A Phase I/IIa Prospective, Randomized, Open-Label Study on the Safety and Efficacy of Nebulized Liposomal Amphotericin for Invasive Pulmonary Aspergillosis.

Although nebulized liposomal amphotericin B (NLAB) is being used in invasive pulmonary aspergillosis (IPA) prophylaxis, no clinical trial has shown its efficacy as a therapeutic strategy. NAIFI is the inaugural randomized, controlled clinical trial designed to examine the safety and effectiveness of NLAB (dosage: 25 mg in 6 mL, three times per week for 6 weeks) against a placebo, in the auxiliary treatment of IPA. Throughout the three-year clinical trial, thirteen patients (six NLAB, seven placebo) were included, with 61% being onco-hematological with less than 100 neutrophils/µL. There were no significant differences noted in their pre- and post-nebulization results of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and oxygen saturation between the groups. Neither bronchospasm nor serum amphotericin B levels were reported in any patients given NLAB. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET-TC) was carried out at the baseline and after 6 weeks. A notable decrease in median SUV (standardized uptake value) was observed in NLAB patients after 6 weeks (-3.6 vs. -0.95, p: 0.039, one tail). Furthermore, a reduction in serum substance galactomannan and beta-D-Glucan was identified within NLAB recipients. NLAB is well tolerated and safe for patients with IPA. Encouraging indirect efficacy data have been derived from image monitoring or biomarkers. However, further studies involving more patients are necessary.

Biomarcadores sanguíneos, de orina y conductas autolesivas e intentos de suicidio repetidos en los adolescentes / Blood and urine biomarkers and repeated self-injurious behaviors and suicide attempts in adolescents

Hay evidencia parcial de que los niveles elevados de la β-endorfina sanguínea se asocian a la adicción suicida en los adultos, pero apenas hay datos sobre los adolescentes. La β-endorfina sanguínea, con un importante papel en los mecanismos de gestión de las adicciones, puede inducir euforia y felicidad, recompensar y reforzar el comportamiento suicida. Para probar si los grandes repetidores de intentos de suicidio (5 o más intentos de suicidio) y de conductas autolesivas (20 o más episodios de autolesiones) tienen unos niveles de biomarcadores más elevados, se selecciona una muestra de 43 pacientes de entre 12 y 17 años que acuden al Servicio de Urgencias Psiquiátricas en el Hospital Universitario Puerta de Hierro Majadahonda. Diez presentan 5 o más intentos de suicidio, 35 presentan 20 o más episodios autolesivos y 10 presentan ambas características, y la mayoría de los adolescentes cumplían criterios de adicción para autolesiones y suicidio. Los resultados sugieren que todos los pacientes que presentaban adicción al suicidio también presentaban adicción a la autolesión. Los niveles de ACTH, cortisol y β-endorfina sanguíneos y de cortisol en orina fueron muy elevados, pero no diferenciaban a los grandes repetidores del resto de adolescentes. (AU)

There is partial evidence that elevated levels of blood β-endorphin are associated with suicidal addiction in adults, but hardly any data on adolescents. Blood β-endorphin, with an important role in addiction management mechanisms, can induce euphoria and happiness, reward and reinforce suicidal behavior. To test whether high repeaters of suicide attempts (5 or more suicide attempts) and self-injurious behaviors (20 or more episodes of self-injury) have higher biomarker levels, a sample of 43 patients aged 12-17 years attending the Psychiatric Emergency Department at the Hospital Universitario Puerta de Hierro Majadahonda is recruited. Ten present 5 or more suicide attempts, 35 present 20 or more self-injurious episodes and 10 present both characteristics, and most of the adolescents meet addiction criteria for self-injury and suicide. The results suggest that all patients with addiction to suicide also had addiction to self-injury. Blood ACTH, cortisol and β-endorphin and urine cortisol levels were very elevated, but did not differentiate heavy repeaters from the rest of the adolescents. (AU)

The Arabidopsis DNA glycosylase MBD4L repairs the nuclear genome in vivo.

DNA glycosylases remove mispaired or modified bases from DNA initiating the base excision repair (BER) pathway. The DNA glycosylase MBD4 (methyl-CpG-binding domain protein 4) has been functionally characterized in mammals, but not yet in plants, where it is called MBD4-like (MBD4L). Mammalian MBD4 and Arabidopsis recombinant MBD4L excise U and T mispaired with G, as well as 5-fluorouracil (5-FU) and 5-bromouracil (5-BrU) in vitro. Here, we investigate the ability of Arabidopsis MBD4L to remove some of these substrates from the nuclear genome in vivo in coordination with uracil DNA glycosylase (AtUNG). We found that mbd4l mutants are hypersensitive to 5-FU and 5-BrU, as they displayed smaller size, less root growth, and higher cell death than control plants in both media. Using comet assays, we determined BER-associated DNA fragmentation in isolated nuclei and observed reduced DNA breaks in mbd4l plants under both conditions, but particularly with 5-BrU. The use of ung and ung x mbd4l mutants in these assays indicated that both MBD4L and AtUNG trigger nuclear DNA fragmentation in response to 5-FU. Consistently, we here report the nuclear localization of AtUNG based on the expression of AtUNG-GFP/RFP constructs in transgenic plants. Interestingly, MBD4L and AtUNG are transcriptionally coordinated but display not completely overlapping functions. MBD4L-deficient plants showed reduced expression of BER genes and enhanced expression of DNA damage response (DDR) gene markers. Overall, our findings indicate that Arabidopsis MBD4L is critical for maintaining nuclear genome integrity and preventing cell death under genotoxic stress conditions.

An impressive case of isolated thoracic impalement.

Case: A 61-year-old male construction worker was admitted to our Emergency Department due to being impaled in the chest after fall onto the long pole of his cement mixer. He was promptly scanned through the CT then transferred to theatre where unique technique for intubation was utilised prior to performing a Video Assisted Thoracoscopic Surgery exploration and extraction of the foreign object. Discussion: Impalement injuries are classified into Types I or II depending on the direction of movement of the human body in relation to the foreign object. There currently is no consensus on the best management of chest wall injuries involving impalements. Our case utilised Video Assisted Thoracoscopic Surgery as the dominant method of intervention together with highly skilled anaesthetic preparation. Conclusion: The combined expert anaesthetic and surgical approach utilised collectively had a role in ensuring the best possible outcome for the patient.

Correlation between the Altered Gut Microbiome and Lifestyle Interventions in Chronic Widespread Pain Patients: A Systematic Review.

Background: Lifestyle interventions have a direct impact on the gut microbiome, changing its composition and functioning. This opens an innovative way for new therapeutic opportunities for chronic widespread patients. Purpose: The goal of the present study was to evaluate a correlation between lifestyle interventions and the gut microbiome in patients with chronic widespread pain (CWP). Methods: The systematic review was conducted until January 2023. Pain and microbiome were the two keywords selected for this revision. The search was conducted in PubMed, Chochrane, PEDro and ScienceDirect, where 3917 papers were obtained. Clinical trials with lifestyle intervention in CWP patients were selected. Furthermore, these papers had to be related with the gut microbiome, excluding articles related to other types of microbiomes. Results: Only six articles were selected under the eligibility criteria. Lifestyle interventions were exercise, electroacupuncture and ingesting a probiotic. Conclusions: Lifestyle intervention could be a suitable choice to improve the gut microbiome. This fact could be extrapolated into a better quality of life and lesser levels of pain.

Ambulatory chest drainage with advanced nurse practitioner-led follow-up facilitates early discharge after thoracic surgery.

OBJECTIVES: To demonstrate the safety and feasibility of advanced nurse practitioner-led (ANP-led) outpatient follow-up after discharge with ambulatory chest drains for prolonged air leak and excessive fluid drainage. METHODS: Patients discharged with ambulatory chest drains between January 2017 and December 2019 were retrospectively reviewed. Discharge criteria included air leak < 200 ml/min or fluid drainage > 100 ml/24 h on a digital drain. Patients were reviewed weekly in the clinic by ANPs, a highly skilled cohort of nurses with physician support available. Outcomes included length of stay, duration of air or fluid leak and complications. RESULTS: Two-hundred patients were included, amounting to 368 clinic episodes. The median age was 68 ± 13 years and 119 (60%) were male. 112 (56%) patients underwent anatomical lung resection (total anatomical lung resections during the study period = 917) equating to a discharge with ambulatory chest drain rate of 12.2% in this group. The median length of stay was 6 ± 3 days and 176 (88%) patients were discharged with air leak versus 24 (12%) with excessive fluid drainage. The median time to drain removal was 12 ± 11 days. Complications occurred in 16 patients (8%) and 12 (6%) required readmission. An estimated 2075 inpatient days were saved over the study period equating to an annual cost saving of £123,167 (US$149,032) per annum. CONCLUSIONS: Patients with air leak or excessive fluid drainage can safely be discharged with ambulatory chest drains, allowing them to return to their familiar home environment safely and quickly. ANP-led clinics are a robust and cost-effective follow-up strategy and are associated with a low complication rate.

Association between Sleep Disorders and Sleep Quality in Patients with Temporomandibular Joint Osteoarthritis: A Systematic Review.

BACKGROUND: Osteoarthritis (OA) is a leading cause of disability, the most common form of chronic disease in the temporomandibular joint (TMJ), and the most severe disease type of temporomandibular disorders (TMD). The etiology of TMD is multifactorial, considering parafunctional habits, sleep bruxism, or sleep disturbance as common factors. Insomnia and apnea are the two most frequent forms of sleep disorders in TMD patients. Due to this, the objective of this systematic review was to highlight whether there is currently scientific evidence in the literature describing that patients with temporomandibular joint osteoarthritis (TMJ-OA) are associated with increased sleep disorders or impaired sleep quality. METHODS: This systematic review was completed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) statement and was registered with PROSPERO prior to completion of the main search. Original observational studies that analyze the association of sleep disorders and sleep quality in patients with TMJ-OA were included in the present review. RESULTS: 770 studies were screened by abstract and title according to inclusion and exclusion criteria, and finally, 7 articles were included in the qualitative synthesis and a total of 772 patients diagnosed with TMJ-OA. CONCLUSIONS: There is insufficient evidence to indicate that patients with TMJ OA are associated with increased sleep disorders or poorer sleep quality.

Convergent Epigenetic Mechanisms Avoid Constitutive Expression of Immune Receptor Gene Subsets.

The gene pool encoding PRR and NLR immune receptors determines the ability of a plant to resist microbial infections. Basal expression of these genes is prevented by diverse mechanisms since their hyperactivity can be harmful. To approach the study of epigenetic control of PRR/NLR genes we here analyzed their expression in mutants carrying abnormal repressive 5-methyl cytosine (5-mC) and histone 3 lysine 9 dimethylation (H3K9me2) marks, due to lack of MET1, CMT3, MOM1, SUVH4/5/6, or DDM1. At optimal growth conditions, none of the mutants showed basal expression of the defense gene marker PR1, but all of them had greater resistance to Pseudomonas syringae pv. tomato than wild type plants, suggesting they are primed to stimulate immune cascades. Consistently, analysis of available transcriptomes indicated that all mutants showed activation of particular PRR/NLR genes under some growth conditions. Under low defense activation, 37 PRR/NLR genes were expressed in these plants, but 29 of them were exclusively activated in specific mutants, indicating that MET1, CMT3, MOM1, SUVH4/5/6, and DDM1 mediate basal repression of different subsets of genes. Some epigenetic marks present at promoters, but not gene bodies, could explain the activation of these genes in the mutants. As expected, suvh4/5/6 and ddm1 activated genes carrying 5-mC and H3K9me2 marks in wild type plants. Surprisingly, all mutants expressed genes harboring promoter H2A.Z/H3K27me3 marks likely affected by the chromatin remodeler PIE1 and the histone demethylase REF6, respectively. Therefore, MET1, CMT3, MOM1, SUVH4/5/6, and DDM1, together with REF6, seemingly contribute to the establishment of chromatin states that prevent constitutive PRR/NLR gene activation, but facilitate their priming by modulating epigenetic marks at their promoters.

Transposon clusters as substrates for aberrant splice-site activation.

Transposed elements (TEs) have dramatically shaped evolution of the exon-intron structure and significantly contributed to morbidity, but how recent TE invasions into older TEs cooperate in generating new coding sequences is poorly understood. Employing an updated repository of new exon-intron boundaries induced by pathogenic mutations, termed DBASS, here we identify novel TE clusters that facilitated exon selection. To explore the extent to which such TE exons maintain RNA secondary structure of their progenitors, we carried out structural studies with a composite exon that was derived from a long terminal repeat (LTR78) and AluJ and was activated by a C > T mutation optimizing the 5' splice site. Using a combination of SHAPE, DMS and enzymatic probing, we show that the disease-causing mutation disrupted a conserved AluJ stem that evolved from helix 3.3 (or 5b) of 7SL RNA, liberating a primordial GC 5' splice site from the paired conformation for interactions with the spliceosome. The mutation also reduced flexibility of conserved residues in adjacent exon-derived loops of the central Alu hairpin, revealing a cross-talk between traditional and auxilliary splicing motifs that evolved from opposite termini of 7SL RNA and were approximated by Watson-Crick base-pairing already in organisms without spliceosomal introns. We also identify existing Alu exons activated by the same RNA rearrangement. Collectively, these results provide valuable TE exon models for studying formation and kinetics of pre-mRNA building blocks required for splice-site selection and will be useful for fine-tuning auxilliary splicing motifs and exon and intron size constraints that govern aberrant splice-site activation.