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BACKGROUND: Opioid use after revision total hip arthroplasty (rTHA) has not been well characterized. The purpose of this study was to characterize preoperative, perioperative, and postoperative opioid use during rTHA. METHODS: Patients undergoing revision THA from 2010 to 2018 were screened for opioid use 3 months before revision surgery and tracked 24 months postoperatively. Patients were categorized as naïve or tolerant. Opioid prescriptions and average morphine milligram equivalents (MME) were compared between the two groups. RESULTS: One hundred twenty-four of 247 patients (50%) in the tolerant group averaged a preoperative MME of 23.7 mg/day. Postoperatively, tolerant patients received significantly higher daily MME at all time points, including at 3 months 31.4 versus 18.1 mg/day (P < 0.001), 6 months 19.9 versus 2.95 mg/day (P < 0.001), 12 months 14.3 versus 3.5 mg/day (P < 0.001), and 24 months 10.7 versus 2.17 mg/day (P < 0.001). Tolerant patients were more likely to have a prescription at 6 months (44% versus 22%), 12 months (41.4% versus 24%), and 24 months (38% versus 19.3%) (P < 0.001, P = 0.002, P < 0.001, respectively). DISCUSSION: Opioid-tolerant patients had higher postoperative MME requirements for longer recovery duration. Both groups reduced opioid use at 3 months and plateaued at 6 months. These findings can help the revision surgeon counsel patients and expectations.

The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effects has succeeded, and the current opioid epidemic affirms that they are a greater hindrance to the field of pain management than ever. Recent attempts at new opioid development have sought to reduce these side effects by minimizing engagement of the regulatory protein arrestin-3 at the mu-opioid receptor, but there is significant controversy around this approach. Here, we discuss the ongoing effort to develop safer opioids and its relevant historical context. We propose a new model that reconciles results previously assumed to be in direct conflict to explain how different signaling profiles at the mu-opioid receptor contribute to opioid tolerance and dependence. Our goal is for this framework to inform the search for a new generation of lower liability opioid analgesics.

BACKGROUND AND OBJECTIVES: The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to expand protection for pneumococcal disease. It contains all 13-valent pneumococcal conjugate vaccine (PCV13) components plus conjugates for 7 additional serotypes. Our primary objective with this study was to evaluate PCV20 tolerability and safety. METHODS: In this phase 3, multi-country, double-blind study, healthy infants born at ≥34 weeks' gestation were randomly assigned 2:1 to receive PCV20 or PCV13 at 2, 4, 6, and 12 to 15 months of age. Safety assessments included local reactions and systemic events within 7 days after each vaccination, adverse events (AEs) from dose 1 to 1 month after dose 3 and from dose 4 to 1 month after dose 4, and serious AEs and newly diagnosed chronic medical conditions from dose 1 through 6 months after the last dose. RESULTS: Participants received PCV20 (N = 1000) or PCV13 (N = 504); 91.7% received all 4 doses. The frequencies of local reactions and systemic events were generally similar in PCV20 and PCV13 groups, with most reported as mild or moderate. The most common local reaction was injection site pain (PCV20, 24.7% to 40.5%; PCV13, 26.8% to 42.0%); irritability was the most common systemic event (PCV20, 54.8% to 68.2%; PCV13, 54.7% to 68.5%). AE frequencies were similar in both groups. No serious AEs were related to study vaccines. Few newly diagnosed chronic medical conditions were reported (2.8% in both groups). PCV20 was safe across multiple countries, in late preterm infants, and when administered with other vaccines. CONCLUSIONS: A 4-dose series of PCV20 had a tolerability and safety profile similar to that of PCV13. [ABSTRACT FROM AUTHOR]

Objectives The objective of this study was to examine the effectiveness and drug tolerability of biological DMARD (bDMARD) and Janus kinase inhibitor (JAKi) monotherapy in patients with RA in a multicentre cohort study. Methods Patients with RA for whom bDMARD/JAKi monotherapy without conventional synthetic DMARDs has been initiated were included. Monotherapy regimens were categorized as IL-6 receptor inhibitors (IL-6Ris), cytotoxic T-lymphocyte–associated protein 4 immunoglobulin (CTLA4Ig), JAKis, or TNF inhibitors (TNFis). Multiple propensity score–based inverse probability weighting (IPW) was used to reduce selection bias. Linear mixed-effect models with IPW were used to examine changes in the DAS in 28 joints using ESR (DAS28)-ESR at 24 weeks, and drug retention was compared between monotherapy groups using IPW Cox proportional hazards models. Results A total of 849 treatment courses were included, involving 635 patients (IL-6Ris, 218; CTLA4Ig, 183; JAKis, 92; TNFis, 356). The change in DAS28-ESR at week 24 as the primary outcome was –0.93 (95% CI: –1.20 to –0.66) lower in the IL-6Ri group than in the TNFi group, while those of the CTLA4Ig and JAKi groups were similar to that of the TNFi group [–0.20 (–0.48 to 0.08), –0.25 (–0.67 to 0.16), respectively]. IL-6Ri use was associated with significantly lower overall drug discontinuation than that for TNFi use [hazard ratio = 0.55 (0.39–0.78), P  = 0.001]. Similar retention rates were identified for the CTLA4Ig and JAKi groups to that of the TNFi group. Conclusion In the analysis with IPW to reduce selection bias, IL-6Ri monotherapy was superior to TNFi monotherapy in terms of effectiveness and drug retention. No significant differences were identified between CTLA4Ig, JAKi and TNFi monotherapy. [ABSTRACT FROM AUTHOR]

Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop indicated for the treatment of Demodex blepharitis. It is the first and currently the only US FDA-approved treatment for this condition. One drop of lotilaner 0.25% instilled in each eye twice daily for 6 weeks was associated with significantly higher rates of collarette reduction to ≤ 2 collarettes (primary endpoint), mite eradication and erythema cure compared to the vehicle control. Lotilaner 0.25% is generally well tolerated, with the most common ocular adverse reaction being instillation site stinging and burning (incidence 10%). The 6-week treatment remained durable with no safety issues during the observational period for up to a year. The eye drop was generally neutral or very comfortable for most patients. Plain Language Summary: Demodex blepharitis is a common eyelid margin disease caused by an infestation of Demodex mites. It is characterized by persistent cylindrical waxy dandruff (collarettes) in the eyelashes, eyelid margin inflammation, redness and eye irritation. Lotilaner ophthalmic solution 0.25% (XDEMVY®; henceforth referred to as lotilaner 0.25%) is a novel prescription eye drop that eradicates Demodex mites. It is FDA-approved in the USA for the treatment of Demodex blepharitis. One drop of lotilaner 0.25% in each eye twice daily for 6 weeks significantly reduces collarettes, decreases or eradicates Demodex mites and reduces eyelid redness in patients with Demodex blepharitis. The treatment is generally well tolerated, with the most common ocular adverse reactions being installation site stinging and burning (incidence 10%). Currently, lotilaner 0.25% is the only US FDA-approved treatment for Demodex blepharitis. [ABSTRACT FROM AUTHOR]

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single‐center, open‐label, two‐period study. In period 1, epoprostenol 8 ng/kg/min was administered alone. In period 2, epoprostenol 8 ng/kg/min was administered following an 8‐day treatment with zamicastat. Since the initial dose of epoprostenol showed to be insufficiently tolerated, it was decreased to 6 ng/kg/min. Blood samples were collected to determine the metabolites of epoprostenol and concentrations of zamicastat and its metabolites. A total of 54 subjects were enrolled and data from 28 subjects were available for pharmacokinetic analysis. The epoprostenol plus zamicastat‐to‐epoprostenol geometric means ratio (GMR) and corresponding 90% confidence interval (CI) for Cav,ss and area under the plasma concentration–time curve from time 0 up to 16 h at steady state (AUC0‐16,ss) of the metabolites of epoprostenol were within the acceptance bioequivalence range (80.00%‐125.00%). The intrasubject coefficient of variation (ISCV) was below 10% for both parameters, on both metabolites. For zamicastat AUC0‐τ,ss, the zamicastat plus epoprostenol‐to‐zamicastat GMR and corresponding 90% CI were within the bioequivalence acceptance range, while for zamicastat Cmax,ss, the lower limit of the 90% CI was slightly below the acceptance range. For zamicastat metabolites, Cmax,ss and AUC0‐τ,ss and the zamicastat plus epoprostenol‐to‐zamicastat GMR were below the acceptance bioequivalence range. ISCV was between 30% and 41% for Cmax,ss and between 21% and 41% for AUC0‐τ,ss, for zamicastat and both metabolites. This study showed that the administration of zamicastat did not significantly modify the cardiovascular effects of epoprostenol and that the interactions between zamicastat and epoprostenol are not expected to be clinically relevant. [ABSTRACT FROM AUTHOR]

Many medications commonly used to treat neuropathic pain are associated with significant, dose-limiting adverse effects, including sedation, dizziness, and fatigue. These adverse effects are due to the activity of these medications within the central nervous system. The objective of this work was to investigate the interactions between peripherally restricted cannabinoid receptor and mu-opioid receptor (MOR) agonists on ongoing and evoked neuropathic pain behaviors in mouse models. RNAscope analysis of cannabinoid receptor type 1 (CB1R) and MOR mRNA demonstrated that the mRNA of both receptors is colocalized in both mouse and human dorsal root ganglion. Single-cell RNAseq of dorsal root ganglion from chronic constriction injury mice showed that the mRNA of both receptors (Cnr1 and Oprm1) is coexpressed across different neuron clusters. MycCB1R and FLAG-MOR were cotransfected into immortalized HEK-293T cells and were found to interact at a subcellular level. We also find that CB-13 (a peripherally restricted dual CB1R and cannabinoid receptor type 2 agonist) and DALDA (a peripherally restricted MOR agonist) both attenuate mechanical hypersensitivity in a murine model of neuropathic pain. Using isobolographic analysis, we demonstrate that when coadministered, these agents synergistically attenuate mechanical hypersensitivity. Importantly, combination dosing of these agents does not cause any detectable preferential behaviors or motor impairment. However, repeated dosing of these agents is associated with the development of tolerance to these drugs. Collectively, these findings suggest that leveraging synergistic pain inhibition between cannabinoid receptor and MOR agonists in peripheral sensory neurons may be worth examining in patients with neuropathic pain. [ABSTRACT FROM AUTHOR]

The aim of this trial was to assess the effectiveness of Sediflù, a medical device containing active herbal ingredients, on nocturnal and diurnal persistent coughs in children, with a duration of 3 to 7 days. Children with a dry and/or productive cough were enrolled in this prospective, interventional, multicenter, placebo-controlled, double-blind, randomized clinical study. Clinical efficacy was assessed through the evaluation of the soothing action of Sediflù against dry and/or productive coughing, both at night and during the day, and other effects of coughing associated with quality of sleep: frequency, child's quality of sleep, parental quality of sleep and severity. Treatment with Sediflù improved both night-time and day-time cough scores from day 2. The diurnal score also improved significantly in the Sediflù group at days 3 and 7. Sediflù syrup can be considered a valid treatment for cough management in younger children with upper respiratory tract infections, shortening the cough duration. [ABSTRACT FROM AUTHOR]

Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 [95% CI 1.02, 1.97]), older (5-year increments aOR 1.10 [95% CI 1.09, 1.11]), White (aOR 2.2 [95% CI 1.88, 2.56]), had advanced education (aOR 3.89 [95% CI 2.97, 5.09]), were employed (aOR 1.89 [95% CI 1.50, 2.40]), or partnered/married (aOR 2 [95% CI 1.72, 2.32]) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 [95% CI 1.31, 5.55]) or who were single/not partnered (aOR 2.33 [CI 95% 1.25, 4.34]) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens. [ABSTRACT FROM AUTHOR]

Background Shorter prophylactic vaccine schedules may offer more rapid protection against Ebola in resource-limited settings. Methods This randomized, observer-blind, placebo-controlled, phase 2 trial conducted in 5 sub-Saharan African countries included people without human immunodeficiency virus (HIV) (PWOH, n = 249) and people with HIV (PWH, n = 250). Adult participants received 1 of 2 accelerated Ebola vaccine regimens (MVA-BN-Filo, Ad26.ZEBOV administered 14 days apart [n = 79] or Ad26.ZEBOV, MVA-BN-Filo administered 28 days apart [n = 322]) or saline/placebo (n = 98). The primary endpoints were safety (adverse events [AEs]) and immunogenicity (Ebola virus [EBOV] glycoprotein–specific binding antibody responses). Binding antibody responders were defined as participants with a >2.5-fold increase from baseline or the lower limit of quantification if negative at baseline. Results The mean age was 33.4 years, 52% of participants were female, and among PWH, the median CD4+ cell count was 560.0 (interquartile range, 418.0–752.0) cells/μL. AEs were generally mild/moderate with no vaccine-related serious AEs or remarkable safety profile differences by HIV status. At 21 days post–dose 2, EBOV glycoprotein–specific binding antibody response rates in vaccine recipients were 99% for the 14-day regimen (geometric mean concentrations [GMCs]: 5168 enzyme-linked immunosorbent assay units [EU]/mL in PWOH; 2509 EU/mL in PWH) and 98% for the 28-day regimen (GMCs: 6037 EU/mL in PWOH; 2939 EU/mL in PWH). At 12 months post–dose 2, GMCs in PWOH and PWH were 635 and 514 EU/mL, respectively, for the 14-day regimen and 331 and 360 EU/mL, respectively, for the 28-day regimen. Conclusions Accelerated 14- and 28-day Ebola vaccine regimens were safe and immunogenic in PWOH and PWH in Africa. Clinical Trials Registration.  NCT02598388. [ABSTRACT FROM AUTHOR]

The emergence of antimicrobial resistance (AMR) across bacterial pathogens presents a serious threat to global health. This threat is further exacerbated in tuberculosis (TB), mainly due to a protracted treatment regimen involving a combination of drugs. A diversity of factors contributes to the emergence of drug resistance in TB, which is caused by the pathogen Mycobacterium tuberculosis (Mtb). While the traditional genetic mutation‐driven drug resistance mechanisms operate in Mtb, there are also several additional unique features of drug resistance in this pathogen. Research in the past decade has enriched our understanding of such unconventional factors as efflux pumps, bacterial heterogeneity, metabolic states, and host microenvironment. Given that the discovery of new antibiotics is outpaced by the emergence of drug resistance patterns displayed by the pathogen, newer strategies for combating drug resistance are desperately needed. In the context of TB, such approaches include targeting the efflux capability of the pathogen, modulating the host environment to prevent bacterial drug tolerance, and activating the host anti‐mycobacterial pathways. In this review, we discuss the traditional mechanisms of drug resistance in Mtb, newer understandings and the shaping of a set of unconventional approaches to target both the emergence and treatment of drug resistance in TB. [ABSTRACT FROM AUTHOR]

Background Evidence concerning tolerability of sodium-glucose co-transporter-2 (SGLT2) inhibitors in older adults is limited due to under-representation in clinical trials. Our study aimed to determine the extent to which SGLT2 inhibitor intolerance increases with age and explore additional factors associated with intolerance. Methods This retrospective observational study included patients in the Veterans Health Administration who initiated an SGLT2 inhibitor between 1 January 2013 and 31 December 2021. One-year discontinuation served as a proxy for intolerance. Relative risk (RR) for 1-year discontinuation was contrasted across age groups using log-binomial regression to adjust for confounding. Results Of 232 495 patients who initiated an SGLT2 inhibitor, 60 582 (26.1%) discontinued within one year. A difference was observed across age groups, <65, 65–74, 75–84 and ≥85 years, where 25.8%, 25.3%, 28.5% and 34.9% of patients discontinued, respectively (P  < .001). After adjustment for confounding factors, patients 75–84 and ≥85 years were at 8% (RR = 1.08; 95% CI: 1.05, 1.10) and 21% increased risk (RR = 1.21; 95% CI: 1.15, 1.26) for discontinuation, respectively, relative to patients <65 years. Additional risk factors were identified: female (RR = 1.41; 95% CI: 1.37, 1.45), estimated glomerular filtration rate stage 4 (RR = 1.49; 95% CI: 1.39, 1.60), underweight (RR = 1.15; 95% CI: 1.03, 1.29), urinary tract infection history (RR = 1.25; 95% CI: 1.21, 1.30) and yeast infection history (RR = 1.39; 95% CI: 1.27, 1.51). Conclusion No clinically meaningful differences in SGLT2 inhibitor intolerance were observed in patients up to 84 years. Our findings support having closer follow-up when initiating in patients 85 years and older. [ABSTRACT FROM AUTHOR]

Sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER) represents a promising novel option for the treatment of narcolepsy. It is the first once-nightly sodium oxybate formulation to be approved in the USA for the treatment of cataplexy or excessive daytime sleepiness (EDS) in adults with narcolepsy. Sodium oxybate ER has a pharmacokinetic profile that supports a single bedtime dose. In a pivotal phase 3 trial, once-nightly sodium oxybate ER dose-dependently increased sleep latency during the daytime, reduced cataplexy and daytime sleepiness, and improved disrupted nighttime sleep (DNS) compared with placebo in patients aged ≥ 16 years with narcolepsy. These improvements were statistically significant and clinically meaningful. Most patients who switched from twice-nightly immediate-release sodium oxybate (hereafter referred to as sodium oxybate IR) to once-nightly sodium oxybate ER in an open-label extension/switching study preferred the once-nightly formulation. Once-nightly sodium oxybate ER was generally well tolerated, including over the longer term, with a tolerability profile consistent with that of twice-nightly sodium oxybate IR. Plain Language Summary: Narcolepsy, a disorder of sleep-wake instability, is a lifelong condition characterized primarily by overwhelming and persistent daytime sleepiness. Other symptoms include sudden muscle weakness associated with strong emotions (cataplexy), disturbed nighttime sleep, sleep paralysis, and vivid hallucinations when falling asleep or when awakening. The standard of care for patients with narcolepsy has been sodium oxybate, which requires twice-nightly dosing. Patients take their first dose at bedtime and must then awaken 2.5–4 h later to take their second dose. A less burdensome once-nightly formulation, sodium oxybate extended-release suspension (LUMRYZ™; hereafter referred to as sodium oxybate ER), has been approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy. In a clinical trial, patients treated with once-nightly sodium oxybate ER were able to stay awake longer during the day, felt less sleepy in the daytime, had fewer cataplexy attacks, and had less disruption to nighttime sleep than placebo recipients. Sodium oxybate ER was generally well tolerated. Nausea, dizziness, bed-wetting, headache, and vomiting were the most common treatment-related adverse events. Thus, once-nightly sodium oxybate ER represents a promising new option for the treatment of narcolepsy. [ABSTRACT FROM AUTHOR]

Background: Sleep disturbance has a prevalence of 30–78% in patients with advanced cancer. While pharmacotherapy is common, randomized controlled studies (RCTs) investigating available agents are limited. This study examines the efficacy and safety of temazepam or melatonin versus placebo for sleep in advanced cancer. Methods: This is a multicenter, randomized, double-blind, placebo-controlled study of temazepam, melatonin prolonged release (PR) or placebo for insomnia in patients with advanced cancer, and an insomnia severity index (ISI) score of >11. Results: Twenty-one participants were randomized: nine to temazepam, eight to melatonin, and four to placebo. Baseline characteristics between groups were similar. The adjusted mean difference in day 8 ISI score versus placebo was −9.1 (95% confidence interval [CI] −17.5, 0.7, p = 0.04) for temazepam and −9.6 (95% CI −18,−1.2, p = 0.03) for melatonin PR. There was no improvement in global quality of life. Both agents were well tolerated. Conclusion: Temazepam and melatonin PR were associated with a clinically significant improvement in patient-reported insomnia severity compared with placebo. Findings need confirmation with larger patient numbers. [ABSTRACT FROM AUTHOR]

Simple Summary: Adjuvant chemotherapy (AC) using S-1 has demonstrated favorable outcomes for patients with pancreatic cancer (PC). However, the current S-1 completion rate is insufficient to achieve its benefits. Moreover, an absence of dependable markers to forecast S-1 completion warrants C-reactive protein-to-albumin ratio (CAR) investigation as a potential predictive factor related to nutritional status. Previously, we revealed that a postoperative CAR value of ≥0.05 serves as a marker predicting S-1 AC treatment non-completion due to adverse events (AEs) in the Ehime study. Thus, this study aims to substantiate the correlation between postoperative CAR and S-1 therapy non-completion due to AEs using an alternative cohort from another institution (the Dokkyo study). Background: S-1 in adjuvant chemotherapy (AC) administration after pancreatic cancer (PC) surgery has been standardized in Japan. The Ehime study confirmed that a postoperative higher C-reactive protein-to-albumin ratio (CAR) value predicted the risk of adverse event (AE)-related S-1 non-completion as an AC in patients with PC after curative surgery. This study aimed to investigate the index to predict S-1 tolerance among patients who underwent curative surgery for PC (the Dokkyo study). Methods: This retrospective validation cohort study included 172 patients at the Department of Hepato-Biliary Pancreatic Surgery, Dokkyo Medical University, Japan, from January 2010 to December 2022. All patients underwent nutritional screening using the postoperative CAR. S-1 completion status and its effect on prognosis were systematically followed up and investigated. We conducted a statistical analysis of predictive markers to investigate their association with S-1 completion. Results: Patients were categorized into the S-1 completion (N = 91) and non-completion (N = 81) groups. The S-1 completion group demonstrated a significantly lower CAR than the S1 non-completion group. Moreover, the current study revealed a significant difference in the S-1 completion rate, applying the CAR cutoff value of 0.05 established in the Ehime study. Additionally, univariate and multivariate analyses confirmed that a CAR of <0.05 was significantly associated with S-1 completion. Conclusions: The Dokkyo study confirmed the results observed in the Ehime study. Consequently, an increased postoperative CAR value appeared as a universal applicable marker for the risk factor of AE-related S-1 non-completion after curative surgery for patients with PC. [ABSTRACT FROM AUTHOR]

Simple Summary: The study evaluated the long-term outcomes of chemoradiotherapy (CRT) with S-1 after limited surgery for T1 or T2 lower rectal cancer. The 3-year and 5-year relapse-free survival rates were 90.17% and 85.87%, respectively, showing favorable outcomes for T1 cancer patients, with effective anal function preservation. However, further treatment is needed to improve outcomes for T2 cancer patients. Background: The short-term outcomes of chemoradiotherapy (CRT) with S-1 (a combination of tegafur, gimeracil, and oteracil) following limited surgery for patients with T1 or T2 lower rectal cancer have shown encouraging results. Objectives: This study was designed to delve deeper into the long-term outcomes of CRT with S-1 after limited surgery, with the goal of evaluating both the long-term efficacy and potential risks associated with this treatment approach in patients diagnosed with T1 or T2 lower rectal cancer. Methods: This was conducted as a multicenter, single-arm, prospective phase II trial. The patient population consisted of individuals clinically diagnosed with either T1 or T2 lower rectal or anal canal cancer, with a maximum tumor diameter of 30 mm and classified as N0 or M0. Patients underwent local excision or endoscopic resection. After surgery, CRT with S-1 was administered to patients meeting several criteria, including the confirmation of well-differentiated or moderately differentiated adenocarcinoma, negative surgical margins, submucosal invasion depth of ≥1000 µm, and high tumor-budding grade (2/3). The primary endpoint of this study was relapse-free survival, while secondary endpoints included local recurrence-free survival, overall survival, anal sphincter preservation rate, and safety. Results: A total of 52 patients were included, with pathological diagnoses revealing T1 in 36 patients and T2 in 16 patients. The 3-year and 5-year relapse-free survival rates were 90.17% and 85.87%, respectively. The 3-year and 5-year local recurrence-free survival rates were 90.17% and 88.07%, respectively, while the 3-year and 5-year overall survival rates were 94.03% and 91.94%, respectively. Conclusions: CRT with S-1 after limited surgery for T1 lower rectal cancer demonstrated favorable outcomes in terms of recurrence, survival, and local control rates while effectively maintaining anal function in patients. However, further treatment approaches may be necessary to improve outcomes for patients diagnosed with stage T2 lower rectal cancer [ABSTRACT FROM AUTHOR]

Simple Summary: There is a significant gap in research and guidelines for treating octogenarian multiple myeloma (MM) patients. This retrospective study examined 101 MM patients, median age 84 years (80–98), treated outside clinical studies at TASMC between 2010 and 2023, aiming to review real-world practices and outcomes experienced by this vulnerable group of patients. Of these patients, 87% received a bortezomib-based regimen; 20% received lenalidomide ± bortezomib; 44% were treated with novel agent-based doublets, and 51% with triplets/quadruplets. Despite the employment of reduced doses of steroids and lenalidomide, treatment-related toxicity was high, including 9% who suffered grade 5 events. Of these patients, 67% received subsequent lines, resulting in an impressive median overall survival of 42 months (1–141) in the entire cohort. These results highlight the effectiveness of personalized therapy for octogenarian multiple myeloma (MM) patients and emphasize the need for further real-time studies to establish guidelines for the management of this vulnerable and growing population. Background: Data on the outcome of octogenarian multiple myeloma (MM) patients (pts), especially if treated outside clinical studies, are scanty. Aims and Methods: MM pts ≥ 80 years, treated at TASMC with first-line therapy between 2010 and 2023, were reviewed. Characteristics and outcomes were analyzed. Results: A total number of 101 pts, of whom 54 were males with a median age of 84 years (80–98), were included. Among them, 67.4% had a Charlson comorbidity index of ≥5, 37% had ISS-3 (International staging system) and 20% had Revised-ISS-3. In our study, 44.5% received doublets and 50.5% received triplets/quadruplets. A bortezomib-based regimen was applied in 87%, and IMiDs were used in 27.7%. Despite an upfront employment of a low lenalidomide dose, dose reductions were required in 48%. Grade ≥ 3 adverse events (AEs) (mainly infections) were documented in 36.6% of patients, including grade 5 events in 9%, all attributed to infections. The overall response rate was 69%, including 31% ≥ VGPRs (Very good partial response). Sixty-seven percent (67%) received second-line therapy, administered within a median period of 12 months (1–84). Within a median follow-up period of 36 m (1–141), the median overall survival (OS) approached 42 m (range: 1–141); being shorter in pts > 84 years (HR = 1.7, p = 0.03), pts with lung disease (HR = 1.8, p = 0.044) and pts with ISS = 3 and R-ISS = 3 (HR = 1.65, p = 0.0016 and HR = 2.45, p = 0.006, respectively); Conclusions: Octogenarians treated outside clinical studies often have a lower tolerance to treatment. Nevertheless, upfront administration of low doses of anti-MM agents provided a response in the majority of patients, translated into impressive OS. Nevertheless, mortality due to AEs was high, emphasizing the need for new, "octogenarian-oriented" treatment protocols. [ABSTRACT FROM AUTHOR]

Hypoparathyroidism is a disease characterized by inadequate or absent parathyroid hormone (PTH) levels. It manifests with hypocalcemia, hyperphosphatemia, and elevated urinary fractional excretion of calcium. The conventional therapy with calcium supplementation and active vitamin D analogs is limited by the pill burden, unstable calcium concentrations, and significant renal and bone complications. Hence, the development of replacement therapies utilizing PTH or PTH-related receptor modulators has emerged as a promising therapeutic avenue. rhPTH (1-84) (NATPARA®) is a once-daily injection of full-length recombinant human parathyroid hormone that was initially approved by the U.S. Food and Drug Administration(FDA) in 2015 for hypoparathyroidism. However, it was recalled from the U.S. market in 2019, and its production will cease globally by the end of 2024. TransCon™ PTH, known as palopegteriparatide, utilizes an innovative technology to provide a sustained release of PTH (1-34) prodrug. It has received approval from the European Medicines Agency and is currently undergoing FDA review. Eneboparatide is a PTH receptor 1 agonist, designed to stimulate a specific receptor configuration. Encaleret is a negative allosteric modulator of the calcium-sensing receptor and rescues the secretion of naive PTH inAutosomal Dominant Hypocalcemia type 1. MBX 2109 is an investigational once-weekly PTH prodrug that addresses thefrequent administration challenge. EB612, the tablet form of PTH(1-34), is the first oral hormone replacement treatment for hypoparathyroidism. Recent developments in the management of chronic hypoparathyroidism hold promise as a therapeutic approach to restore physiological function, manage symptoms, and prevent associated complications. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness, tolerability, and safety of topical amitriptyline as a potential route of administration for the management of burning mouth syndrome. Background: Burning mouth syndrome is a complex, idiopathic, and debilitating orofacial pain disorder that impairs quality of life, with a prevalence of up to 18% in menopausal women. Available drugs to alleviate its burning sensation have inconsistent and limited efficacy. Given its physicochemical properties, excellent tolerability, and ability to target peripheral pathways, topical amitriptyline seems a promising mechanistically specific analgesic drug for burning mouth syndrome. Methods: In this retrospective cross‐sectional real‐world evidence study, patients with burning mouth syndrome who were prescribed topical amitriptyline for 8 weeks were identified. Eligibility criteria stemmed from ICHD‐3, ICOP, and consensus definitions. The primary outcome measure was mean daily pain intensity (on a 0–10 scale); secondary outcomes included adverse events and patient global impression of improvement. Data are given as the mean ± SD. Results: A total of 15 patients fulfilling the eligibility criteria were included and analyzed. Mean daily pain was 6.7 ± 2.1 at baseline and 3.7 ± 2.3 after treatment, with a mean reduction of 3.1 ± 2.8 (p = 0.002). Half of the patients experienced a decrease in pain by at least 50% (p = 0.008). Several mild adverse events were reported, such as somnolence or dry mouth. Conclusions: Topical amitriptyline may be a safe and potent route of administration in the treatment of burning mouth syndrome, a hypothesis to be tested in further controlled trials. [ABSTRACT FROM AUTHOR]

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression. [ABSTRACT FROM AUTHOR]

To evaluate Tonsitin (10% DL -lactic acid) safety, tolerability, and efficacy, as a treatment for recurrent tonsillitis (RT) in children. This is a clinical prospective, randomized, double blind pilot study, to evaluate the safety, tolerability and efficacy of Tonsitin in healthy children with RT. Safety evaluated in terms of adverse events (AEs), tolerability in terms of compliance, and efficacy in terms of tonsils' size and frequency of tonsillitis, and quality of life. The study included 51 children. The treatment regimen was tolerable among the participants. Six children experienced AEs, but mostly mild. Tonsil size declined in both groups, but these results did not reach statistical significance. Tonsillitis episodes' frequencies were random and not significant. Tonsitin treatment was found to be feasible in the clinical setup and was well tolerated, and appears to be safe. Study efficacy results did not reach statistical significance. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to evaluate the influence of anti‐infliximab (IFX) antibodies on three different points of care: response/tolerance to IFX, tapering strategy, and in a subsequent treatment with a second tumor necrosis factor inhibitor (TNFi). Methods: A prospective cohort of 60 patients with radiographic axial spondyloarthritis who received IFX were evaluated retrospectively regarding clinical/laboratorial data, IFX levels, and anti‐IFX antibodies at baseline, after 6, 12 to 14, 22 to 24, 48 to 54, 96 to 102 weeks, and before tapering or switching. Results: Anti‐IFX antibodies were detected in 27 patients (45%), of whom 23 (85.1%) became positive in the first year of IFX treatment. In comparison to the group that was negative for anti‐IFX antibodies, patients who were positive for anti‐IFX antibodies demonstrated the following: less use of methotrexate as a concomitant treatment to IFX (5 [18.5%] vs 14 [42.4%]; P = 0.048), more infusion reactions at 22 to 24 weeks (P = 0.020) and 48 to 54 weeks (P = 0.034), more treatment failures (P = 0.028) at 48 to 54 weeks, reduced overall IFX survival (P < 0.001), and lower sustained responses (P = 0.044). Of note, patients who were positive for anti‐IFX antibodies exhibited a shorter tapering survival (9.9 months [95% confidence interval (CI) 4.0–15.8] vs 63.4 months [95% CI 27.9–98.8]; P = 0.004) in comparison with patients who were negative for anti‐IFX antibodies. Conversely, for patients who failed IFX, patients who were positive for anti‐IFX antibodies had better clinical response to the second TNFi at three months (15 [83.3%] vs 3 [27.3%]; P = 0.005) and six months (15 [83.3%] vs 4 [36.4%]; P = 0.017) than the patients who were negative for anti‐IFX antibodies after switching. Conclusion: This study provided novel data that anti‐IFX antibodies is a parameter for reduced tapering survival, reinforcing its detection to guide clinical decision. Additionally, we confirmed in a long‐term cohort the anti‐IFX antibody association with worse IFX performance and as predictor of the second TNFi good clinical response. [ABSTRACT FROM AUTHOR]

Background and objective: Multiple randomized controlled studies have shown that pirfenidone and nintedanib are effective and safe for treating idiopathic pulmonary fibrosis. This study aimed to evaluate their efficacy, safety, and tolerability in a real-world setting. Methods: We searched PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases for real-world studies published up to March 3, 2023, on pirfenidone and nintedanib for idiopathic pulmonary fibrosis. Results: A total of 74 studies with 23,119 participants were included. After 12 months of treatment, the change from baseline in percent predicted FVC (%FVC) was − 0.75% for pirfenidone and − 1.43% for nintedanib. The change from baseline in percent predicted DLCO (%DCLO) was − 2.32% for pirfenidone and − 3.95% for nintedanib. The incidence of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) was 12.5% for pirfenidone and 14.4% for nintedanib. The IPF-related mortality rates of pirfenidone and nintedanib were 13.4% and 7.2%, respectively. The all-cause mortality was 20.1% for pirfenidone and 16.6% for nintedanib. In the pirfenidone group, 16.6% of patients discontinued treatment because of adverse events, and in the nintedanib group, 16.2% of patients discontinued treatment because of adverse events. The incidence of adverse events was 56.4% and 69.7% for pirfenidone and nintedanib, respectively. Conclusion: The results of this study indicate that pirfenidone and nintedanib are both effective in slowing down the decline of lung function in IPF patients in real-world settings. The incidence of adverse events with pirfenidone is lower than that with nintedanib, but both are below the clinical trial data, and no new major adverse events have been observed. The discontinuation rates due to adverse reactions of the two drugs are consistent with clinical trial data, indicating good tolerability. However, the mortality rates and AE-IPF incidence rates of these two drugs in real-world settings are higher than those in previous clinical trials, with pirfenidone patients showing a higher mortality rate. Further large-sample studies are needed to investigate the risks of these drugs in these aspects. Additionally, we recommend that future real-world studies pay more attention to patients' subjective symptoms and conduct stratified analyses of the efficacy and safety of pirfenidone and nintedanib based on factors such as patients' baseline lung function, comorbidities, and age, in order to provide more personalized medication advice for IPF patients in clinical practice. [ABSTRACT FROM AUTHOR]

Minimally invasive injectable dermal fillers are one of the most commonly used aesthetic treatments for facial soft tissue restoration. Different formulations may be used simultaneously to target multiple areas of concern. Due to differences in their rheological properties that directly impact the recommended injection technique and overall result, the formulations in the Aliaxin® line are each designed to target different soft facial tissues. This case series addresses two potential treatment approaches and a combination approach specifically developed to achieve harmony and promote a full but soft facial appearance. To reach this goal, we used two different formulations: Aliaxin® Shape and Restore (ASR) and Aliaxin® Global Performance (AGP). Four patients, 35-55 years received treatments with ASR, AGP, or both products. Utilizing the two protocols simultaneously achieved targeted support, lift, and volume, along with effective full facial softening and an authentic aesthetic outcome. [ABSTRACT FROM AUTHOR]

PURPOSE: High-dose methotrexate (HD-MTX) is the backbone of curative therapy for CNS lymphoma. Because of toxicity, MTX is administered in the inpatient setting along with hyperhydration and monitoring until MTX clearance is documented (3-5 days). Frequent hospitalizations result in patient time away from work, home, and exposure to potential iatrogenic/nosocomial complications. Here, we aim to demonstrate feasibility of HD-MTX administration in the outpatient setting with low-dose glucarpidase facilitating clearance. METHODS: This is a prospective nonrandomized study of outpatient HD-MTX followed by glucarpidase 2000u (ClinicalTrials.gov identifier: NCT03684980). Eligible patients had CNS lymphoma, creatinine <1.3 mg/dL, and previously tolerated HD-MTX. Patients were enrolled between May 2020 December 2021 for one HD-MTX treatment. Patients could re-enroll for subsequent doses of HD-MTX as eligibility and slots permitted. MTX 3.5 g/m2 was administered once over 2 hours, preceded by standard hydration and followed by an additional 2 hours of dextrose 5% in water with NaHCO3 75 mEq at 150 cc/h. Glucarpidase 2000u was administered once in the clinic 24 hours later. The primary end point was MTX level 48 hours after HD-MTX. RESULTS: Twenty doses of outpatient HD-MTX with glucarpidase were administered to seven patients. After 20 of 20 (100%) treatments, serum MTX levels were reduced to <100 nmol/L. Treatments were well-tolerated, and no admissions were required. One patient received additional outpatient hydration for elevated creatinine. Development of antiglucarpidase antibody was rare and did not affect treatment. CONCLUSION: Outpatient HD-MTX with glucarpidase is safe and well-tolerated and has the potential to alter standard treatment for CNS lymphoma. CNS lymphoma patients received glucarpidase to avoid hospitalization for MTX therapy. [ABSTRACT FROM AUTHOR]

Aging and age‐related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti‐inflammatory drugs (NSAIDs) have shown their promise in mitigating age‐related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age‐related changes in drug metabolism and tolerance, which could result in age‐dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk‐1/skn‐1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk‐1 was knocked out in the pmk‐1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age‐dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population. This study examined the effects of common NSAIDs on lifespan and heat resistance in young and old Caenorhabditis elegans. Aspirin and ibuprofen extended lifespan by reducing ROS, while acetaminophen and indomethacin accelerated aging and increased oxidative stress damage in older worms. Knocking out the pmk‐1 gene mitigated the harmful effects of acetaminophen and indomethacin. These results suggest potential risks of NSAIDs use in the elderly, warranting further research. [ABSTRACT FROM AUTHOR]

Candida albicans invasive candidiasis is considered a global health problem. In such cases, biofilm formation on implanted devices represents a therapeutic challenge and the presence of metabolically inactive persistent cells (PCs) in these communities increases their tolerance to fungicidal drugs. This study investigated the influence of amoxicillin, AMX; cefepime, CEF; gentamicin, GEN; amikacin, AMK; vancomycin, VAN; and ciprofloxacin, CIP; on the production of PCs in biofilms of C. albicans bloodstream isolates. 48 h-mature biofilms (n = 6) grown in RPMI-1640 supplemented with antibiotics were treated with 100 μg ml−1 amphotericin B and then evaluated for PCs. Biofilms grown in the presence of antibiotics produced more PCs, up to 10×, when exposed to AMX and CIP; 5 × to CEF; and 6 × to GEN and VAN. The results indicate that antibiotics can modulate PC production in C. albicans biofilms. This scenario may have clinical repercussions in immunocompromised patients under broad-spectrum antibiotic therapy. LAY SUMMARY: Biofilms are microbial communities tolerant to antifungals. Our research showed that antibiotics stimulate the formation of persistent cells within Candida albicans biofilms. These are dormant, metabolically silent cells that resist to therapy and can be related to metastatic and recalcitrant infections. [ABSTRACT FROM AUTHOR]

Background: Efficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab's tolerability and safety profile in individuals experiencing episodic and chronic migraines. Methods: The study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption ('drug holiday') of up to 24 weeks. Results: 701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed. Conclusions: APOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment. Trial registration: ClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06. [ABSTRACT FROM AUTHOR]

Simple Summary: A systematic review was carried out to provide evidence regarding the role of stereotactic body radiation therapy (SBRT) for oligometastatic urothelial cancer (omUC). The present work aims to summarize and critically analyze the available data, with a focus on controversial areas and future directions in this emerging field. Eight studies were identified. Heterogeneous SBRT dose/fractionation and metastatic setting did not allow for a meta-analysis. SBRT showed a good toxicity profile, and the better outcomes for both local control and survival were associated with a biologically effective dose (BED10) ≥ 78 Gy. Background: Stereotactic body radiation therapy (SBRT) is the most commonly used metastasis-directed therapy (MDT) for oligometastatic urothelial carcinoma (omUC). Despite efforts in defining this disease entity, open questions remain concerning the role of MDT and the use of biomarkers, imaging, and its combination with systemic therapies. The aim of the present systematic review is to provide an updated overview of the current clinical evidence on SBRT for omUC in terms of survival and local control benefits. We also aim to provide updates on controversial areas and future directions in this emerging field. Methods: With a systematic approach, following PRISMA recommendations, we searched two databases to identify and select articles published up until March 2024 reporting the use of SBRT for omUC with or without concomitant systemic therapies. Prospective randomized or non-randomized studies as well as retrospective studies were included. Results: Eight studies were selected for data extraction and 293 omUC patients treated with SBRT were collectively analyzed. In metachronous omUC patients, SBRT delivered with ablative doses (BED10 ≥ 78 Gy) was associated with a 2-year overall survival (OS) rate of 50.7% (95% CI 35.1–64.4%). The use of sub-ablative SBRT doses (BED10 = 43.2 Gy) in combination with immunotherapy did not demonstrate significant clinical outcome improvement in two prospective studies. The overall tolerance was good, with only one study reporting toxicity of grade 3 in up to 18% of the patients treated with SBRT in combination with immunotherapy. Conclusions: SBRT is an effective and widely available MDT option in omUC, although this is based on a limited number of studies. Despite the attempt to use SBRT as an immune response trigger in combination with immunotherapy, no significant improvement in survival outcomes has been observed. The integration of new systemic agents with MDT will likely define a new scenario for the treatment of omUC. The review protocol was registered in PROSPERO, ID: CRD42024522381. [ABSTRACT FROM AUTHOR]

Systemic infection with Candida albicans poses a significant risk for people with weakened immune systems and carries a mortality rate of up to 60%. However, current therapeutic options have several limitations, including increasing drug tolerance, notable off-target effects, and severe adverse reactions. Over the past four decades, the progress in developing drugs to treat Candida albicans infections has been sluggish. This comprehensive review addresses the limitations of existing drugs and summarizes the efforts made toward redesigning and innovating existing or novel drugs through nanotechnology. The discussion explores the potential applications of nanomedicine in Candida albicans infections from four perspectives: nano-preparations for anti-biofilm therapy, innovative formulations of "old drugs" targeting the cell membrane and cell wall, reverse drug resistance therapy targeting subcellular organelles, and virulence deprivation therapy leveraging the unique polymorphism of Candida albicans. These therapeutic approaches are promising to address the above challenges and enhance the efficiency of drug development for Candida albicans infections. By harnessing nano-preparation technology to transform existing and preclinical drugs, novel therapeutic targets will be uncovered, providing effective solutions and broader horizons to improve patient survival rates. [ABSTRACT FROM AUTHOR]

Abstract\nNovelty statementThis study was developed to evaluate the removal potential of ibuprofen, naproxen and 17-β-estradiol in artificial wetlands constructed on a laboratory scale, using eight experimental devices planted with L. octovalvis species, tested with gravel substrate and without gravel substrate, which were fortified with synthetic mixtures at concentrations of 1, 2 and 5 mg/L of the three compounds, during a batch exposure time of nine days. The removal efficiency for 17-β-estradiol was 94.5 ± 2.47%, followed by ibuprofen 94.03 ± 1.96% and naproxen 81.57 ± 8.74%, respectively. The treatment with the highest removal was the one performed without the presence of gravel substrate. The highest removal efficiency occurred from the third day of exposure for the three compounds, so it was established as the optimum residence time. The model that best explained the adsorption process of the three compounds studied, was the Langmuir isotherm. The observed results demonstrate that L. octovalvis can be used as a native species in artificial wetlands for the efficient removal of pharmaceutical compounds.Through the use of a macrophyte plant native to the state of Morelos, an artificial wetland was built, which was capable of removing several drugs with tolerance to changes in concentration, which constitutes an economic and sustainable alternative that can be coupled to the treatment of wastewater contaminated with this type of compounds. [ABSTRACT FROM AUTHOR]

Drug resistance in Plasmodium falciparum presents a formidable challenge to the humanity. And, unavailability of an eective vaccine worsens the situation further. Autophagy is one of the mechanisms employed by parasite to evade drug pressure to survive. Autophagy induced by the P. falciparum in response to the oleuropein pressure may answer many questions related to the parasite survival as well as evolving drug tolerance. The survival/autophagy axis could be an important avenue to explore in order to address certain questions related to the evolution of drug resistance. In addition, humanized mouse model of P. falciparum infection could serve as an important preclinical tool to investigate the oleuropein-induced autophagy, potentially helping to dissect the mechanisms underlying the development of antimalarial drug resistance. [ABSTRACT FROM AUTHOR]

Caffeine is a natural compound that inhibits the major cellular signaling regulator target of rapamycin (TOR), leading to widespread effects including growth inhibition. Saccharomyces cerevisiae yeast can adapt to tolerate high concentrations of caffeine in coffee and cacao fermentations and in experimental systems. While many factors affecting caffeine tolerance and TOR signaling have been identified, further characterization of their interactions and regulation remain to be studied. We used experimental evolution of S. cerevisiae to study the genetic contributions to caffeine tolerance in yeast, through a collaboration between high school students evolving yeast populations coupled with further research exploration in university labs. We identified multiple evolved yeast populations with mutations in PDR1 and PDR5 , which contribute to multidrug resistance, and showed that gain-of-function mutations in multidrug resistance family transcription factors Pdr1 , Pdr3 , and Yrr1 differentially contribute to caffeine tolerance. We also identified loss-of-function mutations in TOR effectors Sit4 , Sky1 , and Tip41 and showed that these mutations contribute to caffeine tolerance. These findings support the importance of both the multidrug resistance family and TOR signaling in caffeine tolerance and can inform future exploration of networks affected by caffeine and other TOR inhibitors in model systems and industrial applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Older patients with locally advanced non-small cell lung cancer may not be candidates for standard treatment due to their poor performance status. Immunotherapy and radiotherapy are well tolerated and may become the treatment of choice for those patients. This hypothesis should be confirmed in future clinical trials. The standard of care for locally advanced non-small-cell lung cancer (NSCLC) is either surgery combined with chemotherapy pre- or postoperatively or concurrent chemotherapy and radiotherapy. However, older and frail patients may not be candidates for surgery and chemotherapy due to the high mortality risk and are frequently referred to radiotherapy alone, which is better tolerated but carries a high risk of disease recurrence. Recently, immunotherapy with immune checkpoint inhibitors (ICIs) may induce a high response rate among cancer patients with positive programmed death ligand 1 (PD-L1) expression. Immunotherapy is also well tolerated among older patients. Laboratory and clinical studies have reported synergy between radiotherapy and ICI. The combination of ICI and radiotherapy may improve local control and survival for NSCLC patients who are not candidates for surgery and chemotherapy or decline these two modalities. The International Geriatric Radiotherapy Group proposes a protocol combining radiotherapy and immunotherapy based on the presence or absence of PD-L1 to optimize the survival of those patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This scoping review explores the use of transdermal fentanyl (TDF) for pain management in patients with cachexia, which is a severe wasting syndrome associated with cancer and other advanced illnesses. While TDF is commonly used in the management of chronic cancer-related and non-cancer related pain, its efficacy and safety in cachectic patients remain unclear due to altered pharmacokinetics (PK) in these individuals. This review examines nine studies that analyzed the impact of cachexia on the efficacy and tolerability of TDF. The findings suggest mixed results: some studies showed that cachexia could reduce TDF effectiveness and increase the required dose, while others found little to no impact or even potential improvement in outcomes. The current evidence is insufficient to provide definitive guidelines for the use of TDF in cachectic patients, highlighting the need for further research in this area. Cachectic patients frequently require transdermal fentanyl (TDF) for pain management, but data on its efficacy and safety are scarce and inconsistent. This scoping review aims to analyze the evidence concerning TDF administration in patients with cachexia irrespective of the underlying pathology. The primary objective is to assess the analgesic efficacy and tolerability of TDF in cachectic patients. The secondary objective is to identify cachexia characteristics that may influence fentanyl pharmacokinetics (PK). A comprehensive search of PubMed, Embase, and Web of Science databases was conducted up to March 2024. The review included observational and clinical studies on cachectic patients with moderate to severe pain treated with TDF patches at any dosage or frequency. Phase 1 trials, animal studies, case reports, preclinical studies and conference abstracts were excluded. Nine studies were included: four studies reported that cachexia negatively impacted TDF efficacy, increasing required doses and lowering plasma concentrations; three studies found minimal or no impact of cachexia on TDF efficacy and PK; two studies suggested that cachexia might improve TDF outcomes. Study quality ranged from moderate to high, according to the National Institutes of Health (NIH) Quality Assessment Tool. The current evidence is insufficient to provide any definitive recommendations for TDF prescribing in cachectic patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Prolonged cisplatin treatment can lead to acquired cancer cell resistance accompanied by various metabolic disturbances, which play an important role in maintaining homeostasis. In particular, resistant cells can regulate energy requirements and evade cisplatin-mediated toxicity via multiple metabolic adaptations. Here we discuss the existing evidence on metabolic alterations in cisplatin-resistant cells and their impact on the development of drug non-response. Cisplatin is one of the most well-known anti-cancer drugs and has demonstrated efficacy against numerous tumor types for many decades. However, a key challenge with cisplatin, as with any chemotherapeutic agent, is the development of resistance with a resultant loss of efficacy. This resistance is often associated with metabolic alterations that allow insensitive cells to divide and survive under treatment. These adaptations could vary greatly among different tumor types and may seem questionable and incomprehensible at first glance. Here we discuss the disturbances in glucose, lipid, and amino acid metabolism in cisplatin-resistant cells as well as the roles of ferroptosis and autophagy in acquiring this type of drug intolerance. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell carcinoma of the anus or anal cancer is increasing in prevalence, and the standard treatment of mitomycin and 5-fluorouracil is too toxic for many patients. Unfortunately, there is currently no standard of care for what to do for this disease when someone is not a candidate for this aggressive treatment. Here, we demonstrate the promising preliminary toxicity profile and efficacy of the combination of weekly carboplatin and paclitaxel chemotherapy for patients with localized anal cancer. This regimen was able to complete 80% of the intended treatments with anticipated toxicities, and 89% achieved a complete clinical response. This combination is a promising regimen and is already being investigated further in a clinical trial. Background: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. Methods: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. Results: Ten patients were included; eight were female, and the median age was 75.5 years (54–87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40–100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4–50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Person-generated health data (PGHD) are valuable for studying outcomes relevant to everyday living, for obtaining information not otherwise available, for long-term follow-up, and in situations where decisions cannot wait for traditional clinical research to be completed. While there is no dispute that these data are subject to bias, insights gained may be better than having an information void, provided the biases are understood and addressed. People will share information known uniquely to them about exposures that may affect drug tolerance, safety, and effectiveness (eg, nonprescription and complementary medications, alcohol, tobacco, illicit drugs, exercise, etc). Patients may be the best source of safety information when long-term follow-up is needed (eg, the 5- to 15-year follow-up required for some gene therapies). Validation studies must be performed to evaluate what people can accurately report and when supplementary confirmation information is needed. However, PGHD has already proven valuable in quantifying and contrasting COVID-19 vaccine benefits and risks and for evaluating disease transmission and the accuracy of COVID-19 testing. Going forward, PGHD will be used for patient-measured and patient-relevant outcomes, including for regulatory purposes, and will be linked to broader health data networks using tokenization, becoming a mainstay for signals about risks and benefits for diverse populations. This article is part of a Special Collection on Pharmacoepidemiology. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. Methods: This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. Results: A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43–98%) for objective response rate, 26% (95% CI = 58–96%) for partial response, 21% (95% CI = 15–28%) for minor response, 14% (95% CI = 3–24%) for complete response, 48% (95% CI = 37–59%) for stable disease, and 8% (95% CI = 4–11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = −1 to 9%) for 6-month PFS, 41% (95% CI = 32–50%) for 2-year PFS, and 29% (95% CI = 22–35%) for 3-year PFS. Conclusion: According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG. [ABSTRACT FROM AUTHOR]

Hedgehog pathway inhibitors (HHIs) have broadened the treatment options available for patients with advanced basal cell carcinoma (BCC) for whom traditional therapeutic approaches are not feasible or effective. Sonidegib and vismodegib are oral HHIs that were approved for treatment of patients with advanced BCC after demonstrating promising efficacy in the pivotal Phase II BOLT (NCT01327053) and ERIVANCE (NCT00833417) trials, respectively. However, the incidence and types of treatment-emergent adverse events (AEs) observed with these agents may limit continuous use of HHIs and ultimately impact clinical outcomes. In this review, we summarize the safety and tolerability profiles of sonidegib and vismodegib and discuss potential management strategies for HHI class-effect AEs, including muscle spasms, creatine phosphokinase increase, alopecia, and dysgeusia. These AEs primarily occur early in treatment and can lead to treatment discontinuation. Differences in the pharmacokinetic profiles of sonidegib and vismodegib may contribute to the variability noted in times to onset and resolution of these and other AEs. Evidence suggests that protocol modifications, such as treatment interruptions and dose reductions, are effective ways to manage AEs while maintaining disease control. Nonpharmacologic and pharmacologic interventions may also be considered as part of an AE management strategy. Overall, healthcare providers and patients with advanced BCC should be aware of the HHI class-effect AEs and plan effective management strategies to avoid treatment discontinuation and optimize therapeutic response. [ABSTRACT FROM AUTHOR]

Boric acid is a broad-spectrum antimicrobial used to treat vulvovaginal candidiasis when patients relapse on the primary azole drug fluconazole. Candida albicans is the most common cause of vulvovaginal candidiasis, colloquially referred to as a "vaginal yeast infection". Little is known about the propensity of C. albicans to develop BA resistance or tolerance (the ability of a subpopulation to grow slowly in high levels of drug). We evolved 96 replicates from eight diverse C. albicans strains to increasing BA concentrations to test the evolvability of BA resistance and tolerance. Replicate growth was individually assessed daily, with replicates passaged when they had reached an optical density consistent with exponential growth. Many replicates went extinct quickly. Although some replicates could grow in much higher levels of BA than the ancestral strains, evolved populations isolated from the highest terminal BA levels (after 11 weeks of passages) surprisingly showed only modest growth improvements and only at low levels of BA. No large increases in resistance or tolerance were observed in the evolved replicates. Overall, our findings illustrate that there may be evolutionary constraints limiting the emergence of BA resistance and tolerance, which could explain why it remains an effective treatment for recurrent yeast infections. [ABSTRACT FROM AUTHOR]

Objective: To report the cardiovascular (CV) safety of dihydroergotamine mesylate (DHE) administered by precision olfactory delivery (INP104) from two clinical trials. Background: Although the absolute risk is low, migraine is associated with an increased risk of CV events. DHE is a highly effective acute treatment for migraine, but due to its theoretical risk of promoting arterial vasoconstriction, DHE is contraindicated in patients with CV disease or an unfavorable risk factor profile. The INP104 is a novel drug‐device combination product approved for acute treatment of migraine that delivers DHE to the upper nasal space using precision olfactory delivery (POD®). Methods: The STOP 101 was a Phase 1 open‐label study that assessed the safety, tolerability, and bioavailability of INP104 1.45 mg, intravenous DHE 1.0 mg, and MIGRANAL (nasal DHE) 2.0 mg in healthy participants. The STOP 301 was a pivotal Phase 3, open‐label study that assessed the safety, tolerability, and exploratory efficacy of INP104 1.45 mg over 24 and 52 weeks in patients with migraine. In both studies, active or a history of CV disease, as well as significant CV risk factors, were exclusion criteria. Results: In STOP 101, 36 participants received one or more doses of investigational product. Treatment with intravenous DHE, but not INP104 or nasal DHE, resulted in clinically relevant changes from baseline in systolic blood pressure (BP; 11.4 mmHg, 95% confidence interval [CI] 7.9–15.0) and diastolic BP (13.3 mmHg, 95% CI 9.4–17.1) at 5 min post‐dose, persisting up to 30 min post‐dose for systolic BP (6.3 mmHg; 95% CI 3.0–9.5) and diastolic BP (7.9 mmHg, 95% CI 3.9–11.9). None of the treatments produced any clinically meaningful electrocardiogram (ECG) changes. In STOP 301, 354 patients received one or more doses of INP104. Over 24 weeks, five patients (1.4%) experienced a non‐serious, vascular treatment‐emergent adverse event (TEAE). Minimal changes were observed for BP and ECG parameters over 24 or 52 weeks. Off‐protocol concomitant use of triptans and other ergot derivatives did not result in any TEAEs. Conclusion: In two separate studies, INP104 demonstrated a favorable CV safety profile when used in a study population without CV‐related contraindications. [ABSTRACT FROM AUTHOR]

Small molecules that stimulate cAMP production in Mycobacterium tuberculosis (Mtb) block the ability of the bacterium to metabolize cholesterol. Perturbing cAMP levels in Mtb hold promise for shortening the duration of combination treatments. Mtb pathogenesis and physiology are impacted by cAMP signaling, including host immune responses, intrinsic drug resistance, and metabolism. The large number of cAMP synthetic and cAMP responsive proteins in Mtb represent additional opportunities to chemically manipulate cAMP signaling in the bacterium. Chemically altering cAMP levels in other bacterial pathogens could be used to combat drug tolerance and/or enhance treatment strategies. Mycobacterium tuberculosis (Mtb) replicates within host macrophages by adapting to the stressful and nutritionally constrained environments in these cells. Exploiting these adaptations for drug discovery has revealed that perturbing cAMP signaling can restrict Mtb growth in macrophages. Specifically, compounds that agonize or stimulate the bacterial enzyme, Rv1625c/Cya, induce cAMP synthesis and this interferes with the ability of Mtb to metabolize cholesterol. In murine tuberculosis (TB) infection models, Rv1625c/Cya agonists contribute to reducing relapse and shortening combination treatments, highlighting the therapeutic potential for this class of compounds. More recently, cAMP signaling has been implicated in regulating fatty acid utilization by Mtb. Thus, a new model is beginning to emerge in which cAMP regulates the utilization of host lipids by Mtb during infection, and this could provide new targets for TB drug development. Here, we summarize the current understanding of cAMP signaling in Mtb with a focus on our understanding of how cAMP signaling impacts Mtb physiology during infection. We also discuss additional cAMP-related drug targets in Mtb and other bacterial pathogens that may have therapeutic potential. [ABSTRACT FROM AUTHOR]

Objective: To investigate the expression of eight subunits of chaperonin containing t-complex 1 (CCT) in thyroid cancer (TC) tissues and their correlation with TC staging, patient prognosis, immune cell infiltration, immune checkpoint expression, and chemotherapy drug sensitivity. Methods: Data from The Cancer Genome Atlas (TCGA) database were used to analyze the expression of each CCT subunit in TC tissues and para-cancerous tissues as well as their relationship with the prognosis of TC patients. The biological function of each CCT subunit was analyzed by the Gene Set Enrichment Analysis (GSEA). Data from the TCGA and TIMER2.0 databases were used to analyze the correlations between the expression of each CCT subunit and the tumor microenvironment, infiltration of immune cells, chemotherapeutic drug sensitivity, and immune checkpoint expression. Results: Database analysis showed high mRNA expression of CCT3, CCT7, and CCT8 and low mRNA expression of CCT1, CCT2, CCT5, and CCT6B in TC tissues (P < 0.01 or P < 0.001). CCT3, CCT6B, and CCT8 mRNA expression were correlated with T staging (P < 0.05 or P < 0.01); CCT6B mRNA expression was associated with lymph node metastasis (P < 0.01); CCT5 mRNA expression was associated with distant metastasis (P < 0.05); and CCT6B may serve as an independent prognostic biomarker for overall survival (OS) in TC patients. CCT subunit expression was primarily enriched in signaling pathways such as graft rejection, complement, and interferongamma.Low expression groups of CCT subunits demonstrated significantly higher TC stromal score, immune infiltration score and composite score than the high expression groups (P < 0.05 or P < 0.01 or P < 0.001), displaying a negative correlation between the expression of each CCT subunit and TC stromal, immune infiltration and composite scores (all P < 0.01). The mRNA expression of each CCT subunit was positively correlated with CD8+ T cell and macrophage infiltration (all P < 0.05), the mRNA expression of most CCT subunits (except CCT6B and CCT7) was positively correlated with neutrophil infiltration (P < 0.05 or P < 0.01 or P < 0.001), whereas the mRNA expression of CCT3, 4, 7, and 8 was negatively correlated with CD4+ T-cell infiltration (all P < 0.05). Compared to the low-expression group, patients with high mRNA expression of most CCT subunit had significantly higher IC50 for chemotherapeutic agents such as sorafenib, levatinib, darafenib, trametinib, vandetanib, and cabozantinib (all P < 0.05 or P < 0.01 or P < 0.001). CCT subunit expression in TC tissues was significantly correlated with the expression of PD-1, PD-L1, PD-L2, CTLA4, CD80, and CD86 (P < 0.05 or P < 0.01 or P < 0.001). Conclusion: CCT complexes may promote TC development by affecting the tumor microenvironment thus impacting patient prognosis, potentially serving as a target for the diagnosis and immunotherapy of refractory TC. [ABSTRACT FROM AUTHOR]

Background: This communication summarizes our single-center experience with the use of anti-IL-1 biologic response modifiers for treating autoimmune and autoinflammatory conditions in children. Methods: We outline our rationale for the off-label use of anakinra and discuss emerging treatment paradigms that necessitate further research and validation. Results: Anakinra has enabled personalized treatment, whether used as a single agent on an as-needed basis, as part of a background treatment regimen, or in combination with colchicine. Our data also highlight the significance of anakinra in treating post-infectious inflammatory diseases, demonstrating its high efficacy in novel applications such as rheumatic fever and post-viral arthritis. Canakinumab, on the other hand, has provided long-term remission. Both medications were well-tolerated, with no serious adverse effects reported. Conclusions: Based on our observations and successful outcomes, we advocate for future collaborative efforts to improve access to anti-IL-1 medications to better manage excessive and harmful inflammation in children. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab). Methods: In this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78 days. Serum drug concentration–time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80–125% bioequivalence criteria. Results: Baseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration–time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects—three in the US-trastuzumab group and one in the BP02 group—discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies. Conclusion: This study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. Trial Registration: ANZCTR number: ACTRN12621000573853. [ABSTRACT FROM AUTHOR]

BackgroundSecond-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the dopamine D3 receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling.MethodsHere, we used a combination of two-photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at D3R.ResultsWe report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist SGA, but not an antagonist SGA, abolishes D3R function through postendocytic receptor degradation by GASP1 (G protein-coupled receptor-associated sorting protein-1).ConclusionsThese results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that postendocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.

Trichophyton rubrum is one of the most frequently isolated fungi in patients with dermatophytosis. Despite its clinical significance, the molecular mechanisms of drug resistance and pathogenicity of T. rubrum remain to be elucidated because of the lack of genetic tools, such as efficient gene targeting systems. In this study, we generated a T. rubrum strain that lacks the nonhomologous end-joining-related gene ku80 (Δku80) and then developed a highly efficient genetic recombination system with gene targeting efficiency that was 46 times higher than that using the wild-type strain. Cyp51A and Cyp51B are 14-α-lanosterol demethylase isozymes in T. rubrum that promote ergosterol biosynthesis and are the targets of azole antifungal drugs. The expression of cyp51A mRNA was induced by the addition of the azole antifungal drug efinaconazole, whereas no such induction was detected for cyp51B, suggesting that Cyp51A functions as an azole-responsive Cyp51 isozyme. To explore the contribution of Cyp51A to susceptibility to azole drugs, the neomycin phosphotransferase (nptII) gene cassette was inserted into the cyp51A 3′-untranslated region of Δku80 to destabilize the mRNA of cyp51A. In this mutant, the induction of cyp51A mRNA expression by efinaconazole was diminished. The minimum inhibitory concentration for several azole drugs of this strain was reduced, suggesting that dermatophyte Cyp51A contributes to the tolerance for azole drugs. These findings suggest that an efficient gene targeting system using Δku80 in T. rubrum is applicable for analyzing genes encoding drug targets. Key Points: A novel gene targeting system using Δku80 strain was established in T. rubrum Cyp51A in T. rubrum responds to the azole antifungal drug efinaconazole Cyp51A contributes to azole drug tolerance in T. rubrum [ABSTRACT FROM AUTHOR]

The limited analgesic efficiency of magnesium restricts its application in pain management. Here, we report boron hydride (BH) with ion currents rectification activity that can enhance the analgesic efficiency of magnesium without the risks of drug tolerance or addiction. We synthesize MgB2, comprising hexagonal boron sheets alternating with Mg2+. In pathological environment, Mg2+ is exchanged by H+, forming two‐dimensional borophene‐analogue BH sheets. BH interacts with the charged cations via cation‐pi interaction, leading to dynamic modulation of sodium and potassium ion currents around neurons. Additionally, released Mg2+ competes Ca2+ to inhibit its influx and neuronal excitation. In vitro cultured dorsal root neurons show a remarkable increase in threshold potential from the normal −35.9 mV to −5.9 mV after the addition of MgB2, indicating potent analgesic effect. In three typical pain models, including CFA‐induced inflammatory pain, CINP‐ or CCI‐induced neuropathic pain, MgB2 exhibits analgesic efficiency approximately 2.23, 3.20, and 2.0 times higher than clinical MgSO4, respectively, and even about 1.04, 1.66, and 1.95 times higher than morphine, respectively. The development of magnesium based intermetallic compounds holds promise in addressing the non‐opioid medical need for pain relief. [ABSTRACT FROM AUTHOR]