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Competing Interests: The author(s) declare no conflict of interest.

Gout is a common form of inflammatory arthritis characterized by the deposition of MSU in the joints and surrounding tissues, which results in inflammation and recurrent painful attacks. Currently, xanthine oxidase inhibitors, i.e., Allopurinol and Febuxostat, are used in the therapy. Recently, nanoparticles (NPs) containing metal oxides and non-metal oxides have also been developed to better manage gout. This comprehensive review summarizes the pathophysiology of gout, currently used drugs in the treatment, followed by emerging therapies for gout., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tuberculosis and Mental Illness (TB-MI) often co-occur with a varying range of interactions of both. The rising incidence of both in Low- and Middle-income countries (LMICs) is an emergent public health problem with accompanying higher morbidity and complications in management. The objective of this review is to gather insights into how healthcare providers can enhance their support for patients with TB-MI, to improve treatment adherence and overall health outcomes. Addressing the complexities of TB-MI treatment requires a multi-component approach that includes psychological interventions, monitoring the course of mental health comorbidities, patient education, looking into barriers to adherence, and involving healthcare providers. These coupled with increased patient awareness, integrated care model, patient education and empowerment, simplified treatment approaches, social support programs, and sensitizing healthcare providers can decrease the burden on the healthcare system while improving patient outcomes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Soumya Swaroop Sahoo reports was provided by All India Institute of Medical Sciences, Bathinda. Soumya Swaroop Sahoo reports a relationship with All India Institute of Medical Sciences, Bathinda that includes: employment., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Mental illness is a hidden epidemic in modern science that has gradually spread worldwide. According to estimates from the World Health Organization (WHO), approximately 10% of the world's population suffers from various mental diseases each year. Worldwide, financial and health burdens on society are increasing annually. Therefore, understanding the different factors that can influence mental illness is required to formulate novel and effective treatments and interventions to combat mental illness. Gut microbiota, consisting of diverse microbial communities residing in the gastrointestinal tract, exert profound effects on the central nervous system through the gut-brain axis. The gut-brain axis serves as a conduit for bidirectional communication between the two systems, enabling the gut microbiota to affect emotional and cognitive functions. Dysbiosis, or an imbalance in the gut microbiota, is associated with an increased susceptibility to mental health disorders and psychiatric illnesses. Gut microbiota is one of the most diverse and abundant groups of microbes that have been found to interact with the central nervous system and play important physiological functions in the human gut, thus greatly affecting the development of mental illnesses. The interaction between gut microbiota and mental health-related illnesses is a multifaceted and promising field of study. This review explores the mechanisms by which gut microbiota influences mental health, encompassing the modulation of neurotransmitter production, neuroinflammation, and integrity of the gut barrier. In addition, it emphasizes a thorough understanding of how the gut microbiome affects various psychiatric conditions., Competing Interests: Declaration of Competing Interest None to declare, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Personalized cancer therapeutics bring directed treatment options to patients based on their tumor's genetic signature. Unfortunately, tumor genomes are remarkably adaptable, and acquired resistance through gene mutation frequently occurs. Identifying mutations that promote resistance within drug-treated patient populations can be cost, resource, and time intensive. Accordingly, base editing, enabled by Cas9-deaminase domain fusions, has emerged as a promising approach for rapid, large-scale gene variant screening in situ. Here, we adapt and optimize a conditional activation-induced cytidine deaminase (AID)-dead Cas9 (dCas9) system, which demonstrates greater heterogeneity of edits with an expanded footprint compared to the most commonly utilized cytosine base editor, BE4. In combination with a custom single guide RNA (sgRNA) library, we identify individual and compound variants in epidermal growth factor receptor (EGFR) and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) that confer resistance to established EGFR inhibitors. This system and analytical pipeline provide a simple, highly scalable platform for cis or trans drug-modifying variant discovery and for uncovering valuable insights into protein structure-function relationships., Competing Interests: Declaration of interests All authors are or were previously full-time employees of Genentech and are shareholders of Roche., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Bromocriptine (BCR) presents poor bioavailability when administered orally because of its low solubility and prolonged first-pass metabolism. This poses a significant challenge in its utilization as an effective treatment for managing Parkinson's disease (PD). The utilization of lipid nanoparticles can be a promising approach to overcome the limitations of BCR bioavailability. The aim of the research work was to develop and evaluate bromocriptine-loaded solid lipid nanoparticles (BCR-SLN) and bromocriptine-loaded nanostructured lipid carriers (BCR-NLC) employing the Box-Behnken design (BBD). BCR-SLNs and BCR-NLCs were developed using the high-pressure homogenization method. The prepared nanoparticles were characterized for particle size (PS), polydispersity index (PDI), and entrapment efficiency (EE). In vitro drug release, cytotoxicity studies, in vivo plasma pharmacokinetic, and brain distribution studies evaluated the optimized lipid nanoparticles. The optimized BCR-SLN had a PS of 219.21 ± 1.3 nm, PDI of 0.22 ± 0.02, and EE of 72.2 ± 0.5. The PS, PDI, and EE of optimized BCR-NLC formulation were found to be 182.87 ± 2.2, 0.16 ± 0.004, and 83.57 ± 1.8, respectively. The in vitro release profile of BCR-SLN and BCR-NLC showed a biphasic pattern, immediate release, and then trailed due to the sustained release. Furthermore, a pharmacokinetic study indicated that both the optimized BCR-SLN and BCR-NLC formulations improve the plasma and brain bioavailability of the drug compared to the BCR solution. Based on the research findings, it can be concluded that the BCR-loaded lipid nanoparticles could be a promising carrier by enhancing the BBB penetration of the drug and helping in the improvement of the bioavailability and therapeutic efficacy of BCR in the management of PD.

Depression is a complex psychiatric disorder influenced by various genetic and environmental factors. Strong evidence has established the contribution of genetic factors in depression through twin studies and the heritability rate for depression has been reported to be 37%. Genetic studies have identified genetic variations associated with an increased risk of developing depression. Imaging genetics is an integrated approach where imaging measures are combined with genetic information to explore how specific genetic variants contribute to brain abnormalities. Neuroimaging studies allow us to examine both structural and functional abnormalities in individuals with depression. This review has been designed to study the correlation of the significant genetic variants with different regions of neural activity, connectivity, and structural alteration in the brain as detected by imaging techniques to understand the scope of biomarkers in depression. This might help in developing novel therapeutic interventions targeting specific genetic pathways or brain circuits and the underlying pathophysiology of depression based on this integrated approach can be established at length., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the intricate landscape of cellular function, proper protein folding is pivotal for cellular processes, particularly within the endoplasmic reticulum (ER). In a recent study, Ko et al. reveal a signaling role for inositol-requiring enzyme 1 (IRE1) in ER stress and identify PHOSPHATASE TYPE 2CA (PP2CA)-INTERACTING RING FINGER PROTEIN 1 (PIR1) as a crucial plant-specific regulator, balancing the unfolded protein response (UPR) and ubiquitin-proteasome system (UPS) by modulating ABI5 stability, unveiling intricate stress response connections., Competing Interests: Declaration of interests None declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Managing critically ill neonates has unique challenges, and the transport team plays an important role in stabilizing and facilitating the transfer of these neonates from lower-level nurseries to tertiary centers, and the use of telemedicine in transport (tele-transport) can potentially benefit patient care. We conducted a multicenter study to assess the readiness for utilizing telemedicine as an adjunct to guide the care of critically ill neonates among physicians and transport team members (TTMs). This is the first multicenter study that explored physicians' and TTMs' perceptions of telemedicine usage and its value in neonatal transport., Methods: A confidential, voluntary survey on pre-implementation attitudes toward telemedicine usage during neonatal transport was conducted as part of a quality improvement initiative. This survey involved physicians and TTMs from four academic institutions whose responses were entered into an online survey using REDCap®. The survey inquired about satisfaction with the current practice of phone consultation and the perception of using telemedicine to optimize the management of neonates during transport., Results: The overall response rate for the survey was 60.1%; 82 of 127 (64.6%) physicians and 64 of 116 (55.2%) TTMs responded to the surveys. Half of the physicians and less than one-fourth of the TTMs had prior experience with telemedicine other than that used on neonatal transport. TTMs expressed greater concern about the inconvenience of video (55% vs. physicians 35% agree or strongly agree ) and its time consumption (84% vs. physicians 50%). More than 70% of physicians and less than half of TTMs endorsed the potential for added value and quality improvement with video capability. Almost half of TTMs reported concern about video calls reducing their autonomy in patient care. Physicians expressed confidence in management decisions they would make after video calls (72% confident or very confident ) and less confidence (49%) about both the phone assessment by TTMs and their decisions based on phone assessment. In contrast, TTMs were confident or very confident (94%) in both sharing their assessment over the phone and executing patient management after a phone call, compared with 70% for decisions made after video calls., Conclusions: Physicians and TTMs had distinct opinions on the use of telemedicine during neonatal transport. Physicians were more likely than TTMs to agree with statements about the potential for improving quality of care, while TTMs were more likely than physicians to say video calls would be time-consuming and inconvenient. We speculate some differences may stem from the TTMs' concern about losing their autonomy. Therefore, during implementation, it is critical for physicians and TTMs to agree on a shared mental model of indications for telemedicine during transport and its value to the patient care., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Outpatient clinical notes are a rich source of information regarding drug safety. However, data in these notes are currently underutilized for pharmacovigilance due to methodological limitations in text mining. Large language models (LLMs) like Bidirectional Encoder Representations from Transformers (BERT) have shown progress in a range of natural language processing tasks but have not yet been evaluated on adverse event (AE) detection. We adapted a new clinical LLM, University of California - San Francisco (UCSF)-BERT, to identify serious AEs (SAEs) occurring after treatment with a non-steroid immunosuppressant for inflammatory bowel disease (IBD). We compared this model to other language models that have previously been applied to AE detection. We annotated 928 outpatient IBD notes corresponding to 928 individual patients with IBD for all SAE-associated hospitalizations occurring after treatment with a non-steroid immunosuppressant. These notes contained 703 SAEs in total, the most common of which was failure of intended efficacy. Out of eight candidate models, UCSF-BERT achieved the highest numerical performance on identifying drug-SAE pairs from this corpus (accuracy 88-92%, macro F1 61-68%), with 5-10% greater accuracy than previously published models. UCSF-BERT was significantly superior at identifying hospitalization events emergent to medication use (P < 0.01). LLMs like UCSF-BERT achieve numerically superior accuracy on the challenging task of SAE detection from clinical notes compared with prior methods. Future work is needed to adapt this methodology to improve model performance and evaluation using multicenter data and newer architectures like Generative pre-trained transformer (GPT). Our findings support the potential value of using large language models to enhance pharmacovigilance., (© 2024 The Authors. Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis -isomer ( 2 ) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27 , which demonstrated measurable cell activity, albeit only at high concentrations., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Ferritin is a multivalent, self-assembling protein scaffold found in most human cell types, in addition to being present in invertebrates, higher plants, fungi, and bacteria, that offers an attractive alternative to polymer-based drug delivery systems (DDS). In this study, the utility of the ferritin cage as a DDS was demonstrated within the context of T cell agonism for tumor killing. Members of the tumor necrosis factor receptor superfamily (TNFRSF) are attractive targets for the development of anticancer therapeutics. These receptors are endogenously activated by trimeric ligands that occur in transmembrane or soluble forms, and oligomerization and cell-surface anchoring have been shown to be essential aspects of the targeted agonism of this receptor class. Here, we demonstrated that the ferritin cage could be easily tailored for multivalent display of anti-OX40 antibody fragments on its surface and determined that these arrays are capable of pathway activation through cell-surface clustering. Together, these results confirm the utility, versatility, and developability of ferritin as a DDS.

Objectives: This study aimed to report the demographic features, clinical presentation, pathological types and long-term outcomes of patients diagnosed with endometrial cancer (EC) in Oman. EC is the sixth most common cancer in women worldwide and the fifth most common cancer in women in Oman. Survival outcomes of EC have not been reported previously from Oman., Methods: This retrospective study was carried out on consecutive patients treated at the Sultan Qaboos University Hospital, Muscat, Oman, between 2008 and 2020. Survival was estimated using the Kaplan and Meier method., Results: A total of 50 patients with EC were included. The median age was 61 years (range: 31-86 years), and 72% of the patients had type I histology. Most patients were diagnosed with stage IA and IB EC (49% and 20%, respectively), and the majority had grade 1 or 2 tumours (40% and 34%, respectively). Overall, the 5-year survival and 10-year survival rates were estimated to be 70% and 56%, respectively. Weight (>75 kg) and body mass index (>30 kg/m 2 ) were significantly associated with better survival. Tumour histology (type I versus type II or carcinosarcoma), grade (1 versus 2 versus 3) and stage (IA or IB versus II-IV) were associated with better overall survival ( P = 0.007, P <0.0001 and P <0.0003, respectively). Patients diagnosed with EC with co-morbidities, other than obesity, had inferior survival compared to those without co-morbidities., Conclusion: Median age at presentation, histological sub-type, clinical stage and outcomes are comparable to the published literature. Almost two-thirds of the patients were obese. These data could be used as a benchmark for outcomes of EC in the region., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (© Copyright 2024, Sultan Qaboos University Medical Journal, All Rights Reserved.)

Strigolactones (SLs) are fundamental to the ability of plants to cope with phosphate deficiency. A recent study by Yuan et al. indicates that the genetic module PHR2/NSP1/NSP2 is crucial in activating SL biosynthesis and signaling under inorganic phosphate (Pi) deficiency. Furthermore, this genetic module is essential for improving Pi and nitrogen homeostasis in rice., Competing Interests: Declaration of interests The authors declare that this manuscript was written without any commercial or financial relationship that could be constructed as a potential conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time., Methods: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed., Results: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1., Conclusions: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker., (© 2024. The Author(s).)

Competing Interests: There are no conflicts of interest.

This concise review navigates the intricate realm of Interleukin-6 (IL-6), an important member of the cytokine family. Beginning with an introduction to cytokines, this narrative review unfolds with the historical journey of IL-6, illuminating its evolving significance. A crucial section unravels the three distinct signaling modes employed by IL-6, providing a foundational understanding of its versatile interactions within cellular landscapes. Moving deeper, the review meticulously dissects IL-6's signaling mechanisms, unraveling the complexities of its pleiotropic effects in both physiological responses and pathological conditions. A significant focus is dedicated to the essential role IL-6 plays in inflammatory diseases, offering insights into its associations and implications for various health conditions. The review also takes a therapeutic turn by exploring the emergence of anti-IL-6 monoclonal inhibitors, marking a profound stride in treatment modalities. Diving into the molecular realm, the review explores small molecules as agents for IL-6 inhibition, providing a nuanced perspective on diverse intervention strategies. As the review embarks on the final chapters, it contemplates future aspects, offering glimpses into potential research trajectories and the evolving landscape of IL-6-related studies., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Human papillomavirus (HPV) is associated with cervical cancer and cervical dysplasia worldwide. Data on HPV prevalence in a region is important because it serves as a predictor of the likelihood of the population in that particular region acquiring cervical cancer. Moreover, with the availability of effective vaccines, the public health system must be aware of the preponderance of HPV to implement the vaccine. The present study was designed to understand the prevalence of HPV and associated factors among the women of South Andaman Island., Methods: A cross-sectional study was conducted among married women of reproductive age (18-59 years) from South Andaman District from 2018 to 2022. Cervical scrapes were collected from participants after obtaining informed written consent for HPV molecular testing (HPV DNA) such as PCR assay. Demographic data was collected using a standard questionnaire and statistical analyses were performed to determine the associated factors., Results: The study showed prevalence of HPV as 5.9%(95% CI: 3.9-7.9) and prevalence of HR-HPV16 was 4.1% (95% CI 2.6 - 5.5) and HR-HPV18 prevalence was 1.8(95% CI: 0.6-3). The independent factors associated the HPV positivity were age above 55 years, menopause, post-menopausal bleeding, blood-stained vaginal discharge and loss of weight. Age was associated with all HPV infections among the South Andaman women., Conclusions: HPV 16 was reported as the predominant high risk HPV type circulating among women of South Andaman. Cervical cancer and precancerous lesions were significantly associated with HPV positivity and High risk HPV 16. Based on the knowledge of the risk factors associated with HPV, implementation of stronger public health awareness and prophylactic HPV vaccination is crucial among the women of this remote island., (© 2024. The Author(s).)

Craniomaxillofacial trauma is primarily diagnosed and managed by oral and maxillofacial surgeons. Among the cases encountered, midface fractures involving orbital walls are highly prevalent. In these fractures, involvement of the orbital walls, particularly floor of the orbit, can lead to considerable aesthetic and functional limitations. From a maxillofacial perspective, indications for surgical repair of orbital floor encompass marked decrease in ocular motility, fracture affecting more than 50% of surface area, an increase in orbital volume exceeding 18% and enophthalmos greater than 2 mm. In the absence of these discernible signs, surgical intervention is not generally indicated. However, in this case, an early adolescent with a history of midface trauma and minimal orbital floor fracture 8 months earlier presented with progressively delayed onset enophthalmos and hypoglobus closely resembling features of silent sinus syndrome. The enophthalmos and hypoglobus were corrected by placing custom-made non-resorbable high-density polyethylene implant in the orbital floor. Postoperative follow-up demonstrated aesthetically and functionally satisfactory outcomes., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine the correlation of lymphocyte subsets and soluble serum inflammatory biomarkers with disease severity in coronavirus disease-2019 infection., Methods: The retrospective study was conducted at the Department of Immunology, Sindh Institute of Urology and Transplantation (SIUI), Karachi, Pakistan from September 1 to November 30, 2021, and comprised data of patients admitted from June to July 2021 who tested positive for coronavirus disease-2019 on the basis of reverse transcription-polymerase chain reaction of nasopharyngeal swab specimens. The patients were categorised into severe group A and non-severe group B. Initial investigations included complete blood count, neutrophil-to-lymphocytes ratio, C-reactive protein, D-Dimers and serum ferritin levels. Lymphocyte subsets included cluster of differentiation-3+, cluster of differentiation-4+/ cluster of differentiation-3+, cluster of differentiation-8+ T lymphocytes, cluster of differentiation-19+B lymphocytes, cluster of differentiation-16+ cluster of differentiation-56+ Natural Killer cells and serum cytokine levels of interleukin-2, interleukin- 4, interleukin-6, interleukin-10, tumour necrosis factor-alpha and interferon gamma. They were correlated with disease severity. Data was analysed using SPSS 20., Results: Of the 54 patients, 33(61.1%) were males and 21(38.9%) were females. There were 29(53.70%) patients in group A with median age 52 years (interquartile range: 43.5-65 years), and 25(46.29%) in group B with median age 50 years (interquartile range: 36.5-59 years) (p=0.241). Disease was significantly more severe in male patients compared to female (p=0.002). In group A, cluster of differentiation-3+ T cells were reduced in 21(72.4%) patients, cluster of differentiation-8+ T cells in 16(55.2%), cluster of differentiation-4+ T cells in 23(79.3%) and cluster of differentiation-19+ B cells in 8(27.6%). In group B, cluster of differentiation-3+ T cells were reduced in 10(40%) subjects, cluster of differentiation-8+ T cells in 7(28%), cluster of differentiation-4+ T cells in 12(48%) and cluster of differentiation-19+ B cells in 4(16%) patients. Serum cytokine levels were not significantly different between the groups (p>0.05). In group A, 7(24.13%) patients died, and in such cases, the neutrophil-to-lymphocytes ratio was significantly higher (p=0.037)., Conclusion: Pro-inflammatory markers and cytokine levels increased, while lymphocyte subsets decreased with increasing severity of the disease.

Background: Restless legs syndrome (RLS) is a neuro-sensorimotor disorder which is scarcely researched and is commonly missed in routine psychiatry practice., Aim: To evaluate the prevalence of RLS and its correlates in patients with anxiety, depression, and somatoform disorders., Methods: A cross-sectional single-center study was undertaken in patients aged 18-65 years suffering from ICD-10 (International Statistical Classification of Diseases-10 th edition) diagnosis of anxiety, depressive, and somatoform disorders. RLS was evaluated by using diagnostic criteria of International Restless Legs Syndrome Study Group (IRLSSG) and severity measured on IRLSSG scale. Depression and anxiety were rated on Hamilton Depression and Anxiety Rating Scales respectively, insomnia severity measured by Insomnia Severity Index (ISI), and quality of life measured by WHO Quality of Life-Brief version (WHO-QOL BREF) scale. Serum ferritin levels were measured for evaluating iron deficiency., Results: The rate of RLS was 66.7%, 50%, and 48% in patients with depressive, anxiety, and somatoform disorders, respectively, with no significant inter-group difference. Nearly one-third of patients suffered from severe to very severe symptoms of RLS, and quality of life was poorest in those with depressive disorders. RLS was significantly higher in females ( P = 0.019), who were married ( P = 0.040), diagnosed with severe depression ( P = 0.029), and abused benzodiazepines ( P = 0.045). On binary logistic regression, female gender and presence of clinical insomnia predicted occurrence of RLS., Conclusion: The prevalence of RLS is very high in patients with common psychiatric disorders which is often missed. Clinical enquiry and examination for reversible causes such as iron deficiency may assist in its diagnosis and improve clinical outcome., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Psychiatry.)

Objective: To investigate the impact of testosterone replacement therapy (TRT) on cardiovascular outcomes in hypogonadal men., Methods: A meta-analysis of 26 randomized controlled trials involving 10 941 participants was conducted. Various clinical outcomes, including all-cause mortality, cardiovascular-related mortality, myocardial infarction, stroke, congestive heart failure, atrial fibrillation, pulmonary embolism, and venous thrombosis, were assessed., Results: No statistically significant differences were observed between the TRT group and the control group in terms of these clinical outcomes. Sensitivity analysis and publication bias assessment supported the robustness of the findings. Meta-regression analysis found no significant associations between clinical outcomes and potential covariates, including age, diabetes, hypertension, dyslipidemia, and smoking., Discussion: Previous research on TRT and cardiovascular events, with comparisons to studies like the Testosterone Trials and the studies conducted by Vigen et al, Finkle et al, Layton et al, and Wallis et al, is provided. The significance of the systematic review and meta-analysis approach is emphasized, particularly its exclusive focus on hypogonadal patients., Conclusion: This study offers reassurance that TRT does not increase mortality risk or worsen cardiovascular outcomes in hypogonadal men. However, further research, especially long-term studies involving diverse populations, is essential to strengthen the evidence base and broaden the applicability of these findings., Competing Interests: Disclosure The authors have no multiplicity of interest to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Background: The use of telemedicine to provide care for critically ill newborn infants has significantly evolved over the last two decades. Children's Health System of Texas and University of Texas Southwestern Medical Center established TeleNICU, the first teleneonatology program in Texas., Objective: To evaluate the effectiveness of Tele Neonatal Intensive Care Unit (TeleNICU) in extending quaternary neonatal care to more rural areas of Texas., Materials and Methods: We conducted a retrospective review of TeleNICU consultations from September 2013 to October 2018. Charts were reviewed for demographic data, reasons for consultation, and consultation outcomes. Diagnoses were classified as medical, surgical, or combined. Consultation outcomes were categorized into transferred or retained. Transport cost savings were estimated based on the distance from the hub site and the costs for ground transportation., Results: TeleNICU had one hub (Level IV) and nine spokes (Levels I-III) during the study period. A total of 132 direct consultations were completed during the study period. Most consultations were conducted with Level III units (81%) followed by level I (13%) and level II (6%) units. Some common diagnoses included prematurity (57%), respiratory distress (36%), congenital anomalies (25%), and neonatal surgical emergencies (13%). For all encounters, 54% of the patients were retained at the spoke sites, resulting in an estimated cost savings of USD0.9 million in transport costs alone. The likelihood of retention at spoke sites was significantly higher for medical diagnoses compared to surgical diagnoses (89% vs. 11%)., Conclusion: Telemedicine effectively expands access to quaternary neonatal care for more rural communities, helps in the triage of neonatal transfers, promotes family centered care, and significantly reduces health care costs., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cardiogenic shock (CS) may have a negative impact on mortality in patients with heart failure (HF) or acute myocardial infarction (AMI). Early prediction of CS can result in improved survival. Artificial intelligence (AI) through machine learning (ML) models have shown promise in predictive medicine. Here, we conduct a systematic review and meta-analysis to assess the effectiveness of these models in the early prediction of CS. A thorough search of the PubMed, Web of Science, Cochrane, and Scopus databases was conducted from the time of inception until November 2, 2023, to find relevant studies. Our outcomes were area under the curve (AUC), the sensitivity and specificity of the ML model, the accuracy of the ML model, and the predictor variables that had the most impact in predicting CS. Comprehensive Meta-Analysis (CMA) Version 3.0 was used to conduct the meta-analysis. Six studies were considered in our study. The pooled mean AUC was 0.808 (95% confidence interval: 0.727, 0.890). The AUC in the included studies ranged from 0.77 to 0.91. ML models performed well, with accuracy ranging from 0.88 to 0.93 and sensitivity and specificity of 58%-78% and 88%-93%, respectively. Age, blood pressure, heart rate, oxygen saturation, and blood glucose were the most significant variables required by ML models to acquire their outputs. In conclusion, AI has the potential for early prediction of CS, which may lead to a decrease in the high mortality rate associated with it. Future studies are needed to confirm the results., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Popat et al.)

As breast cancer remains leading cause of cancer death globally, it is essential to develop an affordable breast cancer therapy in underdeveloped countries. Drug repurposing offers potential to address gaps in breast cancer treatment. Molecular networking studies were performed for drug repurposing approach by using heterogeneous data. The PPI networks were built to select the target genes from the EGFR overexpression signaling pathway and its associated family members. The selected genes EGFR, ErbB2, ErbB4 and ErbB3 were allowed to interact with 2637 drugs, leads to PDI network construction of 78, 61, 15 and 19 drugs, respectively. As drugs approved for treating non cancer-related diseases or disorders are clinically safe, effective, and affordable, these drugs were given considerable attention. Calcitriol had shown significant binding affinities with all four receptors than standard neratinib. The RMSD, RMSF, and H-bond analysis of protein-ligand complexes from molecular dynamics simulation (100 ns), confirmed the stable binding of calcitriol with ErbB2 and EGFR receptors. In addition, MMGBSA and MMP BSA also affirmed the docking results. These in-silico results were validated with in-vitro cytotoxicity studies in SK-BR-3 and Vero cells. The IC50 value of calcitriol (43.07 mg/ml) was found to be lower than neratinib (61.50 mg/ml) in SK-BR-3 cells. In Vero cells the IC50 value of calcitriol (431.05 mg/ml) was higher than neratinib (404.95 mg/ml). It demonstrates that calcitriol suggestively downregulated the SK-BR-3 cell viability in a dose-dependent manner. These implications revealed calcitriol has shown better cytotoxicity and decreased the proliferation rate of breast cancer cells than neratinib.Communicated by Ramaswamy H. Sarma.

Developing biomaterials for hip prostheses is challenging and requires dedicated attention from researchers. Hip replacement is an inevitable and remarkable orthopedic therapy for enhancing the quality of patient life for those who have arthritis as well as trauma. Generally, five types of hip replacement procedures are successfully performed in the current medical market: total hip replacements, hip resurfacing, hemiarthroplasty, bipolar, and dual mobility systems. The average life span of artificial hip joints is about 15 years, and several studies have been conducted over the last 60 years to improve the performance and thereby increase the lifespan of artificial hip joints. Present-day prosthetic hip joints are linked to the wide availability of biomaterials. Metals, ceramics, and polymers are some of the most promising types of biomaterials; nevertheless, each biomaterial has advantages and disadvantages. Metals and ceramics fail in most applications owing to stress shielding and the emission of wear debris; ongoing research is being carried out to find a remedy to these unfavorable responses. Recent research found that polymers and composites based on polymers are significant alternative materials for artificial joints. With growing research and several biomaterials, recent reviews lag in effectively addressing hip implant materials' individual mechanical, tribological, and physiological behaviors. This Review comprehensively investigates the historical evolution of artificial hip replacement procedures and related biomaterials' mechanical, tribological, and biological characteristics. In addition, the most recent advances are also discussed to stimulate and guide future researchers as they seek more effective methods and synthesis of innovative biomaterials for hip arthroplasty application.

Background: Breastfeeding is a critical health intervention in infants. Recent literature reported that the COVID-19 pandemic resulted in significant mental health issues in pregnant and breastfeeding women due to social isolation and lack of direct professional support. These maternal mental health issues affected infant nutrition and decreased breastfeeding rates during COVID-19. Twitter, a popular social media platform, can provide insight into public perceptions and sentiment about various health-related topics. With evidence of significant mental health issues among women during the COVID-19 pandemic, the perception of infant nutrition, specifically breastfeeding, remains unknown., Methods: We aimed to understand public perceptions and sentiment regarding breastfeeding during the COVID-19 pandemic through Twitter analysis using natural language processing techniques. We collected and analyzed tweets related to breastfeeding and COVID-19 during the pandemic from January 2020 to May 2022. We used Python software (v3.9.0) for all data processing and analyses. We performed sentiment and emotion analysis of the tweets using natural language processing libraries and topic modeling using an unsupervised machine-learning algorithm., Results: We analyzed 40,628 tweets related to breastfeeding and COVID-19 generated by 28,216 users. Emotion analysis revealed predominantly "Positive emotions" regarding breastfeeding, comprising 72% of tweets. The overall tweet sentiment was positive, with a mean weekly sentiment of 0.25 throughout, and was affected by external events. Topic modeling revealed six significant themes related to breastfeeding and COVID-19. Passive immunity through breastfeeding after maternal vaccination had the highest mean positive sentiment score of 0.32., Conclusions: Our study provides insight into public perceptions and sentiment regarding breastfeeding during the COVID-19 pandemic. Contrary to other topics we explored in the context of COVID (e.g., ivermectin, disinformation), we found that breastfeeding had an overall positive sentiment during the pandemic despite the documented rise in mental health challenges in pregnant and breastfeeding mothers. The wide range of topics on Twitter related to breastfeeding provides an opportunity for active engagement by the medical community and timely dissemination of advice, support, and guidance. Future studies should leverage social media analysis to gain real-time insight into public health topics of importance in child health and apply targeted interventions., (© 2023. The Author(s).)

Background: The COVID-19 pandemic has created an unprecedented situation which the treatment of maxillofacial trauma, especially mandibular fractures that were previously managed using general anaesthesia had to be performed under local anaesthesia. In these cases, there was a requirement for an anaesthetic agent that would have a rapid onset but also provide a prolonged effect. The aim of the study was to evaluate the onset, duration, depth, required volume of anaesthesia of lidocaine with epinephrine versus combination of lidocaine and bupivacaine with epinephrine anaesthetic agents in surgical management of isolated mandibular fracture patients., Methods: A total of 30 patients with isolated mandibular fractures reported to our hospital included the study group. Patients were randomly distributed to two groups, Group A and Group B. Group A received local anaesthesia using 2% Lidocaine with 1:80,000 adrenaline and Group B received 0.5% Bupivacaine with 1:2,00,000 adrenaline combined with 2% Lidocaine with 1:80,000 adrenaline at a ratio of 1:1. The outcome variables were recorded and the data was tabulated and analysed using un-paired students t test., Results: The combination of anaesthetic agents had longer duration of action (mean: 182.47 min, P-value: 0.001) and required lesser volume of anaesthetic solutions (mean: 5.38 mL, P-value: 0.001) as compared to usage of lidocaine alone. Although combination group showed quicker onset (mean: 4 min 8 s), the result was insignificant (p-value: 0.345)., Conclusion: The study found that the combination of lidocaine and bupivacaine could serve as a potential anaesthetic cocktail in effective surgical management of isolated mandibular fractures., Clinical Relevance: Maxillofacial injuries can be managed efficiently under local anaesthesia using combination of lidocaine and bupivacaine., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response., Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy., (©2023 The Authors; Published by the American Association for Cancer Research.)

Competing Interests: There are no conflicts of interest.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice ( Hnf4a ΔIEC ) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4a ΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4a ΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4-5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4a ΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4a ΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4a ΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4a ΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. IMPORTANCE The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes., Competing Interests: The authors declare no conflict of interest.

Background: Human Papillomavirus (HPV) causes various types of cancer in both men and women. Woman with HPV infection has a risk of developing invasive cervical cancer. Globally, HPV 16 and 18 were predominant. This study aims to find the distribution of various HPV types in South Andaman., Methods: A cross-sectional study was conducted among women in South Andaman, where cervical scrapes were collected after collecting written informed consent. Detection of HPV genotypes was carried out by using a PCR assay. Further, sequencing analysis was performed using MEGA11 to identify various genotypes in this territory., Result: Of these 1000 samples, 32 were positive for HR-HPV 16, and four were positive for HR-HPV 18. Fifteen HPV genotypes were detected using molecular evolutionary analysis. Six cases were identified with multiple genotypes. The most prevalent genotype is HPV 16 which belongs to Lineage-A and sub-lineage A2. HPV 18 identified in South Andaman belonged to the lineage A1 to A5., Discussion: Various HPV types were identified among women in South Andaman. Global burden of cervical cancer associated with various HPV sub-lineages. HPV-16 A1 sub-lineage was globally widespread, whereas sub-lineages A1, A2 and D1 prevailed in South Andaman., Conclusions: HR-HPV identified in this study enlightens the importance of HPV vaccination among women in remote places. These findings will help to strengthen public health awareness programs and prevention strategies for women in remote areas.

Many plants associate with arbuscular mycorrhizal (AM) fungi for nutrient acquisition, and most legumes also associate with nitrogen-fixing rhizobial bacteria for nitrogen acquisition. The association of plants with AM fungi and rhizobia depends on the perception of lipo-chitooligosaccharides (LCOs) produced by these micro-symbionts. Recent studies reveal that cereals can perceive LCOs better in soil deprived of phosphate (Pi) and nitrogen to activate symbiosis signaling and form efficient AM symbiosis. Nevertheless, the Pi deficiency in the soil hinders the symbiotic association of legumes with rhizobia, ultimately reducing nitrogen fixation. Here, we discuss a mechanistic overview of the factors regulating root nodule symbiosis under Pi-deficient conditions and further emphasize the possible ways to overcome this hurdle. Ignoring the low Pi problem not only can compromise the functionality of the nitrogen cycle by nitrogen fixation through legumes but can also put food security at risk globally. This review aims to bring the scientific community's attention toward the detrimental response of legumes toward Pi-deficient soil for the formation of root nodule symbiosis and hence reduced nitrogen fixation. In this review, we have highlighted the recent studies that have advanced our understanding of these critical areas and discussed some future directions. Furthermore, this review highlights the importance of communicating science with farmers and the agriculture community to fully harness the potential of the symbiotic association of plants in nutrient-deficient soil for sustainable agriculture., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objective : Constipation is a prevalent gastrointestinal condition that has a substantial impact on individuals and healthcare systems. This condition adversely affects health-related quality of life and leads to escalated healthcare expenses due to an increase in office visits, referrals to specialists, and hospital admission. This study aimed to evaluate the prevalence, recognition, risk factors, and course of constipation among hospitalized patients in medical wards. Materials and Methods: A prospective study was conducted, including all adult patients admitted to the General Medicine Unit between 1 February 2022 and 31 August 2022. Constipation was identified using the Constipation Assessment Scale (CAS), and relevant factors were extracted from the patients' medical records. Results: Among the patients who met the inclusion criteria (n = 556), the prevalence of constipation was determined to be 55.6% (95% CI 52.8-58.4). Patients with constipation were found to be older ( p < 0.01) and had higher frailty scores ( p < 0.01). Logistic regression analysis revealed that heart failure (Odds ratio (OR) 2.1; 95% CI 1.2-3.7; p = 0.01), frailty score (OR 1.4; 95% CI 1.2-1.5; p < 0.01), and dihydropyridines calcium channel blockers (OR 1.8; 95% CI 1.2-2.8; p < 0.01) were independent risk factors for constipation. Furthermore, the medical team did not identify constipation in 217 patients (64.01%). Conclusions: Constipation is highly prevalent among medically hospitalized patients. To ensure timely recognition and treatment, it is essential to incorporate a daily constipation assessment scale into each patient's medical records.

Background: Surgical extraction of impacted mandibular third molars is the most common procedure performed by oral surgeons. The procedure cannot be performed effectively without achieving profound anesthesia. During this procedure, patients may feel pain during surgical bone removal (at the cancellous level) or during splitting and luxation of the tooth, despite administration of routine nerve blocks. Administration of intraosseous (IO) lignocaine injections during third molar surgeries to provide effective anesthesia for pain alleviation has been documented. However, whether the anesthetic effect of lignocaine is the only reason for pain alleviation when administered intraosseously remains unclear. This conundrum motivated us to assess the efficacy of IO normal saline versus lignocaine injections during surgical removal of impacted mandibular third molars. The aim of this study was to assess the efficacy of IO normal saline as a viable alternative or adjunct to lignocaine for alleviation of intraoperative pain during surgical removal of impacted mandibular third molars., Methods: This randomized, double-blind, interventional study included 160 patients who underwent surgical extraction of impacted mandibular third molars and experienced pain during surgical removal of the buccal bone or sectioning and luxation of the tooth. The participants were divided into two groups: the study group, which included patients who would receive IO saline injections, and the control group, which included patients who would receive IO lignocaine injections. Patients were asked to complete a visual analog pain scale (VAPS) at baseline and after receiving the IO injections., Results: Of the 160 patients included in this study, 80 received IO lignocaine (control group), whereas 80 received IO saline (study group) following randomization. The baseline VAPS score of the patients and controls was 5.71 ± 1.33 and 5.68 ± 1.21, respectively. The difference between the baseline VAPS scores of the two groups was not statistically significant (P > 0.05). The difference between the numbers of patients who experienced pain relief following administration of IO lignocaine (n=74) versus saline (n=69) was not statistically significant (P > 0.05). The difference between VAPS scores measured after IO injection in both groups was not statistically significant (P >0.05) (1.05 ± 1.20 for the control group vs. 1.72 ± 1.56 for the study group)., Conclusion: The study demonstrates that IO injection of normal saline is as effective as lignocaine in alleviating pain during surgical removal of impacted mandibular third molars and can be used as an effective adjunct to conventional lignocaine injection., Competing Interests: DECLARATION OF INTERESTS: The authors have no conflicts of interest to declare., (Copyright © 2023 Journal of Dental Anesthesia and Pain Medicine.)

Wnt ligands are critical for tissue homeostasis and form a complex with LRP6 and frizzled coreceptors to initiate Wnt/β-catenin signaling. Yet, how different Wnts achieve various levels of signaling activation through distinct domains on LRP6 remains elusive. Developing tool ligands that target individual LRP6 domains could help elucidate the mechanism of Wnt signaling regulation and uncover pharmacological approaches for pathway modulation. We employed directed evolution of a disulfide constrained peptide (DCP) to identify molecules that bind to the third β-propeller domain of LRP6. The DCPs antagonize Wnt3a while sparing Wnt1 signaling. Using PEG linkers with different geometries, we converted the Wnt3a antagonist DCPs to multivalent molecules that potentiated Wnt1 signaling by clustering the LRP6 coreceptor. The mechanism of potentiation is unique as it occurred only in the presence of extracellular secreted Wnt1 ligand. While all DCPs recognized a similar binding interface on LRP6, they displayed different spatial orientations that influenced their cellular activities. Moreover, structural analyses revealed that the DCPs exhibited new folds that were distinct from the parent DCP framework they were evolved from. The multivalent ligand design principles highlighted in this study provide a path for developing peptide agonists that modulate different branches of cellular Wnt signaling.

Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Key Message: We highlight the newly emerged regulatory role of a mitotic kinase AUR1, its activator, and its microtubule-associated proteins (MAPs) in infection thread formation for root nodule symbiosis., (© 2023. The Author(s).)

Main Conclusion: Lysin motif (LysM)-receptor-like kinase (RLK) and leucine-rich repeat (LRR)-RLK mediated signaling play important roles in the development and regulation of root nodule symbiosis in legumes. The availability of water and nutrients in the soil is a major limiting factor affecting crop productivity. Plants of the Leguminosae family form a symbiotic association with nitrogen-fixing Gram-negative soil bacteria, rhizobia for nitrogen fixation. This symbiotic relationship between legumes and rhizobia depends on the signal exchange between them. Plant receptor-like kinases (RLKs) containing lysin motif (LysM) and/or leucine-rich repeat (LRR) play an important role in the perception of chemical signals from rhizobia for initiation and establishment of root nodule symbiosis (RNS) that results in nitrogen fixation. This review highlights the diverse aspects of LysM-RLK and LRR receptors including their specificity, functions, interacting partners, regulation, and associated signaling in RNS. The activation of LysM-RLKs and LRR-RLKs is important for ensuring the successful interaction between legume roots and rhizobia. The intracellular regions of the receptors enable additional layers of signaling that help in the transduction of signals intracellularly. Additionally, symbiosis receptor-like kinase (SYMRK) containing the LRR motif acts as a co-receptor with Nod factors receptors (LysM-RLK). Cleavage of the malectin-like domain from the SYMRK ectodomain is a mechanism for controlling SYMRK stability. Overall, this review has discussed different aspects of legume receptors that are critical to the perception of signals from rhizobia and their subsequent role in creating the mutualistic relationship necessary for nitrogen fixation. Additionally, it has been discussed how crucial it is to extrapolate the knowledge gained from model legumes to crop legumes such as chickpea and common bean to better understand the mechanism underlying nodule formation in crop legumes. Future directions have also been proposed in this regard., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Nodule cysteine-rich (NCR) peptides have a major role in the differentiation of endocytosed bacteria into nitrogen-fixing bacteroids. A recent paper by Sankari et al. indicates that NCR247 is essential for the uptake of iron, a mineral nutrient required for nitrogenase activity. Furthermore, the special ability of NCR247 to sequester haem suggests potential applications for human health., Competing Interests: Declaration of interests The authors declare that this manuscript was written in the absence of any commercial or financial relationship that could be constructed as a potential conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Legumes form a symbiotic association with rhizobia and fix atmospheric nitrogen in specialized root organs known as nodules. It is well known that salt stress inhibits root nodule symbiosis by decreasing rhizobial growth, rhizobial infection, nodule number, and nitrogenase activity in diverse legumes. Despite this knowledge, the genetic and molecular mechanisms governing salt stress's inhibition of nodulation and nitrogen fixation are still elusive. In this Viewpoint, we summarize the most recent knowledge of the genetic mechanisms that shape this symbiosis according to the salt levels in the soil. We emphasize the relevance of modulating the activity of the transcription factor Nodule Inception to properly shape the symbiosis with rhizobia accordingly. We also highlight the knowledge gaps that are critical for gaining a deeper understanding of the molecular mechanisms underlying the adaptation of the root nodule symbiosis to salt-stress conditions. We consider that filling these gaps can help to improve legume nodulation and harness its ecological benefits even under salt-stress conditions., (© 2022 The Authors. New Phytologist © 2022 New Phytologist Foundation.)

The use of novel oral anticoagulants (NOAC) in patients with moderate to severe mitral stenosis (MS) and atrial fibrillation (AF) is not recommended. We aimed to evaluate the efficacy and safety of NOAC usage compared to vitamin K antagonist (VKA) in patients with moderate to severe MS and AF. We conducted a systematic review to identify articles that compared warfarin to NOAC in patients with moderate to severe MS and AF. Only four studies (two observational studies and two trials) met our search criteria and reported a total of 7529 patients with MS and AF with MS and AF, 4138 of them treated with NOAC. In both observational studies, the severity of MS was not determined, and there was heterogeneity in MS etiology. Nevertheless, both studies showed a positive signal toward the efficacy and safety of NOAC compared to VKA in this population. A randomized pilot trial (n=40) was done on patients with moderate to severe MS, and it showed further acceptable efficacy and safety for rivaroxaban use. However, a larger randomized controlled trial (n=4531) disclosed that VKA (warfarin) led to a significantly lower rate of a composite of cardiovascular events or mortality than rivaroxaban, without a higher rate of major bleeding but not fatal bleeding. Our systematic review provides exploratory information on NOAC safety and effectiveness in patients with MS; it also discourages using NOACs for patients with moderate to severe MS and supports the current treatment guidelines. However, more dedicated clinical trials evaluating the use of NOACs in moderate to severe MS are underway. They will categorically establish the safety profile and clinical effectiveness of NOAC in this high-risk population., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Al Rawahi et al.)

Background: Targeted therapies, specifically ErbB family tyrosine kinase inhibitors, have demonstrated potential for improving outcomes in patients with ErbB2-positive breast cancer. Despite their effectiveness, these therapies are associated with limitations, including high costs, side effects, drug resistance, lack of specificity, and toxicity. To overcome these challenges, drug repurposing has emerged as a promising strategy in breast cancer treatment., Objective: The aim of this investigation was to assess the influence of calcitriol on breast cancer cell lines expressing ErbB2 and comparing its effects with the conventional treatment, neratinib., Methods: We employed an MTT test to determine cell viability and utilized staining techniques to assess cell apoptosis. Flow cytometry was used to evaluate cell cycle arrest, while a scratch wound healing test was performed to examine cancer cell migration ability. Additionally, gene expression studies were conducted for calcitriol and neratinib to support our hypothesis regarding the ErbB2 gene., Results: The repurposing of calcitriol demonstrated enhanced efficacy in suppressing cancer cell growth in ErbB2- positive breast cancer. Proportionally, calcitriol significantly reduced the viability of SK-BR-3 cells, similar to neratinib. Furthermore, calcitriol exhibited significant cytotoxicity against neratinib and substantially reduced breast cancer cell growth. These findings were corroborated by the wound healing assay, cell cycle arrest analysis, and gene expression studies, demonstrating comparable efficacy to the standard treatment, neratinib., Conclusion: The findings from this investigation offer compelling proof that highlights the promising role of calcitriol as an adjuvant drug with antiproliferative and antitumoral effects in the management of ErbB2-positive breast carcinoma patients. Therefore, we recommend further evaluation of calcitriol in clinical settings, particularly for the treatment of ErbB2-positive breast cancer, as it shows promise as a valuable therapeutic option., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The epidermis is a barrier that prevents water loss while keeping harmful substances from penetrating the host. The impermeable cornified layer of the stratum corneum is maintained by balancing continuous turnover driven by epidermal basal cell proliferation, suprabasal cell differentiation, and corneal shedding. The epidermal desquamation process is tightly regulated by balance of the activities of serine proteases of the Kallikrein-related peptidases (KLK) family and their cognate inhibitor lymphoepithelial Kazal type-related inhibitor (LEKTI), which is encoded by the serine peptidase inhibitor Kazal type 5 gene. Imbalance of proteolytic activity caused by a deficiency of LEKTI leads to excessive desquamation due to increased activities of KLK5, KLK7, and KLK14 and results in Netherton syndrome (NS), a debilitating condition with an unmet clinical need. Increased activity of KLKs may also be pathological in other dermatoses such as atopic dermatitis (AD). Here, we describe the discovery of inhibitory antibodies against murine KLK5 and KLK7 that could compensate for the deficiency of LEKTI in NS. These antibodies are protective in mouse models of NS and AD and, when combined, promote improved skin barrier integrity and reduced inflammation. To translate these findings, we engineered a humanized bispecific antibody capable of potent inhibition of human KLK5 and KLK7. A crystal structure of KLK5 bound to the inhibitory Fab revealed that the antibody binds distal to its active site and uses a relatively unappreciated allosteric inhibition mechanism. Treatment with the bispecific anti-KLK5/7 antibody represents a promising therapy for clinical development in NS and other inflammatory dermatoses.