-
PLoS Pathogens Jun 2024Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins...
Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.
PubMed: 38900833
DOI: 10.1371/journal.ppat.1012317 -
PloS One 2024This paper presents a compact 5G wideband antenna designed for body-centric networks (BCN. The single element antenna design includes a simple T-shaped radiator patch...
This paper presents a compact 5G wideband antenna designed for body-centric networks (BCN. The single element antenna design includes a simple T-shaped radiator patch with ring shaped ground plane and transformer impedance feedline. First, the antenna was simulated in free-space, and its resonant frequency is found to be 27 GHz, falling within 5G's n261 band. The proposed single radiator antenna has a size of 23.375 mm3, and it offers a wide impedance bandwidth of 2.0 GHz (26-28 GHz). Parametric studies demonstrated that by increasing the length of slots in patch, the antenna frequency can be reduced further. Single radiator antenna is used as 8-element MIMO structure. Parallel adjacent antenna in X-direction has minimal coupling effect, whereas antenna placed in Y-direction has high coupling effect. Thus, coupling is reduced by etching a wall of slots in ground plane. It alters the surface current interference in Y-direction and limits the coupling effect. The antenna is investigated to use in body area network applications. To evaluate its on-body performance, an equivalent body model is virtually developed. The on-body performance is assessed by placing the antenna in close proximity to body model. Stable and robust performance is achieved for the on-body operation. At the resonant point, the antenna exhibits a reflection coefficient of -30 dB (free space) and -40 dB (on-body), high isolation of above 20 dB between adjacent radiators and above 30 dB for other radiators. Antenna has stable performance for different body tissues and on the non-planar structures. Bidirectional radiation pattern with gain of 2.53 dB and broadside type orientations with gain of 4.64 dB are achieved for free space and on body operations respectively. low specific absorption rate makes antenna safe for health care devices. Further, diversity performance is measured in terms of envelope correlation coefficient (ECC), and diversity gain (DG). Maximum Value of ECC is 0.005 and minimum value DG is 9.97 at 27 GHz which confirms the excellence of antenna for MIMO applications.
Topics: Wireless Technology; Equipment Design; Humans
PubMed: 38900804
DOI: 10.1371/journal.pone.0305524 -
PLoS Neglected Tropical Diseases Jun 2024In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of... (Randomized Controlled Trial)
Randomized Controlled Trial
A phase II, non-comparative randomised trial of two treatments involving liposomal amphotericin B and miltefosine for post-kala-azar dermal leishmaniasis in India and Bangladesh.
BACKGROUND
In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF.
METHODOLOGY/PRINCIPAL FINDINGS
An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred.
CONCLUSIONS/SIGNIFICANCE
Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia.
TRIAL REGISTRATION
CTRI/2017/04/008421.
Topics: Humans; Amphotericin B; Phosphorylcholine; Bangladesh; Male; Antiprotozoal Agents; Adult; Adolescent; Female; Middle Aged; Young Adult; Child; India; Leishmaniasis, Visceral; Treatment Outcome; Leishmaniasis, Cutaneous; Drug Therapy, Combination
PubMed: 38900786
DOI: 10.1371/journal.pntd.0012242 -
Insights Into Imaging Jun 2024To evaluate the safety of a minimum continuous positive airway pressure of 4 cmHO (CPAP + 4) during computed tomography (CT)-guided radiofrequency ablation (RFA)...
OBJECTIVE
To evaluate the safety of a minimum continuous positive airway pressure of 4 cmHO (CPAP + 4) during computed tomography (CT)-guided radiofrequency ablation (RFA) for lung malignancies under procedural sedation and analgesia (PSA).
METHODS
This was a prospective, randomised, single-blind, parallel-group, placebo-controlled trial with an open-label medical device conducted at a single tertiary university hospital in Barcelona, Spain. Forty-six patients over 18 years of age scheduled for CT-guided RFA of a malignant pulmonary tumour under PSA were randomised to receive either CPAP + 4 or a modified mask for placebo CPAP (Sham-CPAP). Exclusion criteria included contraindications for RFA, refusal to participate, inability to understand the procedure or tolerate the CPAP test, lung biopsy just prior to RFA, intercurrent diseases, or previous randomisation for additional pulmonary RFA. Primary outcomes were the percentage of patients reporting at least one serious adverse event (SAE), classification for complications from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), and Clavien-Dindo classifications for complications, hospital stay, and readmissions. Secondary outcomes included adverse events (AEs), respiratory parameters, airway management, and the local radiological efficacy of pulmonary ablation.
RESULTS
CPAP + 4 prolonged hospital stay (1.5 ± 1.1 vs. 1.0 ± 0 inpatient nights, p = 0.022) and increased the risk of AE post-RFA (odds ratio (95% CI): 4.250 (1.234 to 14.637), p = 0.021 with more pneumothorax cases (n = 5/22, 22.7% vs. n = 0/24, 0%, p = 0.019). Per-protocol analysis revealed more SAEs and CIRSE grade 3 complications in the CPAP + 4 group (23.5% vs. 0%, p = 0.036). No significant differences were found in the effectiveness of oxygenation, ventilation, or pulmonary ablation.
CONCLUSION
CPAP is unsafe during CT-guided RFA for lung cancer under PSA even at the lowest pressure setting.
TRIAL REGISTRATION
ClinicalTrials.Gov, ClinicalTrials.gov ID NCT02117908, Registered 11 April 2014, https://www.
CLINICALTRIALS
gov/study/NCT02117908 CRITICAL RELEVANCE STATEMENT: This study highlights the hazards of continuous positive airway pressure during radiofrequency ablation of lung cancer, even at minimal pressures, deeming it unsafe under procedural sedation and analgesia in pulmonary interventional procedures. Findings provide crucial insights to prioritise patient safety.
KEY POINTS
No prior randomised controlled trials on CPAP safety in percutaneous lung thermo-ablation. Standardised outcome measures are crucial for radiology research. CPAP during lung RFA raises hospital stay and the risk of complications. CPAP is unsafe during CT-guided RFA of lung cancer under procedural sedoanalgesia.
PubMed: 38900225
DOI: 10.1186/s13244-024-01721-9 -
Bone & Joint Open Jun 2024Ankle fractures are common, mainly affecting adults aged 50 years and over. To aid recovery, some patients are referred to physiotherapy, but referral patterns vary,...
AIMS
Ankle fractures are common, mainly affecting adults aged 50 years and over. To aid recovery, some patients are referred to physiotherapy, but referral patterns vary, likely due to uncertainty about the effectiveness of this supervised rehabilitation approach. To inform clinical practice, this study will evaluate the effectiveness of supervised versus self-directed rehabilitation in improving ankle function for older adults with ankle fractures.
METHODS
This will be a multicentre, parallel-group, individually randomized controlled superiority trial. We aim to recruit 344 participants aged 50 years and older with an ankle fracture treated surgically or non-surgically from at least 20 NHS hospitals. Participants will be randomized 1:1 using a web-based service to supervised rehabilitation (four to six one-to-one physiotherapy sessions of tailored advice and prescribed home exercise over three months), or self-directed rehabilitation (provision of advice and exercise materials that participants will use to manage their recovery independently). The primary outcome is participant-reported ankle-related symptoms and function six months after randomization, measured by the Olerud and Molander Ankle Score. Secondary outcomes at two, four, and six months measure health-related quality of life, pain, physical function, self-efficacy, exercise adherence, complications, and resource use. Due to the nature of the interventions, participants and intervention providers will be unblinded to treatment allocation.
CONCLUSION
This study will assess whether supervised rehabilitation is more effective than self-directed rehabilitation for adults aged 50 years and older after ankle fracture. The results will provide evidence to guide clinical practice. At the time of submission, the trial is currently completing recruitment, and follow-up will be completed in 2024.
PubMed: 38898823
DOI: 10.1302/2633-1462.56.BJO-2023-0183 -
CPT: Pharmacometrics & Systems... Jun 2024OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug-drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates...
OATP1B facilitates the uptake of xenobiotics into hepatocytes and is a prominent target for drug-drug interactions (DDIs). Reduced systemic exposure of OATP1B substrates has been reported following multiple-dose rifampicin; one explanation for this observation is OATP1B induction. Non-uniform hepatic distribution of OATP1B may impact local rifampicin tissue concentrations and rifampicin-mediated protein induction, which may affect the accuracy of transporter- and/or metabolizing enzyme-mediated DDI predictions. We incorporated quantitative zonal OATP1B distribution data from immunofluorescence imaging into a PBPK modeling framework to explore rifampicin interactions with OATP1B and CYP substrates. PBPK models were developed for rifampicin, two OATP1B substrates, pravastatin and repaglinide (also metabolized by CYP2C8/CYP3A4), and the CYP3A probe, midazolam. Simulated hepatic uptake of pravastatin and repaglinide increased from the periportal to the pericentral region (approximately 2.1-fold), consistent with OATP1B distribution data. Simulated rifampicin unbound intracellular concentrations increased in the pericentral region (1.64-fold) compared to simulations with uniformly distributed OATP1B. The absolute average fold error of the rifampicin PBPK model for predicting substrate maximal concentration (C) and area under the plasma concentration-time curve (AUC) ratios was 1.41 and 1.54, respectively (nine studies). In conclusion, hepatic OATP1B distribution has a considerable impact on simulated zonal substrate uptake clearance values and simulated intracellular perpetrator concentrations, which regulate transporter and metabolic DDIs. Additionally, accounting for rifampicin-mediated OATP1B induction in parallel with inhibition improved model predictions. This study provides novel insight into the effect of hepatic OATP1B distribution on site-specific DDI predictions and the impact of accounting for zonal transporter distributions within PBPK models.
PubMed: 38898552
DOI: 10.1002/psp4.13188 -
Molecular Medicine (Cambridge, Mass.) Jun 2024The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in...
BACKGROUND
The epithelial-mesenchymal transition (EMT) of human bronchial epithelial cells (HBECs) is essential for airway remodeling during asthma. Wnt5a has been implicated in various lung diseases, while its role in the EMT of HBECs during asthma is yet to be determined. This study sought to define whether Wnt5a initiated EMT, leading to airway remodeling through the induction of autophagy in HBECs.
METHODS
Microarray analysis was used to investigate the expression change of WNT5A in asthma patients. In parallel, EMT models were induced using 16HBE cells by exposing them to house dust mites (HDM) or interleukin-4 (IL-4), and then the expression of Wnt5a was observed. Using in vitro gain- and loss-of-function approaches via Wnt5a mimic peptide FOXY5 and Wnt5a inhibitor BOX5, the alterations in the expression of the epithelial marker E-cadherin and the mesenchymal marker protein were observed. Mechanistically, the Ca/CaMKII signaling pathway and autophagy were evaluated. An autophagy inhibitor 3-MA was used to examine Wnt5a in the regulation of autophagy during EMT. Furthermore, we used a CaMKII inhibitor KN-93 to determine whether Wnt5a induced autophagy overactivation and EMT via the Ca/CaMKII signaling pathway.
RESULTS
Asthma patients exhibited a significant increase in the gene expression of WNT5A compared to the healthy control. Upon HDM and IL-4 treatments, we observed that Wnt5a gene and protein expression levels were significantly increased in 16HBE cells. Interestingly, Wnt5a mimic peptide FOXY5 significantly inhibited E-cadherin and upregulated α-SMA, Collagen I, and autophagy marker proteins (Beclin1 and LC3-II). Rhodamine-phalloidin staining showed that FOXY5 resulted in a rearrangement of the cytoskeleton and an increase in the quantity of stress fibers in 16HBE cells. Importantly, blocking Wnt5a with BOX5 significantly inhibited autophagy and EMT induced by IL-4 in 16HBE cells. Mechanistically, autophagy inhibitor 3-MA and CaMKII inhibitor KN-93 reduced the EMT of 16HBE cells caused by FOXY5, as well as the increase in stress fibers, cell adhesion, and autophagy.
CONCLUSION
This study illustrates a new link in the Wnt5a-Ca/CaMKII-autophagy axis to triggering airway remodeling. Our findings may provide novel strategies for the treatment of EMT-related diseases.
Topics: Humans; Wnt-5a Protein; Epithelial-Mesenchymal Transition; Autophagy; Asthma; Epithelial Cells; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Bronchi; Male; Cell Line; Female; Middle Aged; Signal Transduction; Adult
PubMed: 38898476
DOI: 10.1186/s10020-024-00862-3 -
Trials Jun 2024Fear memory extinction is closely related to insomnia. Repetitive transcranial magnetic stimulation (rTMS) is safe and effective for treating insomnia disorder (ID), and...
BACKGROUND
Fear memory extinction is closely related to insomnia. Repetitive transcranial magnetic stimulation (rTMS) is safe and effective for treating insomnia disorder (ID), and it has been shown to be an efficient method for modulating fear extinction. However, whether rTMS can improve fear extinction memory in ID patients remains to be studied. In this study, we specifically aim to (1) show that 1 Hz rTMS stimulation could improve fear extinction memory in ID patients and (2) examine whether changes in sleep mediate this impact.
METHODS AND DESIGN
We propose a parallel group randomised controlled trial of 62 ID participants who meet the inclusion criteria. Participants will be assigned to a real rTMS group or a sham rTMS group. The allocation ratio will be 1:1, with 31 subjects in each group. Interventions will be administered five times per week over a 4-week period. The assessments will take place at baseline (week 0), post-intervention (week 4), and 8-week follow-up (week 8). The primary outcome measure of this study will be the mean change in the Pittsburgh Sleep Quality Index (PSQI) scores from baseline to post-intervention at week 4. The secondary outcome measures include the mean change in skin conductance response (SCR), fear expectation during fear extinction, Insomnia Severity Index (ISI), Zung Self-Rating Anxiety Scale (SAS), and the Zung Self-Rating Depression Scale (SDS).
DISCUSSION
This study will be the first examination of the impact of rTMS on fear memory extinction in ID patients.
TRIAL REGISTRATION
Chinese Clinical Trials Register ChiCTR2300076097. Registered on 25 September 2021.
Topics: Humans; Sleep Initiation and Maintenance Disorders; Fear; Extinction, Psychological; Transcranial Magnetic Stimulation; Randomized Controlled Trials as Topic; Adult; Treatment Outcome; Middle Aged; Female; Male; Memory; Young Adult; Time Factors; Adolescent; Sleep
PubMed: 38898471
DOI: 10.1186/s13063-024-08198-3 -
Trials Jun 2024Dupuytren's contractures (DC) are fibrous cords under the skin of the hand that cause one or more fingers to curl gradually and irreversibly towards the palm. These...
BACKGROUND
Dupuytren's contractures (DC) are fibrous cords under the skin of the hand that cause one or more fingers to curl gradually and irreversibly towards the palm. These contractures are usually painless but can cause a loss of hand function. Two treatments for Dupuytren's contractures are widely used within the National Health Service (NHS) in the UK: removal of the contractures via surgery (limited fasciectomy) and division of the contractures via a needle inserted through the skin (needle fasciotomy). This study aims to establish the clinical and cost-effectiveness of needle fasciotomy (NF) versus limited fasciectomy (LF) for the treatment of DC in the NHS, in terms of patient-reported hand function and resource utilisation.
METHODS/DESIGN
Hand-2 is a national multi-centre, two-arm, parallel-group randomised, non-inferiority trial. Patients will be eligible to join the trial if they are aged 18 years or older, have at least one previously untreated finger with a well-defined Dupuytren's contracture of 30° or greater that causes functional problems and is suitable for treatment with either LF or NF. Patients with a contracture of the distal interphalangeal joint only are ineligible. Eligible consenting patients will be randomised 1:1 to receive either NF or LF and will be followed up for 24 months post-treatment. A QuinteT Recruitment Intervention will be used to optimise recruitment. The primary outcome measure is the participant-reported assessment of hand function, assessed by the Hand Health Profile of the Patient Evaluation Measure (PEM) questionnaire at 12 months post-treatment. Secondary outcomes include other patient-reported measures, loss of finger movement, and cost-effectiveness, reported over the 24-month post-treatment. Embedded qualitative research will explore patient experiences and acceptability of treatment at 2 years post-surgery.
DISCUSSION
This study will determine whether treatment with needle fasciotomy is non-inferior to limited fasciectomy in terms of patient-reported hand function at 12 months post-treatment.
TRIAL REGISTRATION
International Standard Registered Clinical/soCial sTudy ISRCTN12525655. Registered on 18th September 2020.
Topics: Dupuytren Contracture; Humans; Fasciotomy; Multicenter Studies as Topic; Cost-Benefit Analysis; Needles; Treatment Outcome; Equivalence Trials as Topic; Recovery of Function; Fingers; United Kingdom; Time Factors; Patient Reported Outcome Measures
PubMed: 38898458
DOI: 10.1186/s13063-024-08003-1 -
GigaScience Jan 2024This study addresses the importance of precise referencing in 3-dimensional (3D) plant phenotyping, which is crucial for advancing plant breeding and improving crop...
BACKGROUND
This study addresses the importance of precise referencing in 3-dimensional (3D) plant phenotyping, which is crucial for advancing plant breeding and improving crop production. Traditionally, reference data in plant phenotyping rely on invasive methods. Recent advancements in 3D sensing technologies offer the possibility to collect parameters that cannot be referenced by manual measurements. This work focuses on evaluating a 3D printed sugar beet plant model as a referencing tool.
RESULTS
Fused deposition modeling has turned out to be a suitable 3D printing technique for creating reference objects in 3D plant phenotyping. Production deviations of the created reference model were in a low and acceptable range. We were able to achieve deviations ranging from -10 mm to +5 mm. In parallel, we demonstrated a high-dimensional stability of the reference model, reaching only ±4 mm deformation over the course of 1 year. Detailed print files, assembly descriptions, and benchmark parameters are provided, facilitating replication and benefiting the research community.
CONCLUSION
Consumer-grade 3D printing was utilized to create a stable and reproducible 3D reference model of a sugar beet plant, addressing challenges in referencing morphological parameters in 3D plant phenotyping. The reference model is applicable in 3 demonstrated use cases: evaluating and comparing 3D sensor systems, investigating the potential accuracy of parameter extraction algorithms, and continuously monitoring these algorithms in practical experiments in greenhouse and field experiments. Using this approach, it is possible to monitor the extraction of a nonverifiable parameter and create reference data. The process serves as a model for developing reference models for other agricultural crops.
Topics: Printing, Three-Dimensional; Phenotype; Beta vulgaris; Plant Breeding
PubMed: 38897734
DOI: 10.1093/gigascience/giae035