Investigating foliar application of bulk and nanoparticles titanium dioxide on fennel productivity to mitigate the negative effects of saline irrigation water.

BACKGROUND: Fennel essential oils are fragrance compounds used in food and pharmaceutical sectors. One of the major impediments to expansion of fennel farming in Egypt's reclamation areas is saline water. Titanium dioxide (TiO2) or TiO2 nano particles (TiO2NP) can be utilized to boost the yield of aromatic plants cultivated under saline irrigation water. Saline water, particularly which contains sodium chloride can harm fennel plant; consequently, it was predicted that fennel production would fail in Egypt's reclaimed area, where the primary source of irrigation is groundwater consisting sodium chloride. This study sought to help fennel respond to sodium chloride by applying Ti forms to their leaves in order to reduce the detrimental effects of sodium chloride on them for expanding their production in the newly reclamation areas as a natural source of essential oil. Ti forms were applied as foliar application at 0, 0.1, 0.2 TiO2, 0.1 TiO2NP, and 0.2 TiO2NP, mM under irrigation with fresh water (0.4 dS m-1), or saline water (51.3 mM or 4.7 dS m-1). RESULTS: Plants exposed to 0.1 mM TiO2NP under fresh water resulted in the maximum values of morphological characters, estragole, oxygenated monoterpenes and photosynthetic pigments; while those subjected to 0.1 mM TiO2NP under saline water gave the greatest values of essential oil, proline, antioxidant enzymes and phenols. The greatest amounts of soluble sugars were recorded with 0.2 mM TiO2NP irrigated with saline water. Plants subjected to 0 mM TiO2 under saline water produced the greatest values of flavonoids, hydrogen peroxide and malondialdehyde. CONCLUSION: To mitigate the negative effects of salty irrigation water on fennel plant production, TiO2NP application is suggested as a potential strategy.

Optimizing tendon repair and regeneration: how does the in vivo environment shape outcomes following rupture of a tendon such as the Achilles tendon?

Risk for rupture of the Achilles tendon, and other tendons increases with age. Such injuries of tissues that function in high load environments generally are believed to heal with variable outcome. However, in many cases, the healing does not lead to a good outcome and the patient cannot return to the previous level of participation in active living activities, including sports. In the past few years, using proteomic approaches and other biological techniques, reports have appeared that identify biomarkers that are prognostic of good outcomes from healing, and others that are destined for poor outcomes using validated criteria at 1-year post injury. This review will discuss some of these recent findings and their potential implications for improving outcomes following connective tissue injuries, as well as implications for how clinical research and clinical trials may be conducted in the future where the goal is to assess the impact of specific interventions on the healing process, as well as focusing the emphasis on regeneration and not just repair.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43-depleted human iPSC-derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43-depleted human iPSC-derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43-depleted human iPSC-derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Efficacy of Atezolizumab Plus Bevacizumab Versus Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma: a Meta-analysis.

INTRODUCTION: Hepatocellular carcinoma is a lethal disease and there has been a debate regarding the first-line treatment of its advanced and unresectable form. Observational studies have explored atezolizumab plus bevacizumab versus lenvatinib, yielding mixed results. This systematic review and meta-analysis aim to compare efficacy and safety of both treatment arms. METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines. Randomized control trials, cohort studies, or case-control that included patients above age 60 with unresectable hepatocellular carcinoma confirmed by radiological imaging were included. At least one of the outcomes: overall survival (OS), progression-free survival (PFS), objective response rate (ORR), duration of response, or adverse events was included in the selected studies. RESULTS: Ten cohorts were included in the analysis with a total of 6493 patients. Nine of the included studies had patients with advanced HCC (BCLC-C) or intermediate HCC (BCLC-B) and 1 study included patients with all three stages (BCLC-A, BCLC-B, and BCLC-C). Of these patients, 2524 patients received atezolizumab plus bevacizumab (A + B) combination while 3969 received lenvatinib. The overall survival was better statistically in the A + B group then the lenvatinib group (MD: - 5.06; 95% CI: - 7.79 to - 2.33; p = 0.0003, I2 = 0%). The progression-free survival was significantly improved in A + B arm as well group (MD: - 4.96; 95% CI: - 7.67 to - 2.26; I2 = 0%, p = 0. 0003). There was no significant difference in objective response rate, disease control rate, and frequency of adverse events in either of the group. CONCLUSION: Our study concluded that combination therapy with atezolizumab plus bevacizumab could increase the survival duration without affecting the disease course. Moreover, while the severity of adverse events was greater in the A + B group, their frequency was comparable to the lenvatinib group.

Unlocking the Power of EHRs: Harnessing Unstructured Data for Machine Learning-based Outcome Predictions.

The integration of Electronic Health Records (EHRs) with Machine Learning (ML) models has become imperative in examining patient outcomes due to the vast amounts of clinical data they provide. However, critical information regarding social and behavioral factors that affect health, such as social isolation, stress, and mental health complexities, is often recorded in unstructured clinical notes, hindering its accessibility. This has resulted in an over-reliance on clinical data in current EHR-based research, potentially leading to disparities in health outcomes. This study aims to evaluate the impact of incorporating patient-specific context from unstructured EHR data on the accuracy and stability of ML algorithms for predicting mortality, using the MIMIC III database. Results from the study confirmed the significance of incorporating patient-specific information into prediction models, leading to a notable improvement in the discriminatory power and robustness of the ML algorithms. Furthermore, the findings underline the importance of considering non-clinical factors related to a patient's daily life, in addition to clinical factors, when making predictions about patient outcomes. The advent of advanced generative models, such as GPT-4, presents new opportunities for effectively extracting social and behavioral factors from unstructured clinical notes, further enhancing the accuracy and stability of ML algorithms in predicting patient outcomes. The results of our study have significant ramifications for improving ML in clinical decision support and patient outcome predictions, specifically highlighting the potential role of generative models like GPT-4 in advancing ML-based outcome predictions.

Complement factor D regulates collagen type I expression and fibroblast migration to enhance human tendon repair and healing outcomes.

Introduction: Dense connective tissues (DCTs) such as tendon, ligament, and cartilage are important stabilizers and force transmitters in the musculoskeletal system. The healing processes after DCT injuries are highly variable, often leading to degenerative changes and poor clinical outcome. Biomarkers in relation to repair quality for human DCTs, especially tendon are lacking. This study expands our previous findings and aimed to characterize the mechanisms by which a potential biomarker of good outcomes, complement factor D (CFD), regulates tendon healing. Methods: Quantitative mass spectrometry (QMS) profiling of tissue biopsies from the inflammatory phase of healing (n = 40 patients) and microdialysates from the proliferative phase of healing (n = 28 patients) were used to identify specific biomarkers for tendon healing. Further bioinformatic and experimental investigations based on primary fibroblasts and fibroblast cell line were used to confirm the identified biomarkers. Results: The QMS profiling of tissue biopsies from the inflammatory phase of healing identified 769 unique proteins, and microdialysates from the proliferative phase of healing identified 1423 unique proteins in Achilles tendon rupture patients. QMS-profiling showed that CFD expression was higher during the inflammatory- and lower during the proliferative healing phase in the good outcome patients. Further bioinformatic and experimental explorations based on both inflammatory and proliferative fibroblast models demonstrated that CFD potentially improved repair by regulating cell migration and modulating collagen type I (Col1a1) expression. Moreover, it was shown that the enhanced Col1a1 expression, through increased fibroblast migration, was correlated with the validated clinical outcome. Discussion: The results of the current studies characterized underlying inflammatory- and proliferative healing mechanisms by which CFD potentially improved tendon repair. These findings may lead to improved individualized treatment options, as well the development of effective therapies to promote good long-term clinical outcomes after tendon and other DCT injuries. Trial registration: http://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.

Gallic acid affects chamomile flower's essential oil.

Chamomile essential oil is used in the food and medicinal industries. Gallic acid has been identified as one of the most significant biological elicitors. At dosages of 0, 5, 10, 15, and 20 mg/L, Gallic acid was sprayed on chamomile plants. The yield of flowers and essential oils in dry flowers were assessed. The averages of data were examined statistically using one-way analysis of variance. Oxygenated sesquiterpenes were a major chemical group, while α-bisabolol oxide A, α-bisabolol and chamazulene were the three main components of essential oil. When administered 15 mg/L Gallic acid, plants produced their most flowers and had the highest quantities of the essential oil, α-bisabolol oxide A, α-bisabolol and chamazulene. Essential oil extracted from untreated control plants had the highest concentration of oxygenated sesquiterpenes. It can be infer that Gallic acid increases the production of essential oil and alters its chemical constituents which alter its biological activity.

Glutathione to ameliorate growth criterions and chemical constituents of geranium irrigated with salt water.

Essential oil of geranium (Pelargonium graveolensL) has biological activities that make it used in food and pharmaceutical manufactures. High salinity is one of the factors that lead to lack of expansion in the production of medicinal and aromatic plants, especially in the new reclaimed soil located at arid and semi arid regions. Glutathione is a natural antioxidant that can help plants to withstand unfavorable environmental conditions such as the salinity of irrigation water. This trial aimed to diminish the undesirable effect of exposure to irrigation with salt water on geranium herbs through subjected them to exogenous application of glutathione. Geranium plants were irrigated with various concentrations of salt water with sodium chloride (0.0, 34.2, 51.3, and 68.4 mM) without (0 mg/L) or with glutathione (375 mg/L). Plants exposed to various rates of saline irrigation water with glutathione resulted in higher values of growth criterions (fresh and dry aerial parts), photosynthetic pigments, carbohydrates, protein, proline, essential oil (% or yield), antioxidant enzymes (peroxidase and superoxide dismutase), nitrogen, phosphorous, potassium, calcium, iron, zinc, manganese and copper than those subjected to saline irrigation water without glutathione. Higher amounts were found in sodium and chloride of plant treated with saline irrigation water than those treated saline irrigation water with glutathione. It may be summarized that productivity of geranium plants can be improved with adapting them under saline irrigation conditions by adding glutathione. This trial benefits the producers of geranium to alleviate the hurtful effects of salinity in reclaimed regions with adding glutathione.

Network proteomic analysis identifies inter-alpha-trypsin inhibitor heavy chain 4 during early human Achilles tendon healing as a prognostic biomarker of good long-term outcomes.

The suboptimal or protracted regeneration of injured connective tissues often results in significant dysfunction, pain, and functional disability. Despite the prevalence of the condition, few studies have been conducted which focused on biomarkers or key molecules involved in processes governing healing outcomes. To gain insight into injured connective tissue repair, and using the Achilles tendon as a model system, we utilized quantitative proteomic and weighted co-expression network analysis of tissues acquired from Achilles tendon rupture (ATR) patients with different outcomes at 1-year postoperatively. Two modules were detected to be associated with prognosis. The initial analysis identified inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a biomarker or hub protein positively associated with better healing outcomes. Additional analysis identified the beneficial role of ITIH4 in inflammation, cell viability, apoptosis, proliferation, wound healing, and for the synthesis of type I collagen in cultured fibroblasts. Functionally, the effects of ITIH4 were found to be mediated by peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways. Taken together, these findings suggest that ITIH4 plays an important role in processes of connective tissue repair and advocate for the potential of ITIH4 as a therapeutic target for injured connective tissue repair. Trial registration: http://clinicaltrials.gov, identifiers NCT02318472, NCT01317160.

Surface Modification of Brass via Ultrashort Pulsed Direct Laser Interference Patterning and Its Effect on Bacteria-Substrate Interaction.

In recent decades, antibiotic resistance has become a crucial challenge for human health. One potential solution to this problem is the use of antibacterial surfaces, i.e., copper and copper alloys. This study investigates the antibacterial properties of brass that underwent topographic surface functionalization via ultrashort pulsed direct laser interference patterning. Periodic line-like patterns in the scale range of single bacterial cells were created on brass with a 37% zinc content to enhance the contact area for rod-shaped Escherichia coli (E. coli). Although the topography facilitates attachment of bacteria to the surface, reduced killing rates for E. coli are observed. In parallel, a high-resolution methodical approach was employed to explore the impact of laser-induced topographical and chemical modifications on the antibacterial properties. The findings reveal the underlying role of the chemical modification concerning the antimicrobial efficiency of the Cu-based alloy within the superficial layers of a few hundred nanometers. Overall, this study provides valuable insight into the effect of alloy composition on targeted laser processing for antimicrobial Cu-surfaces, which facilitates the thorough development and optimization of the process concerning antimicrobial applications.

Capsules with Ileocolonic-Targeted Release of Vitamin B2, B3, and C (ColoVit) Intended for Optimization of Gut Health: Development and Validation of the Production Process.

The ileocolonic-targeted delivery of vitamins can establish beneficial alterations in gut microbial composition. Here, we describe the development of capsules containing riboflavin, nicotinic acid, and ascorbic acid covered with a pH-sensitive coating (ColoVit) to establish site-specific release in the ileocolon. Ingredient properties (particle size distribution, morphology) relevant for formulation and product quality were determined. Capsule content and the in vitro release behaviour were determined using a HPLC-method. Uncoated and coated validation batches were produced. Release characteristics were evaluated using a gastro-intestinal simulation system. All capsules met the required specifications. The contents of the ingredients were in the 90.0-120.0% range, and uniformity requirements were met. In the dissolution test a lag-time in drug release of 277-283 min was found, which meets requirements for ileocolonic release. The release itself is immediate as shown by dissolution of the vitamins of more than 75% in 1 h. The production process of the ColoVit formulation was validated and reproducible, it was shown that the vitamin blend was stable during the production process and in the finished coated product. The ColoVit is intended as an innovative treatment approach for beneficial microbiome modulation and optimization of gut health.

eEF2 improves dense connective tissue repair and healing outcome by regulating cellular death, autophagy, apoptosis, proliferation and migration.

Outcomes following human dense connective tissue (DCT) repair are often variable and suboptimal, resulting in compromised function and development of chronic painful degenerative diseases. Moreover, biomarkers and mechanisms that guide good clinical outcomes after DCT injuries are mostly unknown. Here, we characterize the proteomic landscape of DCT repair following human Achilles tendon rupture and its association with long-term patient-reported outcomes. Moreover, the potential regulatory mechanisms of relevant biomarkers were assessed partly by gene silencing experiments. A mass-spectrometry based proteomic approach quantified a large number (769) of proteins, including 51 differentially expressed proteins among 20 good versus 20 poor outcome patients. A novel biomarker, elongation factor-2 (eEF2) was identified as being strongly prognostic of the 1-year clinical outcome. Further bioinformatic and experimental investigation revealed that eEF2 positively regulated autophagy, cell proliferation and migration, as well as reduced cell death and apoptosis, leading to improved DCT repair and outcomes. Findings of eEF2 as novel prognostic biomarker could pave the way for new targeted treatments to improve healing outcomes after DCT injuries.Trial registration: NCT02318472 registered 17 December 2014 and NCT01317160 registered 17 March 2011, with URL http://clinicaltrials.gov/ct2/show/NCT02318472 and http://clinicaltrials.gov/ct2/show/study/NCT01317160 .

Large Renal Abscess in Pregnancy: Case Report of a Rare Finding.

The incidence of renal abscesses during pregnancy has not been well-established. A renal abscess is usually secondary to the complications of acute pyelonephritis and can lead to severe consequences, including fetal and/or maternal death. Little is known about the incidence of renal abscesses in pregnant women; however, the literature consistently refers to it as an extremely rare occurrence. We report a case of a large renal abscess discovered in the early postpartum period following a recurrent urinary tract infection and flank pain during pregnancy. The patient was successfully managed with abscess drainage and prolonged antibiotics.

Co-Occurring X-Linked Agammaglobulinemia and X-Linked Chronic Granulomatous Disease: Two Isolated Pathogenic Variants in One Patient.

We present a unique and unusual case of a male patient diagnosed with two coexisting and typically unassociated X-linked conditions: he was initially diagnosed with X-linked agammaglobulinemia (XLA) followed by a diagnosis of X-linked chronic granulomatous disease (XCGD) and an as of yet unpublished hypomorphic gp91phox variant in the CYBB gene. The latter was tested after the finding of granulomatous gingivitis. Hematopoietic stem cell transplant (HSCT) was performed due to severe colitis and nodular regenerative hyperplasia (NRH) of the liver. Following transplant, complete donor engraftment was observed with the restoration of a normal oxidative burst and full restoration of normal levels of circulating, mature CD19+ B cells. This case is singular in that it does not involve a contiguous gene syndrome in which deleted genes are in close proximity to either BTK and CYBB, which has been previously reported. To our knowledge, this is the first reported case of XLA and XCGD co-existing in a single patient and of having both inborn errors of immunity successfully treated by HSCT.

Identification of Lipid Biomarkers for Chronic Joint Pain Associated with Different Joint Diseases.

Lipids, especially lysophosphatidylcholine LPC16:0, have been shown to be involved in chronic joint pain through the activation of acid-sensing ion channels (ASIC3). The aim of the present study was to investigate the lipid contents of the synovial fluids from controls and patients suffering from chronic joint pain in order to identify characteristic lipid signatures associated with specific joint diseases. For this purpose, lipids were extracted from the synovial fluids and analyzed by mass spectrometry. Lipidomic analyses identified certain choline-containing lipid classes and molecular species as biomarkers of chronic joint pain, regardless of the pathology, with significantly higher levels detected in the patient samples. Moreover, correlations were observed between certain lipid levels and the type of joint pathologies. Interestingly, LPC16:0 levels appeared to correlate with the metabolic status of patients while other choline-containing lipids were more specifically associated with the inflammatory state. Overall, these data point at selective lipid species in synovial fluid as being strong predictors of specific joint pathologies which could help in the selection of the most adapted treatment.

Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.

Functional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility of de novo protein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generate de novo proteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generated de novo proteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that these de novo peptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development.

The Effect of Group Training or Spinal Orthosis on Quality of Life and Potential Plasma Markers of Pain in Older Women With Osteoporosis. A Randomized Controlled Trial.

Objective: Primary purpose was to examine the effects of exercise and use of a spinal orthosis on quality of life (QoL). Secondary, to explore the effects of above-mentioned interventions on plasma levels of potential markers of pain: substance P (SP), calcitonin gene-related peptide (CGRP), and interleukin-6 (IL-6). Design: Randomized controlled trial. Setting: Community-dwelling women in Stockholm. Participants: A total of 113 women aged 60-93 years suffering from back pain and self-reported osteoporosis (n=113). Interventions: The randomized controlled trial was 3-armed: participation in an equipment exercise group, treatment with an activating spinal orthosis or controls. The intervention time was 6 months. Main Outcome Measures: QoL (QUALEFFO-41 and SF-36), plasma levels of SP, CGRP, and IL-6 measured at baseline and after 6 months in all 3 arms. Results: No improvement of QoL was found. Comparing change in mobility (QUALEFFO-41), the effect in least squares means was lower in the spinal orthosis group compared with controls. In the exercise group, the role emotional score (SF-36) deteriorated during the intervention. Effect size varied between 0.02 and 0.6. There was no change in the levels of CGRP or SP, while IL-6 levels were lower at 6 months in the spinal orthosis group compared with the other groups. At least 1 previous vertebral fracture was verified by X-ray in 46 women. Conclusion: The interventions showed none or negative effect on QoL, which was unexpected. The modest effect size may prompt a cautious interpretation. We found a lowering of IL-6 levels in the spinal orthosis group, but more studies are needed.

Clinical Aspects of B Cell Immunodeficiencies: The Past, the Present and the Future.

B cells and antibodies are indispensable for host immunity. Our understanding of the mechanistic processes that underpin how B cells operate has left an indelible mark on the field of clinical pathology, and recently has also dramatically reshaped the therapeutic landscape of diseases that were once considered incurable. Evaluating patients with primary immunodeficiency diseases (PID)/inborn errors of immunity (IEI) that primarily affect B cells, offers us an opportunity to further our understanding of how B cells develop, mature, function and, in certain instances, cause further disease. In this review we provide a brief compendium of IEI that principally affect B cells at defined stages of their developmental pathway, and also attempt to offer some educated viewpoints on how the management of these disorders could evolve over the years.

In-utero exposure to immunosuppressive medications resulting in abnormal newborn screening for severe combined immunodeficiency: a case series on natural history and management.

Exposure to immunosuppressive medication in utero is an important cause of secondary T cell lymphopenia in infancy, which can be detected via T cell receptor excision circle (TREC) quantification on severe combined immunodeficiency (SCID) newborn screening (NBS). At present, there is a paucity of literature surrounding management of these infants. A protocol including recommendations for vaccinations and follow-up is needed to augment care. Patients referred to immunology for abnormal TREC results on NBS were identified as having in utero exposure to immunosuppressive medications and were followed until lymphopenia improved. The natural history of these patients' lymphopenia was used to develop general management guidelines. Four infants with low TRECs secondary to in utero immunosuppressive exposure were evaluated. Medication exposures included azathioprine, infliximab, hydroxychloroquine, and fingolimod. All infants were born full term. TRECs ranged from 101-206 (normal value in IL ≥ 250 at time of testing, B-actin control). T cell lymphopenia (CD3 < 1500) was present in 50% of cases. Undetectably low effector CD4 naïve T cell population was present in 100% of cases. Mitogen proliferation was uniformly normal. Severity of TREC abnormality did not correlate with presence of T cell lymphopenia. Immune abnormalities normalized in 75% patients by age 4 months. All age-appropriate vaccinations, including live vaccines, were administered to all patients by age 4 months. It is critical to assess for in utero immunosuppressive exposure in infants with abnormal TREC results on NBS. In the infants evaluated, secondary T cell lymphopenia associated with maternal immunosuppressive use resolved or significantly improved by age 4 months. Once abnormal TREC count is deemed to be secondary to in utero immunosuppression and there are no other contraindications, infants may safely receive live vaccination, are able to drink breast milk, and do not require prophylactic anti-microbials.