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1.
BMC Infect Dis ; 24(1): 733, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39054424

ABSTRACT

Elevated resistance to pyrethroids in major malaria vectors has led to the introduction of novel insecticides including neonicotinoids. There is a fear that efficacy of these new insecticides could be impacted by cross-resistance mechanisms from metabolic resistance to pyrethroids. In this study, after evaluating the resistance to deltamethrin, clothianidin and mixture of clothianidin + deltamethrin in the lab using CDC bottle assays, the efficacy of the new IRS formulation Fludora® Fusion was tested in comparison to clothianidin and deltamethrin applied alone using experimental hut trials against wild free-flying pyrethroid-resistant Anopheles funestus from Elende and field An. gambiae collected from Nkolondom reared in the lab and released in the huts. Additionally, cone tests on the treated walls were performed each month for a period of twelve months to evaluate the residual efficacy of the sprayed products. Furthermore, the L1014F-kdr target-site mutation and the L119F-GSTe2 mediated metabolic resistance to pyrethroids were genotyped on a subset of mosquitoes from the EHT to assess the potential cross-resistance. All Anopheles species tested were fully susceptible to clothianidin and clothianidin + deltamethrin mixture in CDC bottle assay while resistance was noted to deltamethrin. Accordingly, Fludora® Fusion (62.83% vs 42.42%) and clothianidin (64.42% vs 42.42%) induced significantly higher mortality rates in EHT than deltamethrin (42.42%) against free flying An. funestus from Elende in month 1 (M1) and no significant difference in mortality was observed between the first (M1) and sixth (M6) months of the evaluation (P > 0.05). However, lower mortality rates were recorded against An. gambiae s.s from Nkolondom (mortality rates 50%, 45.56% and 26.68%). In-situ cone test on the wall showed a high residual efficacy of Fludora® Fusion and clothianidin on the susceptible strain KISUMU (> 12 months) and moderately on the highly pyrethroid-resistant An. gambiae strain from Nkolondom (6 months). Interestingly, no association was observed between the L119F-GSTe2 mutation and the ability of mosquitoes to survive exposure to Fludora® Fusion, whereas a trend was observed with the L1014F-kdr mutation. This study highlights that Fludora® Fusion, through its clothianidin component, has good potential of controlling pyrethroid-resistant mosquitoes with prolonged residual efficacy. This could be therefore an appropriate tool for vector control in several malaria endemic regions.


Subject(s)
Anopheles , Insecticide Resistance , Insecticides , Malaria , Mosquito Control , Mosquito Vectors , Pyrethrins , Animals , Pyrethrins/pharmacology , Anopheles/drug effects , Anopheles/genetics , Insecticide Resistance/genetics , Insecticides/pharmacology , Mosquito Control/methods , Cameroon , Mosquito Vectors/drug effects , Mosquito Vectors/genetics , Malaria/transmission , Malaria/prevention & control , Guanidines/pharmacology , Nitriles/pharmacology , Female , Thiazoles/pharmacology , Neonicotinoids/pharmacology , Housing
2.
Reprod Toxicol ; : 108670, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39032759

ABSTRACT

Tributyltin (TBT) and mercury (Hg) are endocrine-disrupting chemicals that individually cause reproductive complications. However, the reproductive consequences of exposure to a mixture of TBT plus Hg are not well known. We hypothesized that exposure to a mixture of TBT plus Hg would alter hypothalamic-pituitary-gonadal (HPG) axis function. Female rats were exposed to this mixture daily for 15 days, after which chemical accumulation in the tissues, morphology, hormone levels, inflammation, fibrosis, and protein expression in the reproductive organs were assessed. Increases in tin (Sn) and Hg levels were detected in the serum, HPG axis, and uterus of TBT-Hg rats. TBT-Hg rats exhibited irregular estrous cycles. TBT-Hg rats showed an increase in gonadotropin-releasing hormone (GnRH) protein expression and follicle-stimulating hormone (FSH) levels and a reduction in luteinizing hormone (LH) levels. Reduced ovarian reserve, antral follicles, corpora lutea (CL) number, and estrogen levels and increased atretic and cystic follicles were found, suggesting that TBT-Hg exposure exacerbated premature ovarian insufficiency (POI) features. Furthermore, TBT-Hg rats exhibited increased ovarian mast cell numbers, expression of the inflammatory markers IL-6 and collagen deposition. Apoptosis and reduced gland number were observed in the uteri of TBT-Hg rats. A reduction in the number of pups/litter for 90 days was found in TBT-Hg rats, suggesting impaired fertility. Strong negative correlations were found between serum and ovarian Sn levels and ovarian Hg levels and ovarian reserve and CL number. Collectively, these data suggest that TBT plus Hg exposure leads to abnormalities in the HPG axis, exacerbating POI features and reducing fertility in female rats.

3.
J Alzheimers Dis ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39031362

ABSTRACT

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-ß (Aß) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aß and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (ß (SE) = -0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (ß (SE) = -0.035(0.009), p = 0.001), inferior temporal (ß (SE) = -0.029(0.010), p = 0.012), and rhinal cortex tau(ß (SE) = -0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities.

4.
Environ Sci Technol ; 2024 Jul 20.
Article in English | MEDLINE | ID: mdl-39031616

ABSTRACT

Polycyclic aromatic hydrocarbons (PAHs), released from petrogenic, pyrogenic or diagenetic sources (degradation of wood materials), are of global concern due to their adverse effects, and potential for long-range transport. While dissolved PAHs have been frequently reported in the literature, there has been no consistent approach of sampling across water bodies. Passive samplers from the AQUA/GAPS-MONET initiative were deployed at 46 sites (28 marine and 18 freshwater), and analyzed for 28 PAHs and six polycyclic musks (PCMs) centrally. Freely dissolved PAH concentrations were dominated by phenanthrene (mean concentration 1500 pg L-1; median 530 pg L-1) and other low molecular weight compounds. Greatest concentrations of phenanthrene, fluoranthene, and pyrene were typically from the same sites, mostly in Europe and North America. Of the PCMs, only galaxolide (72% of samples) and tonalide (61%) were regularly detected, and were significantly cross-correlated. Benchmarking of PAHs relative to penta- and hexachlorobenzene confirmed that the most remote sites (Arctic, Antarctic, and mountain lakes) displayed below average PAH concentrations. Concentrations of 11 of 28 PAHs, galaxolide and tonalide were positively correlated (P < 0.05) with population density within a radius of 5 km of the sampling site. Characteristic PAH ratios gave conflicting results, likely reflecting multiple PAH sources and postemission changes.

5.
Case Rep Ophthalmol Med ; 2024: 3449614, 2024.
Article in English | MEDLINE | ID: mdl-38962424

ABSTRACT

The Australian paralysis tick (Ixodes holocyclus) is found along the east coast of Australia. Tick bites may result in paralysis ranging from muscular weakness to ascending paralysis requiring respiratory support. Ocular complications and facial nerve involvement are rare. We present a rare occurrence of tick-bite-associated visual loss, proptosis, and multiple cranial neuropathies not previously reported in the literature. The tick was removed, and the patient's symptoms improved following treatment with steroids and oral doxycycline. The vision and sensory changes are not explained by the Ixodes toxin; thus, we hypothesize this is related to orbital apex inflammation.

6.
Anal Verbal Behav ; 40(1): 76-87, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38962521

ABSTRACT

In the current study, eight college students were exposed to a successive matching-to-sample (S-MTS) procedure utilizing non-verbal auditory stimuli consisting of common sounds. During emergent relations tests, participants were asked to talk aloud, and their vocal-verbal statements were transcribed and categorized as class-consistent, class-inconsistent, or irrelevant. All participants met emergence criterion for symmetry and four did so for transitivity/equivalence. Analysis of vocal-verbal statements showed a positive correlation between class-consistent statements emitted by participants and correct selection responses during S-MTS tasks. Such results suggest possible verbal mediation during emergent relations tests.

7.
Orthopedics ; 47(4): e211-e213, 2024.
Article in English | MEDLINE | ID: mdl-39038106

ABSTRACT

Ulnar-shortening osteotomy is a reliable solution to treat ulnar impaction syndrome, but it has a significant rate of nonunion as a known complication. Generally nonunion after the procedure is attributed to noninfectious causes. When infections happen, they follow the microbiological trends of nonunions elsewhere in the body. We present a case of ulnar-shortening osteotomy using an oblique-cut osteotomy system that resulted in septic nonunion. At the time of revision surgery, Cutibacterium acnes and Staphylococcus hominis were isolated from the osteotomy site. The patient was successfully treated using intravenous antibiotics and the two-stage Masquelet technique and eventually went on to bony union. As C acnes is rarely encountered in this context, this report highlights the need to consider all possible pathogens in the workup of a potentially septic nonunion. Surgeons should consider bacteria such as C acnes that require prolonged incubation for isolation from cultures, which may not be part of many institutions' usual protocol. [Orthopedics. 2024;47(4):e211-e213.].


Subject(s)
Anti-Bacterial Agents , Osteotomy , Humans , Osteotomy/adverse effects , Anti-Bacterial Agents/therapeutic use , Ulna/surgery , Gram-Positive Bacterial Infections/microbiology , Gram-Positive Bacterial Infections/diagnosis , Fractures, Ununited/surgery , Fractures, Ununited/microbiology , Male , Surgical Wound Infection/microbiology , Surgical Wound Infection/drug therapy , Surgical Wound Infection/diagnosis , Surgical Wound Infection/etiology , Female , Reoperation , Adult , Propionibacteriaceae/isolation & purification
8.
Alzheimers Dement ; 2024 Jul 22.
Article in English | MEDLINE | ID: mdl-39039896

ABSTRACT

INTRODUCTION: Understanding early neuropathological changes and their associations with cognition may aid dementia prevention. This study investigated associations of cerebral amyloid and tau positron emission tomography (PET) retention with cognition in a predominately middle-aged community-based cohort and examined factors that may modify these relationships. METHODS: 11C-Pittsburgh compound B amyloid and 18F-flortaucipir tau PET imaging were performed. Associations of amyloid and tau PET with cognition were evaluated using linear regression. Interactions with age, apolipoprotein E (APOE) ε4 status, and education were examined. RESULTS: Amyloid and tau PET were not associated with cognition in the overall sample (N = 423; mean: 57 ± 10 years; 50% female). However, younger age (< 55 years) and APOE ε4 were significant effect modifiers, worsening cognition in the presence of higher amyloid and tau. DISCUSSION: Higher levels of Aß and tau may have a pernicious effect on cognition among APOE ε4 carriers and younger adults, suggesting a potential role for targeted early interventions. HIGHLIGHTS: Risk and resilience factors influenced cognitive vulnerability due to Aß and tau. Higher fusiform tau associated with poorer visuospatial skills in younger adults. APOE ε4 interacted with Aß and tau to worsen cognition across multiple domains.

9.
Int J Pharm ; 661: 124406, 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38955240

ABSTRACT

Integrating pH sensor with controlled antibiotic release is fabricated on silk to create a theranostic wound dressing. Alginate (ALG) hydrogel and graphene oxide (GO) loaded with levofloxacin (LVX) and a pH indicator are applied to fabricate a pH-responsive theranostic wound dressing. The modified silk color changes from yellow to green in response to elevated skin pH, indicating the skin infection. The semi-quantitative analysis was conducted using ImageJ, revealing significant color changes across the wide range. At elevated pH levels, the ionization of the COOH bonds within ALG induces repulsion among the COO- groups, thereby accelerating the release of the incorporated drug compared to release under lower pH. At an infected pH of 8, ALG hydrogel triggers LVX releasing up to 135.86 ± 0.3 µg, while at a normal pH of 7, theranostic silk releases 123.13 ± 0.26 µg. Incorporating GO onto silk fibers enhances LVX loading and sustains LVX release. Furthermore, these modified silks possess antimicrobial abilities without causing irritation or allergies on the human skin. This theranostic silks represents a major step forward in smart wound care, introducing a versatile platform of smart wound care.

10.
Article in English | MEDLINE | ID: mdl-38958881

ABSTRACT

KEY POINTS: Inhalational exposure (IE) history assessment is important and may guide chronic rhinosinusitis disease management. Combined exposure status was the most significant factor across differential gene expression analyse IE history was associated with pro-inflammatory transcriptome changes and worse clinical outcomes.

11.
iScience ; 27(6): 110110, 2024 Jun 21.
Article in English | MEDLINE | ID: mdl-38974472

ABSTRACT

Increased cases of sepsis during COVID-19 in the absence of known bacterial pathogens highlighted role of viruses as causative agents of sepsis. In this study, we investigated clinical, laboratory, proteomic, and metabolomic characteristics of viral sepsis patients (n = 45) and compared them to non-sepsis patients with COVID-19 (n = 186) to identify molecular mechanisms underlying the pathology of viral sepsis in COVID-19. We identified unique metabolomic and proteomic signatures that suggest a substantial perturbation in the coagulation, complement, and platelet activation pathways in viral sepsis. Our proteomic data indicated elevated coagulation pathway protein (fibrinogen), whereas a decrease in many of the complement proteins was observed. These alterations were associated with the functional consequences such as susceptibility to secondary bacterial infections and potentially contributing to both local and systemic disease phenotypes. Our data provide novel aspect of COVID-19 pathology that is centered around presence of sepsis phenotype in COVID-19.

12.
Blood Adv ; 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38991137

ABSTRACT

Children and adults with sickle cell disease (SCD) have increases in morbidity and mortality with COVID-19 infections. The ASH Research Collaborative Sickle Cell Disease Research Network performed a prospective COVID-19 vaccine study to assess antibody responses and analyze whether mRNA vaccination precipitated any adverse effects unique to individuals with SCD. Forty-one participants received two doses of the Pfizer-BioNTech vaccine and provided baseline blood samples prior to vaccination and 2 months after the initial vaccination for analysis of IgG reactivity against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Six month IgG reactivity against the viral RBD was also available in 37 patients. Post-vaccination reactogenicity was common and similar to the general population. There were no fevers that required inpatient admission. Vaso-occlusive pain within 2-3 days of 1st or 2nd vaccination was reported by 5 (12%) participants including 4 (10%) who sought medical care. Twenty-seven participants (66%) were seropositive at baseline, and all 14 (34%) initially seronegative participants converted to seropositive post vaccination. Overall, mRNA vaccination had a good risk benefit-profile in individuals with sickle cell disease.This mRNA vaccine study also marks the first evaluation of vaccine safety and antibody response in very young children with sickle cell disease. NCT05139992.

13.
BMJ Case Rep ; 17(7)2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38991565

ABSTRACT

A man in his mid-70s with a complex medical history, including splenectomy, presented with fever and rigours. Workup revealed Salmonella enterica serotype typhimurium bacteraemia and right internal iliac artery endarteritis. Two weeks following a 6-week course of antibiotics, he had a recurrence of Salmonella bacteraemia requiring an extended course of treatment.


Subject(s)
Anti-Bacterial Agents , Bacteremia , Endarteritis , Iliac Artery , Salmonella Infections , Splenectomy , Humans , Male , Salmonella Infections/complications , Salmonella Infections/diagnosis , Salmonella Infections/drug therapy , Bacteremia/drug therapy , Bacteremia/complications , Bacteremia/microbiology , Iliac Artery/diagnostic imaging , Anti-Bacterial Agents/therapeutic use , Aged , Recurrence , Salmonella typhimurium/isolation & purification
14.
Pract Radiat Oncol ; 2024 Jul 09.
Article in English | MEDLINE | ID: mdl-38992491

ABSTRACT

PURPOSE: New technologies are continuously emerging in radiation oncology. Inherent technological limitations can result in healthcare disparities in vulnerable patient populations. These limitations must be considered for existing and new technologies in the clinic to provide equitable care. MATERIALS AND METHODS: We created a health disparity risk assessment metric inspired by failure mode and effects analysis (FMEA). We provide sample patient populations and their potential associated disparities, guidelines for clinics and vendors, and example applications of the methodology. RESULTS: A disparity risk priority number (dRPN) can be calculated from the product of three quantifiable metrics: the percent of patients impacted (P), the severity of the impact of dosimetric uncertainty or quality of the radiation plan (S), and the clinical dependence on the evaluated technology (C). The dRPN can be used to rank the risk of sub-optimal care due to technical limitations when comparing technologies and to plan interventions when technology is shown to have inequitable performance in the patient population of a clinic. CONCLUSION: The proposed methodology may simplify the evaluation of how new technology impacts vulnerable populations, help clinics quantify the limitations of their technological resources, and plan appropriate interventions to improve equity in radiation treatments.

15.
Article in English | MEDLINE | ID: mdl-39018573

ABSTRACT

BACKGROUND: Despite widespread acceptance of the importance of diversity in leadership, systemic challenges in leadership attainment in orthopaedic surgery still exist for several groups. We hypothesize that women, underrepresented in medicine groups, and Asians have decreased odds of achieving program director and chairperson positions compared with peers. METHODS: Demographic data were collected from the Association of American Medical Colleges for faculty, program directors, and chairpersons in orthopaedic surgery. Odds ratios were calculated treating race, ethnicity, or sex as the predictor variables and attainment of a leadership position as the outcome, comparing the composition of program directors in 2020 and chairpersons in 2019 with faculty in 2019. RESULTS: Significantly decreased odds were found for women at 0.37 (0.264 to 0.51 [P < 0.0001]) and the Other category at 0.16 (0.065 to 0.3864 [P = 0.0001]) while significantly increased odds were found for White and Black/African American faculty at 1.32 (1.02 to 1.71 [P = 0.0314]) and 1.95 (1.17 to 3.26 [P = 0.011]), respectively, in holding program director positions. Significantly decreased odds of attaining chairpersonship were found for women at 0.17 (0.07 to 0.41 [P = 0.0075]) and Asian faculty at 0.33 (0.14 to 0.75 [P = 0.0062]) while White faculty demonstrated significantly increased odds at 2.43 (1.41 to 4.19 [P = 0.0013]). CONCLUSIONS: Women showed markedly decreased odds of leadership attainment while Black/African American faculty had increased likelihood of becoming program directors but were not markedly more likely to become chairs. Asian faculty were less likely to become program directors and markedly less likely to become chairs. While decreased odds for women were expected based on current literature, decreased odds of Asians becoming chairs and an increased likelihood of Black/African American orthopaedic surgeons becoming program directors but not attaining the role of chairs at the same rate were novel findings, revealing concerning trends for these groups.

16.
Neurology ; 103(3): e209665, 2024 Aug 13.
Article in English | MEDLINE | ID: mdl-39008782

ABSTRACT

BACKGROUND AND OBJECTIVES: Amyloid pathology, vascular disease pathology, and pathologies affecting the medial temporal lobe are associated with cognitive trajectories in older adults. However, only limited evidence exists on how these pathologies influence cognition in the oldest old. We evaluated whether amyloid burden, white matter hyperintensity (WMH) volume, and hippocampal volume (HV) are associated with cognitive level and decline in the oldest old. METHODS: This was a longitudinal, observational community-based cohort study. We included participants with 18F-florbetapir PET and MRI data from the 90+ Study. Amyloid load was measured using the standardized uptake value ratio in the precuneus/posterior cingulate with eroded white matter mask as reference. WMH volume was log-transformed. All imaging measures were standardized using sample means and SDs. HV and log-WMH volume were normalized by total intracranial volume using the residual approach. Global cognitive performance was measured by the Mini-Mental State Examination (MMSE) and modified MMSE (3MS) tests, repeated every 6 months. We used linear mixed-effects models with random intercepts; random slopes; and interaction between time, time squared, and imaging variables to estimate the associations of imaging variables with cognitive level and cognitive decline. Models were adjusted for demographics, APOE genotype, and health behaviors. RESULTS: The sample included 192 participants. The mean age was 92.9 years, 125 (65.1%) were female, 71 (37.0%) achieved a degree beyond college, and the median follow-up time was 3.0 years. A higher amyloid load was associated with a lower cognitive level (ßMMSE = -0.82, 95% CI -1.17 to -0.46; ß3MS = -2.77, 95% CI -3.69 to -1.84). A 1-SD decrease in HV was associated with a 0.70-point decrease in the MMSE score (95% CI -1.14 to -0.27) and a 2.27-point decrease in the 3MS score (95% CI -3.40 to -1.14). Clear nonlinear cognitive trajectories were detected. A higher amyloid burden and smaller HV were associated with faster cognitive decline. WMH volume was not significantly associated with cognitive level or decline. DISCUSSION: Amyloid burden and hippocampal atrophy are associated with both cognitive level and cognitive decline in the oldest old. Our findings shed light on how different pathologies contributed to driving cognitive function in the oldest old.


Subject(s)
Cognitive Dysfunction , Hippocampus , Magnetic Resonance Imaging , Positron-Emission Tomography , White Matter , Humans , Female , Male , White Matter/diagnostic imaging , White Matter/pathology , White Matter/metabolism , Hippocampus/diagnostic imaging , Hippocampus/pathology , Hippocampus/metabolism , Aged, 80 and over , Longitudinal Studies , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/pathology , Cognitive Dysfunction/metabolism , Cognition/physiology , Cohort Studies , Organ Size , Ethylene Glycols , Aniline Compounds , Amyloid beta-Peptides/metabolism , Amyloid/metabolism
17.
ERJ Open Res ; 10(4)2024 Jul.
Article in English | MEDLINE | ID: mdl-39040578

ABSTRACT

Introduction: Brensocatib is an investigational, oral, reversible inhibitor of dipeptidyl peptidase-1 shown to prolong time to first exacerbation in adults with bronchiectasis. Outlined here are the clinical trial design, and baseline characteristics and treatment patterns of adult patients enrolled in the phase 3 ASPEN trial (NCT04594369). Methods: The ASPEN trial is a global study enrolling patients with a clinical history consistent with bronchiectasis (cough, chronic sputum production and/or recurrent respiratory infections), diagnosis confirmed radiologically and ≥2 exacerbations in the prior 12 months. It was designed to evaluate the impact of two brensocatib doses (10 mg and 25 mg) on exacerbation rate over a 52-week treatment period versus placebo. Comprehensive clinical data, including demographics, disease severity, lung function, Pseudomonas aeruginosa status and quality of life, were collected at baseline. Results: 1682 adults from 35 countries were randomised from December 2020 to March 2023. Mean age was 61.3 years and 64.7% were female. ∼70% had moderate-to-severe Bronchiectasis Severity Index (BSI) scores, 29.3% had ≥3 exacerbations in the prior 12 months and 35.7% were positive for P. aeruginosa. Mean BSI scores were highest in Australia/New Zealand (8.3) and lowest in Latin America (5.9). Overall, the most common aetiology was idiopathic (58.4%). In P. aeruginosa-positive versus P. aeruginosa-negative patients, lung function was lower, with greater long-term macrolide (21.5% versus 14.0%) and inhaled corticosteroid use (63.5% versus 53.9%). There was wide regional variation in long-term antibiotic use in patients with bronchiectasis and P. aeruginosa. Discussion: ASPEN baseline characteristics and treatment profiles were representative of a global bronchiectasis population.

18.
Article in English | MEDLINE | ID: mdl-38976363

ABSTRACT

INTRODUCTION: This proof-of-concept, open-label phase 1b study evaluated the safety and efficacy of cilofexor, a potent selective farnesoid X receptor agonist, in patients with compensated cirrhosis due to primary sclerosing cholangitis. METHODS: Escalating doses of cilofexor (30 mg [weeks 1-4], 60 mg [weeks 5-8], 100 mg [weeks 9-12]) were administered orally once daily over 12 weeks. The primary endpoint was safety. Exploratory measures included cholestasis and fibrosis markers and pharmacodynamic biomarkers of bile acid homeostasis. RESULTS: Eleven patients were enrolled (median age: 48 years; 55% men). The most common treatment-emergent adverse events (TEAEs) were pruritus (8/11 [72.7%]), fatigue, headache, nausea, and upper respiratory tract infection (2/11 [18.2%] each). Seven patients experienced a pruritus TEAE (one grade 3) considered drug-related. One patient temporarily discontinued cilofexor owing to peripheral edema. There were no deaths, serious TEAEs, or TEAEs leading to permanent discontinuation. Median changes (interquartile ranges) from baseline to week 12 (predose, fasting) were -24.8% (-35.7 to -7.4) for alanine transaminase, -13.0% (-21.9 to -8.6) for alkaline phosphatase, -43.5% (-52.1 to -30.8) for γ-glutamyl transferase, -12.7% (-25.0 to 0.0) for total bilirubin, and -21.2% (-40.0 to 0.0) for direct bilirubin. Least-squares mean percentage change (95% confidence interval) from baseline to week 12 at trough was -55.3% (-70.8 to -31.6) for C4 and -60.5% (-81.8 to -14.2) for cholic acid. Fasting fibroblast growth factor 19 levels transiently increased after cilofexor administration. DISCUSSION: Escalating doses of cilofexor over 12 weeks were well tolerated and improved cholestasis markers in patients with compensated cirrhosis due to primary sclerosing cholangitis (NCT04060147).

19.
Electrochim Acta ; 4942024 Aug 01.
Article in English | MEDLINE | ID: mdl-38881690

ABSTRACT

Laser-induced graphene (LIG) electrodes have become popular for electrochemical sensor fabrication due to their simplicity for batch production without the use of reagents. The high surface area and favorable electrocatalytic properties also enable the design of small electrochemical devices while retaining the desired electrochemical performance. In this work, we systematically investigated the effect of LIG working electrode size, from 0.8 mm to 4.0 mm diameter, on their electrochemical properties, since it has been widely assumed that the electrochemistry of LIG electrodes is independent of size above the microelectrode size regime. The background and faradaic current from cyclic voltammetry (CV) of an outer-sphere redox probe [Ru(NH3)6]3+ showed that smaller LIG electrodes had a higher electrode roughness factor and electroactive surface ratio than those of the larger electrodes. Moreover, CV of the surface-sensitive redox probes [Fe(CN)6]3- and dopamine revealed that smaller electrodes exhibited better electrocatalytic properties, with enhanced electron transfer kinetics. Scanning electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy showed that the physical and chemical surface structure were different at the electrode center versus the edges, so the electrochemical properties of the smaller electrodes were improved by having rougher surface and more density of the graphitic edge planes, and more oxide-containing groups, leading to better electrochemistry. The difference could be explained by the different photothermal reaction time from the laser scribing process that causes different stable carbon morphology to form on the polymer surface. Our results give a new insight on relationships between surface structure and electrochemistry of LIG electrodes and are useful for designing miniaturized electrochemical devices.

20.
Cornea ; 2024 Jun 18.
Article in English | MEDLINE | ID: mdl-38886882

ABSTRACT

PURPOSE: The goal of this study was to explore whether the donor history of sleep apnea affects corneal tissue evaluation parameters. METHODS: This was a retrospective study assessing the impact of donor history of sleep apnea in a dataset obtained from the Eversight Eye Bank. Comparative analysis and multivariate regression were used to assess differences in key parameters including endothelial cell density (ECD) and central corneal thickness. RESULTS: Data analyzed consisted of 50,170 tissues from 25,399 donors with no history of sleep apnea and 5473 tissues from 2774 donors with a history of sleep apnea. Tissue from donors with a history of sleep apnea showed lower ECD than those from donors with no history of sleep apnea (-51 cells/mm2, P < 0.001). Multivariate linear regression demonstrated that history of sleep apnea was a predictor of lower ECD by 13.72 cells/mm2 (P = 0.0264). Secondary analysis demonstrated that underweight and obese body mass indexes were significant predictors of increased ECD in donors with no history of sleep apnea (P < 0.0001, P = 0.025, respectively). Body mass index category was not a significant predictor of ECD in donors with a history of sleep apnea. In a smaller subset of 10,756 tissues, sleep apnea was not a significant predictor of central corneal thickness. CONCLUSIONS: This is the first study to demonstrate that a donor's history of sleep apnea is associated with a lower ECD in a large eye bank dataset. Future studies are needed to investigate whether history of sleep apnea affects posttransplantation outcomes.

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