine minimum inhibitory concentrations (MICs) (0.04 to ≥ 32 µg/ml). Elevated terbinafine MICs can be attributed to mutations in the squalene epoxidase gene (single mutations: Leu393Phe, Leu393Ser, Phe397Leu, and double mutations: Leu393Phe/Ala448Thr, Phe397Leu/Ala448Thr). Itraconazole MICs had a lower range when compared with that of terbinafine (0.008-16 µg/ml, with most MICs falling between 0.008 µg/ml and < 1 µg/ml). The interpretation of AFST results remains challenging due to protocol variations and a lack of established breakpoints. Adoption of molecular methods for resistance detection, coupled with AFST, may provide a better evaluation of the in vitro resistance status of T. indotineae. There is limited information on treatment options for patients with confirmed T. indotineae infections by molecular diagnosis; preliminary evidence generated from case reports and case series points to itraconazole as an effective treatment modality, while terbinafine and griseofulvin are generally not effective. For physicians working outside of endemic regions, there is currently an unmet need for standardized clinical trials to establish treatment guidelines; in particular, combination therapy of oral and topical agents (e.g., itraconazole and ciclopirox), as well as with other azoles (i.e., fluconazole, voriconazole, ketoconazole), warrants further investigation as multidrug resistance is a possibility for T. indotineae.

Single-Point Nail Sampling to Diagnose Onychomycosis Caused by Non-Dermatophyte Molds: Utility of Polymerase Chain Reaction (PCR) and Histopathology.

The three most commonly used methods for diagnosing non-dermatophyte mold (NDM) onychomycosis are culture, polymerase chain reaction (PCR), and histopathology. Toenail samples from 512 patients (1 sample/patient) with suspected onychomycosis were examined using all three diagnostic tests. A statistically significant association was found between PCR and histopathology results, as well as between fungal culture and histopathology results. All PCR-positive and culture-positive dermatophyte samples were confirmed by histopathology. However, 15/116 (12.9%) of culture-positive NDM samples had negative histopathology results, while all PCR-positive NDM samples were confirmed by histopathology. The overall rate of dermatophyte detection was higher using PCR compared to culture (38.9% vs. 11.7%); the lower rate of NDM detection by PCR (11.7% vs. 38.9%) could be attributed to the restriction of the assay design to seven pre-selected targets. When repeat sampling in the clinic is not possible, a combination of NDM detection by PCR and positive histopathology of hyphae may be a proxy for NDM infection, particularly where the NDM occurs without a concomitant dermatophyte. There was a high degree of correlation between negative PCR and negative histopathology. A negative PCR result with negative histopathology findings may be a reliable proxy for the diagnosis of non-fungal dystrophy.

The treatment of plantar warts using microwave-A review of 85 consecutive cases in the United States.

BACKGROUND: Plantar warts (verrucae plantaris) are a common source of pain for patients and are often refractory to treatment. Previous work has shown a high clearance rate of verrucae using a surface-based microwave device (Swift®). AIMS: To assess the efficacy, defined as the complete visible clearance of warts, in patients with verrucae plantaris receiving microwave treatment. PATIENTS: We undertook a retrospective review and identified records of 85 patients who underwent a course of microwave treatment at a single US-based podiatry centre. Efficacy was analyzed on the basis on intention-to-treat. RESULTS: In patients who received ≥1 session there was a complete clearance rate of 60.0% (51/85) (intention-to-treat; 59 patients completed treatment, 26 lost to follow-up) and 86.4% (51/59) per treatment completion; no significant differences in clearance rates of children and adults were observed (61.0% [25/41] vs. 59.1% [26/44]). There were 31 patients who received three sessions of microwave therapy with a clearance rate of 71.0% (22/31) as per intention-to-treat (27 patients completed treatment, 4 lost to follow-up). An average of 2.3 sessions (SD: 1.1; range: 1-6) was required for the complete clearance of plantar warts. Complete clearance was also observed in some patients with recalcitrant warts following additional treatment sessions (42.9% [3/7]). A significant reduction in wart related pain was reported for all patients undergoing treatment. Some patients continued to report a reduced amount of pain post-therapy compared with pretherapy. CONCLUSIONS: Microwave treatment of verrucae plantaris appears to be a safe and effective procedure.

Impacts of Chronic Obstructive Pulmonary Disease Care Pathway on Healthcare Utilization and Costs: A Matched Multiple Control Cohort Study in Saskatchewan, Canada.

OBJECTIVES: This study aimed to evaluate the real-world impacts of a chronic obstructive pulmonary disease (COPD) care pathway program on healthcare utilization and costs in Saskatchewan, Canada. METHODS: A difference-in-differences evaluation of a real-life deployment of a COPD care pathway, using patient-level administrative health data in Saskatchewan, was conducted. The intervention group (n = 759) included adults (35+ years) with spirometry-confirmed COPD diagnosis recruited into the care pathway program in Regina between April 1, 2018 and March 31, 2019. The 2 control groups comprised adults (35+ years) with COPD who lived in Saskatoon during the same period (n = 759) or Regina between April 1, 2015 and March 31, 2016 (n = 759) who did not participate in the care pathway. RESULTS: Compared with the individuals in the Saskatoon control groups, individuals in the COPD care pathway group had shorter inpatient hospital length of stay (average treatment effect on the treated [ATT] -0.46, 95% CI -0.88 to -0.04) but a higher number of general practitioner visits (ATT 1.46, 95% CI 1.14 to 1.79) and specialist physician visits (ATT 0.84, 95% CI 0.61 to 1.07). Regarding healthcare costs, individuals in the care pathway group had higher COPD-related specialist visit costs (ATT $81.70, 95% CI $59.45 to $103.96) but lower COPD-related outpatient drug dispensation costs (ATT -$4.81, 95% CI -$9.34 to -$0.27). CONCLUSIONS: The care pathway reduced inpatient hospital length of stay, but increased general practitioner and specialist physician visits for COPD-related services within the first year of implementation.

Detection of Squalene Epoxidase Mutations in United States Patients with Onychomycosis: Implications for Management.

Resistance to oral terbinafine, the most commonly used antifungal to treat dermatophytosis and onychomycosis worldwide, is being increasingly reported. In this study, we aimed to investigate the species distribution and prevalence of squalene epoxidase mutations among toenail dermatophyte isolates. Samples from 15,683 patients suspected of onychomycosis visiting the offices of dermatologists and podiatrists in the United States were analyzed. Clinical information was reviewed, and dermatophyte species with or without squalene epoxidase mutations were detected using multiplex real-time PCRs. The frequency of dermatophytes was 37.6%; of isolates belonging to the Trichophyton genus, 88.3% were the T. rubrum complex, and 11.2% were the T. mentagrophytes complex. Individuals aged >70 years exhibited higher infection rates for the T. mentagrophytes complex. The overall mutation rate among Trichophyton spp. was 3.7%, with a higher mutation rate detected in the T. mentagrophytes complex (4.3 vs. 3.6%). Commonly detected mutations were T1189C/Phe397Leu (34.5%), T1306C/Phe415Ser (16.0%), and C1191A/Phe397Leu (11.0%). Squalene epoxidase gene mutations associated with decreased terbinafine susceptibility have been identified in United States patients with toenail onychomycosis. Physicians should be aware of the risk factors for resistance development and engage in antifungal stewardship practices such as directed diagnosis and treatment of dermatophytosis and onychomycosis.

Combatting antifungal resistance: Paradigm shift in the diagnosis and management of onychomycosis and dermatomycosis.

Antifungal resistance has become prevalent worldwide. Understanding the factors involved in spread of resistance allows the formulation of strategies to slow resistance development and likewise identify solutions for the treatment of highly recalcitrant fungal infections. To investigate the recent explosion of resistant strains, a literature review was performed focusing on four main areas: mechanisms of resistance to antifungal agents, diagnosis of superficial fungal infections, management, and stewardship. The use of traditional diagnostic tools such as culture, KOH analysis and minimum inhibitory concentration values on treatment were investigated and compared to the newer techniques such as molecular methods including whole genome sequencing, and polymerase chain reaction. The management of terbinafine-resistant strains is discussed. We have emphasized the need for antifungal stewardship including increasing surveillance for resistant infection.

Factors Associated With Musculoskeletal Pain Among Hair Transplant Surgeons: Analyses of Survey Data and Review of the Literature.

BACKGROUND: The prevalence of work-related musculoskeletal disorders (WRMD) is increasing among all surgical specialties. OBJECTIVE: Results of a cross-sectional survey of hair transplant surgeons were analyzed, with the aims to (1) determine the prevalence of WRMD, (2) assess risk factors associated with musculoskeletal (MSK) symptoms, and (3) identify mitigation measures. MATERIALS AND METHODS: A survey pertaining to demographics, MSK-related symptoms and its impacts, and pain mitigation measures taken, if any, were distributed to 834 hair transplant surgeons. Risk factors associated with pain severity were assessed using linear regression. RESULTS: Overall, 78.5% (73 of 93) respondents had experienced pain when performing surgery. Musculoskeletal symptoms were most severe in the neck, followed by upper/lower back, and extremities. Number of grafts performed per session of follicular unit extraction positively correlated with pain severity; female surgeons and surgeons aged >71 years were at higher risk. A majority expressed concern that WRMD may limit their career and agreed to a need for improved workplace education. Strength training and ergonomic improvements of surgical procedure were not commonly adopted. CONCLUSION: In sum, WRMD can be debilitating in health care professionals. Workplace ergonomic adjustments and physical exercise programs may be warranted to better mitigate MSK symptoms.

The emergence of Trichophyton indotineae: Implications for clinical practice.

Emergence and increase of terbinafine-resistant dermatophytosis led to the identification of Trichophyton mentagrophytes internal transcriber space (ITS) genotype VIII in 2017, later renamed as Trichophyton indotineae and classified as a separate species in 2020. With its suspected origin in South Asia, this novel strain has emerged in Bahrain, Canada, Denmark, Finland, France, Germany, India, Iran, Japan, Russia, and Switzerland, with its spread attributed primarily to travel and migration. Diagnosis using routine mycology laboratory techniques is unable to distinguish T. indotineae from T. mentagrophytes and T. interdigitale; specific identification requires genomic sequencing to identify unique, specific markers. One speculated reason for this recent outbreak is the unrestricted use of topical steroid creams and antifungal agents. Patients with extensive tinea corporis and cruris due to T. indotineae present with inflammatory red plaques in multiple body sites. The majority of these infections prove to be resistant to conventional antifungals, including allylamines and azoles (itraconazole and fluconazole), thus emphasizing the need for antifungal susceptibility testing before treatment initiation and for reassessing in nonresponsive patients. Molecular studies have identified several point mutations in the ERG1 (terbinafine resistance) and ERG11 (azole resistance) genes, which need to be analyzed further. Use of relatively new agents, such as voriconazole and luliconazole, as well as device modalities and combination therapy, could be investigated for recalcitrant T. indotineae infections.

Strategies for the enhancement of nail plate permeation of drugs to treat onychomycosis.

Onychomycosis is caused by dermatophytes, non-dermatophytes and yeasts. It has a global prevalence of 5.5%, requires long treatment periods, and has high relapse rates following therapy. Oral antifungals are generally the most common treatment. While effective, they have limitations such as drug-drug interactions, hepatotoxicity and adverse side effects; thus, they cannot be used in several populations. Topical antifungals do not have the safety limitations but are typically not as effective. The primary challenge of topical treatment is the permeation of drug molecules across the nail plate barrier, which is a highly cross-linked keratin network. The use of drugs and formulations with favourable characteristics such as small size, absence of lipophilicity, hydrophilic nature, hydrating properties and appropriate pH can greatly improve permeation. Here, we review physical, nanoparticle-based, formulation-based, mechanical and chemical drug delivery strategies to improve the permeation of drugs across the nail plate.

Elucidating the cellular uptake mechanisms of heptamethine cyanine dye analogues for their use as an anticancer drug-carrier molecule for the treatment of glioblastoma.

The development of chemotherapies for glioblastoma is hindered by their limited bioavailability and toxicity on normal brain function. To overcome these limitations, we investigated the structure-dependent activity of heptamethine cyanine dyes (HMCD), a group of tumour-specific and BBB permeable near-infrared fluorescent dyes, in both commercial (U87MG) and patient-derived GBM cell lines. HMCD analogues with strongly ionisable sulphonic acid groups were not taken up by patient-derived GBM cells, but were taken up by the U87MG cell line. HMCD uptake relies on a combination of transporter uptake through organic anion-transporting polypeptides (OATPs) and endocytosis into GBM cells. The uptake of HMCDs was not affected by p-glycoprotein efflux in GBM cells. Finally, we demonstrate structure-dependent cytotoxic activity at high concentrations (EC50 : 1-100 µM), likely due to mitochondrial damage-induced apoptosis. An in vivo orthotopic glioblastoma model highlights tumour-specific accumulation of our lead HMCD, MHI-148, for up to 7 days following a single intraperitoneal injection. These studies suggest that strongly ionisable groups like sulphonic acids hamper the cellular uptake of HMCDs in patient-derived GBM cell lines, highlighting cell line-specific differences in HMCD uptake. We envisage these findings will help in the design and structural modifications of HMCDs for drug-delivery applications for glioblastoma.

Reclaimed and Up-Cycled Cathodes for Lithium-Ion Batteries.

As electric vehicles become more widely used, there is a higher demand for lithium-ion batteries (LIBs) and hence a greater incentive to find better ways to recycle these at their end-of-life (EOL). This work focuses on the process of reclamation and re-use of cathode material from LIBs. Black mass containing mixed LiMn2O4 and Ni0.8Co0.15Al0.05O2 from a Nissan Leaf pouch cell are recovered via two different recycling routes, shredding or disassembly. The waste material stream purity is compared for both processes, less aluminium and copper impurities are present in the disassembled waste stream. The reclaimed black mass is further treated to reclaim the transition metals in a salt solution, Ni, Mn, Co ratios are adjusted in order to synthesize an upcycled cathode, LiNi0.6Mn0.2Co0.2O2 via a co-precipitation method. The two reclamation processes (disassembly and shredding) are evaluated based on the purity of the reclaimed material, the performance of the remanufactured cell, and the energy required for the complete process. The electrochemical performance of recycled material is comparable to that of as-manufactured cathode material, indicating no detrimental effect of purified recycled transition metal content. This research represents an important step toward scalable approaches to the recycling of EOL cathode material in LIBs.