Excellent accuracy of trained neonatal nurses in the detection of referral-warranted retinopathy of prematurity within an established telemedicine screening programme.

AIM: To evaluate level of agreement of specialist trained retinopathy of prematurity (ROP) nurses compared with an experienced paediatric ophthalmologist in detection of referral-warranted ROP (RWROP) using wide-field digital retinal imaging. METHODS: This is a prospective, observational, blinded study of neonates in a level III neonatal intensive care unit, from July 2020 to November 2022. Image capture using wide-field digital retinal imaging followed by ROP grading and staging was completed by trained ROP nurses. This was then compared with findings by an experienced paediatric ophthalmologist. The primary outcome was presence of RWROP in either eye. RESULTS: One hundred and ninety-five neonates (55% male) with a total of 768 screening visits were included. At the initial screen, nurse and ophthalmologist agreed about presence of RWROP for 191 of 195 neonates (98%, kappa = 0.79, P < 0.0001), with 100% sensitivity for RWROP detection. Including all 768 screening episodes, agreement was 98% for RWROP. There was disagreement in 16 screenings (2%) for 11 (6%) neonates. Of the five screenings (0.7%) that the ophthalmologist thought were RWROP and the nurse did not, three were disagreements about whether the zone was posterior zone 2 or zone 1. CONCLUSIONS: We found excellent levels of agreement and add evidence that interpretations by specialist trained nurses could be safely integrated into a 'hybrid ROP screening system'.

Evaluation of the clinical outcomes and patient satisfaction related to the use of internal eye shields for electron external beam radiation therapy.

INTRODUCTION: Cancers around the eye are often treated using orthovoltage machines or by plastic surgery, neither of which are widely available in regional Australia. External beam radiation therapy (EBRT) using electrons and an internal eye shield is an alternative, relatively underreported technique which can provide similar cosmetic and functional outcomes. This report aimed to describe the process for the use of internal eye shields at GenesisCare Fraser Coast Radiation Oncology (GCFCRO) and the associated clinical outcomes and patient perceptions of the delivery and results of this procedure. METHODS: This project was conducted in two phases. Phase I was an audit of the departmental technique and short-term clinical outcomes of 17 patients who received EBRT for skin cancer near the eyes at GCFCRO in partnership with Wide Bay Hospital and Health Service (WBHHS). Phase II was a survey of nine of those patients to elicit the patient perspective of the delivery and long-term outcomes of the treatment. RESULTS: Phase I revealed the departmental procedures for simulation, planning and treatment at GCFCRO are consistent with other departments published protocols. Phase II results detailed positive patient perspectives regarding cosmetic outcomes and receipt of EBRT for skin cancer near their eyes. CONCLUSION: EBRT with an internal eye shield is an acceptable alternative modality to surgery for squamous cell carcinomas (SCC) and basal cell carcinomas (BCC) around the eye in the definitive and adjuvant setting. This is particularly important in regional locations to facilitate patients receiving high-quality care and outcomes locally.

Goal-directed action preparation in humans entails a mixture of corticospinal neural computations.

The seemingly effortless ability of humans to transition from thinking about actions to initiating them relies on sculpting corticospinal output from primary motor cortex. This study tested whether canonical additive and multiplicative neural computations, well-described in sensory systems, generalize to the corticospinal pathway during human action preparation. We used non-invasive brain stimulation to measure corticospinal input-output across varying action preparation contexts during instructed-delay finger response tasks. Goal-directed action preparation was marked by increased multiplicative gain of corticospinal projections to task-relevant muscles and additive suppression of corticospinal projections to non-selected and task-irrelevant muscles. Individuals who modulated corticospinal gain to a greater extent were faster to initiate prepared responses. Our findings provide physiological evidence of combined additive suppression and gain modulation in the human motor system. We propose these computations support action preparation by enhancing the contrast between selected motor representations and surrounding background activity to facilitate response selection and execution.

Enhancing Intrusion Detection in Wireless Sensor Networks Using a GSWO-CatBoost Approach.

Intrusion detection systems (IDSs) in wireless sensor networks (WSNs) rely heavily on effective feature selection (FS) for enhanced efficacy. This study proposes a novel approach called Genetic Sacrificial Whale Optimization (GSWO) to address the limitations of conventional methods. GSWO combines a genetic algorithm (GA) and whale optimization algorithms (WOA) modified by applying a new three-population division strategy with a proposed conditional inherited choice (CIC) to overcome premature convergence in WOA. The proposed approach achieves a balance between exploration and exploitation and enhances global search abilities. Additionally, the CatBoost model is employed for classification, effectively handling categorical data with complex patterns. A new technique for fine-tuning CatBoost's hyperparameters is introduced, using effective quantization and the GSWO strategy. Extensive experimentation on various datasets demonstrates the superiority of GSWO-CatBoost, achieving higher accuracy rates on the WSN-DS, WSNBFSF, NSL-KDD, and CICIDS2017 datasets than the existing approaches. The comprehensive evaluations highlight the real-time applicability and accuracy of the proposed method across diverse data sources, including specialized WSN datasets and established benchmarks. Specifically, our GSWO-CatBoost method has an inference time nearly 100 times faster than deep learning methods while achieving high accuracy rates of 99.65%, 99.99%, 99.76%, and 99.74% for WSN-DS, WSNBFSF, NSL-KDD, and CICIDS2017, respectively.

Feasibility and acceptability for LION, a fully remote, randomized clinical trial within the VA for light therapy to improve sleep in Veterans with and without TBI: An MTBI2 sponsored protocol: LION: A remote RCT protocol within VA.

Sleep-wake disturbances frequently present in Veterans with mild traumatic brain injury (mTBI). These TBI-related sleep impairments confer significant burden and commonly exacerbate other functional impairments. Therapies to improve sleep following mTBI are limited and studies in Veterans are even more scarce. In our previous pilot work, morning bright light therapy (MBLT) was found to be a feasible behavioral sleep intervention in Veterans with a history of mTBI; however, this was single-arm, open-label, and non-randomized, and therefore was not intended to establish efficacy. The present study, LION (light vs ion therapy) extends this preliminary work as a fully powered, sham-controlled, participant-masked randomized controlled trial (NCT03968874), implemented as fully remote within the VA (target n=120 complete). Randomization at 2:1 allocation ratio to: 1) active: MBLT (n=80), and 2) sham: deactivated negative ion generator (n=40); each with identical engagement parameters (60-min duration; within 2-hrs of waking; daily over 28-day duration). Participant masking via deception balanced expectancy assumptions across arms. Outcome measures were assessed following a 14-day baseline (pre-intervention), following 28-days of device engagement (post-intervention), and 28-days after the post-intervention assessment (follow-up). Primary outcomes were sleep measures, including continuous wrist-based actigraphy, self-report, and daily sleep dairy entries. Secondary/exploratory outcomes included cognition, mood, quality of life, circadian rhythm via dim light melatonin onset, and biofluid-based biomarkers. Participant drop out occurred in <10% of those enrolled, incomplete/missing data was present in <15% of key outcome variables, and overall fidelity adherence to the intervention was >85%, collectively establishing feasibility and acceptability for MBLT in Veterans with mTBI.

Amelioration of age-related cognitive decline and anxiety in mice by Centella asiatica extract varies by sex, dose and mode of administration.

Background: A water extract (CAW) of the Ayurvedic plant Centella asiatica administered in drinking water has been shown to improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice are compared. Methods: Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.2, 0.5 or 1% w/w) to provide 0, 200 mg/kg/d, 500 mg/kg/d or 1,000 mg/kg/d CAW for a total of 5 weeks. An additional group of eighteen-month-old mice were treated with CAW (10 mg/mL) in their drinking water CAW for a total of 5 weeks to deliver the same exposure of CAW as the highest dietary dose (1,000 mg/kg/d). CAW doses delivered were calculated based on food and water consumption measured in previous experiments. In the fourth and fifth weeks, mice underwent behavioral testing of cognition, anxiety and depression (n = 12 of each sex per treatment group in each test). Results: Aged mice of both sexes showed cognitive deficits relative to young mice while only female aged mice showed increased anxiety compared to the young female mice and no differences in depression were observed between the different ages. CAW (1,000 mg/kg/d) in the drinking water improved deficits in aged mice in learning, executive function and recognition memory in both sexes and attenuated the increased measures of anxiety observed in the aged female mice. However, CAW in the diet only improved executive function in aged mice at the highest dose (1,000 mg/kg/d) in both sexes and did so less robustly than when given in the water. There were no effects of CAW on depression-like behavior in aged animals regardless of whether it was administered in the diet or the water. Conclusions: These results suggest that CAW can ameliorate age-related changes in measures of anxiety and cognition and that the mode of administration is important for the effects of CAW on resilience to these age-related changes.

Association between Genetic Polymorphism of SCN1A, GABRA1 and ABCB1 and Drug Responsiveness in Vietnamese Epileptic Children.

Background and Objectives: Drug resistant epilepsy (DRE) is a major hurdle in epilepsy, which hinders clinical care, patients' management and treatment outcomes. DRE may partially result from genetic variants that alter proteins responsible for drug targets and drug transporters in the brain. We aimed to examine the relationship between SCN1A, GABRA1 and ABCB1 polymorphism and drug response in epilepsy children in Vietnam. Materials and Methods: In total, 213 children diagnosed with epilepsy were recruited in this study (101 were drug responsive and 112 were drug resistant). Sanger sequencing had been performed in order to detect six single nucleotide polymorphisms (SNPs) belonging to SCN1A (rs2298771, rs3812718, rs10188577), GABRA1 (rs2279020) and ABCB1 (rs1128503, rs1045642) in study group. The link between SNPs and drug response status was examined by the Chi-squared test or the Fisher's exact test. Results: Among six investigated SNPs, two SNPs showed significant difference between the responsive and the resistant group. Among those, heterozygous genotype of SCN1A rs2298771 (AG) were at higher frequency in the resistant patients compared with responsive patients, playing as risk factor of refractory epilepsy. Conversely, the heterozygous genotype of SCN1A rs3812718 (CT) was significantly lower in the resistant compared with the responsive group. No significant association was found between the remaining four SNPs and drug response. Conclusions: Our study demonstrated a significant association between the SCN1A genetic polymorphism which increased risk of drug-resistant epilepsy in Vietnamese epileptic children. This important finding further supports the underlying molecular mechanisms of SCN1A genetic variants in the pathogenesis of drug-resistant epilepsy in children.

Use of antimicrobials and other medical products in an ethnic minority context of South-Central Vietnam: A qualitative study of vulnerability.

Despite the global threat of antimicrobial resistance (AMR), evidence on the use and quality of medicines at community level is limited, particularly in impoverished, rural areas where prevalence of (bacterial) infections is high. To better understand the processes that drive vulnerability to AMR' effects, this study aimed to assess social factors underpinning access to-and use of-medical products and healthcare, among people from the Raglai ethnic minority in Ninh Thuan Province, Vietnam. We conducted ethnographic research in eight villages in 2018-2019, using interviewing and participant observation methods for data collection. Different types of informants (including community members and healthcare providers) were selected using purposive sampling strategies and analysis was retroductive. Our findings show that, despite the existence of a government-funded health insurance scheme, Raglai people's flexible therapeutic itineraries did not systematically start with formal healthcare. Different types of care (private/informal, public, shamanic) were combined in parallel or in alternation, determined by distance to the provider, cost, workload, perceived diagnostic capacity, perceived severity and aetiology of the illness, and trust in the provider. Available medicines were often tablets dispensed in plastic bags containing labelled tablets, unlabelled tablets (in bulk) or tablets ground to powder. Treatment was often considered effective when it relieved symptoms, which led to abandonment of the treatment course. When symptoms did not speedily abate, the illness aetiology would be reinterpreted, and "stronger" medicines would be sought. The precarious socio-economic status of some Raglai drove them in cycles of severe poverty when additional unforeseen factors such as illness, animal disease or loss of crops arose, hampering access to (in)formal healthcare providers and/or appropriate diagnosis and treatment. We conclude that Raglai communities are structurally unable to buffer themselves against the threat and consequences of AMR. Despite this vulnerability, they are among the least targeted by efforts to optimize antibiotic use, which are concentrated in secondary and tertiary healthcare facilities targeted at urban populations.

Mode of administration influences plasma levels of active Centella asiatica compounds in 5xFAD mice while markers of neuroinflammation remain unaltered.

Introduction: A water extract of Centella asiatica (L.) Urban [Apiaceae] (CAW) has demonstrated cognitive-enhancing effects in mouse models of Alzheimer's disease and aging, the magnitude of which is influenced by whether CAW is delivered in the drinking water or the diet. These cognitive benefits are accompanied by improvements in oxidative stress and mitochondrial function in the brain, two pathways related to the neuroinflammatory response. The effect of CAW on neuroinflammation, however, has not been directly studied. Here, we investigated the effect of CAW on neuroinflammation in 5xFAD mice and compared plasma levels of CAW's active compounds following two modes of CAW administration. Methods: Eight-to-nine-month-old male and female 5xFAD mice and their wild-type littermates were administered CAW in their diet or drinking water (0 or 1,000 mg/kg/day) for five weeks. Immunohistochemistry was performed for ß-amyloid (Aß), glial fibrillary acidic protein (GFAP), and Griffonia simplicifolia lectin I (GSL I) in the cortex and hippocampus. Gene expression of inflammatory mediators (IL-6, TNFα, IL-1ß, TREM2, AIF1, CX3CR1, CX3CL1, CD36, C3AR1, RAGE, CCR6, CD3E) was measured in the deep grey matter. Results: CAW decreased cortical Aß plaque burden in female 5xFAD mice administered CAW in the drinking water but had no effect on Aß plaques in other treatment groups. CAW did not impact elevated levels of GFAP or GSL I in 5xFAD mice, regardless of sex, brain region, or mode of CAW administration. In the deep grey matter, CAW increased C3AR1 expression in 5xFAD females administered CAW in the drinking water and decreased IL-1ß expression in 5xFAD males administered CAW in the diet. CAW had no effect, however, on gene expression levels of any other inflammatory mediator in the deep grey, for either sex or mode of CAW administration. Mice administered CAW in the drinking water versus the diet had significantly higher plasma levels of CAW compounds. Discussion: CAW had little impact on the neuroinflammatory markers selected for evaluation in the present study, suggesting that the cognitive benefits of CAW may not be mediated by an anti-inflammatory effect or that additional molecular markers are needed to fully characterize the effect of CAW on neuroinflammation.

The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impact on normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

Amelioration of age-related cognitive decline and anxiety in mice by Centella asiatica extract varies by sex, dose and mode of administration.

We have previously reported that a water extract (CAW) of the Ayurvedic plant Centella asiatica administered in drinking water can improve cognitive deficits in mouse models of aging and neurodegenerative diseases. Here we compared the effects of CAW administered in drinking water or the diet on cognition, measures of anxiety and depression-like behavior in healthy aged mice. Three- and eighteen-month-old male and female C57BL6 mice were administered rodent AIN-93M diet containing CAW (0, 0.2, 0.5 or 1% w/w) to provide 0, 200 mg/kg/d, 500 mg/kg/d or 1000 mg/kg/d for a total of 5 weeks. An additional group of eighteen-month-old mice were treated with CAW (10 mg/mL) in their drinking water for a total of five weeks to deliver the same exposure of CAW as the highest dietary dose (1000 mg/kg/d). CAW doses delivered were calculated based on food and water consumption measured in previous experiments. In the fourth and fifth weeks, mice underwent behavioral testing of cognition, anxiety and depression (n=12 of each sex per treatment group in each test). Aged mice of both sexes showed cognitive deficits relative to young mice while only female aged mice showed increased anxiety compared to the young female mice and no differences in depression were observed between the different ages. CAW (1000 mg/kg/d) in the drinking water improved deficits in aged mice in learning, executive function and recognition memory in both sexes and attenuated the increased measures of anxiety observed in the aged female mice. However, CAW in the diet only improved executive function in aged mice at the highest dose (1000 mg/kg/d) in both sexes and did so less robustly than when given in the water. There were no effects of CAW on depression-like behavior in aged animals regardless of whether it was administered in the diet or the water. These results suggest that CAW can ameliorate age-related changes in measures of anxiety and cognition and that the mode of administration is important for the effects of CAW on resilience to these age-related changes.

Zona pellucida removal resulted in a successful live birth: Report on a case with recurrent implantation failure due to embryonic bacteria contamination.

Key clinical message: In in vitro fertilization (IVF), laser offers several advantages. In this study, we employed laser to eliminate the zona pellucida of a contaminated embryo. This approach helps to rescue embryo with bacterial contamination, and improve embryo-endometrium interaction. Abstract: To present a case report on the removal of a contaminated zona pellucida from an embryo of patient with a history of recurrent implantation failure (RIF), which was followed by a successful live birth. We present the case of a 34-year-old patient with a history of 3 years of infertility who underwent in vitro fertilization. During the culture process, the embryos became contaminated, leading to three failed implantations. Despite the aneuploidy of the embryo and the implementation of a washing technique, the contamination persisted. In the final attempt, the contaminated zona pellucida was successfully removed using laser, followed by embryo transfer, resulting in a live birth. We provided detailed clinical information, including patient demographics, infertility history, ovarian response, evidence of bacterial contamination, embryo development, treatment protocols, and outcomes. Laser excision of the zona pellucida is a safe and effective method for addressing bacterial infection in embryos.

Variations in Cortical Functional Gradients Relate to Dimensions of Psychopathology in Preschool Children.

OBJECTIVE: It is unclear how the functional brain hierarchy is organized in preschool-aged children, and whether alterations in the brain organization are linked to mental health in this age group. Here, we assessed whether preschool-aged children exhibit a brain organizational structure similar to that of older children, how this structure might change over time, and whether it might reflect mental health. METHOD: This study derived functional gradients using diffusion embedding from resting state functional magnetic resonance imaging data of 4.5-year-old children (N = 100, 42 male participants) and 6.0-year-old children (N = 133, 62 male participants) from the longitudinal Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We then conducted partial least-squares correlation analyses to identify the association between the impairment ratings of different mental disorders and network gradient values. RESULTS: The main organizing axis of functional connectivity (ie, principal gradient) separated the visual and somatomotor regions (ie, unimodal) in preschool-aged children, whereas the second axis delineated the unimodal-transmodal gradient. This pattern of organization was stable from 4.5 to 6 years of age. The second gradient separating the high- and low-order networks exhibited a diverging pattern across mental health severity, differentiating dimensions related to attention-deficit/hyperactivity disorder and phobic disorders. CONCLUSION: This study characterized, for the first time, the functional brain hierarchy in preschool-aged children. A divergence in functional gradient pattern across different disease dimensions was found, highlighting how perturbations in functional brain organization can relate to the severity of different mental health disorders.

Pediatric Profound Dengue Shock Syndrome and Use of Point-of-Care Ultrasound During Mechanical Ventilation to Guide Treatment: Single-Center Retrospective Study, 2013-2021.

OBJECTIVES: Profound dengue shock syndrome (DSS) complicated by severe respiratory failure necessitating mechanical ventilation (MV) accounts for high case fatality rates among PICU-admitted patients. A major challenge to management is the assessment of intravascular volume, which can be hampered by severe plasma leakage and the use of MV. DESIGN: Retrospective cohort, from 2013 to 2021. PATIENTS: Sixty-seven children with profound DSS supported by MV, some of whom underwent bedside point-of-care ultrasound (POCUS) for assessment and monitoring of hemodynamics and fluid administration. SETTING: PICU of the tertiary Children's Hospital No. 2 in Vietnam. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data clinical and laboratory data during PICU stay. In particular, during use of MV (i.e., at times 0-, 6-, and 24-hr after commencement) and fluid resuscitation. The primary study outcome was 28-day in-hospital mortality, and the secondary outcomes were associations with changes in hemodynamics, blood lactate, and vasoactive-inotrope score (VIS). Patients had a median age of 7 years (interquartile range, 4-9). Use of POCUS during fluid management (39/67), as opposed to not using (28/67), was associated with lower mortality (6/39 [15%] vs. 18/28 [64%]; difference 49 % [95% CI, 28-70%], p < 0.001). Use of POCUS was associated with lower odds of death (adjusted odds ratio 0.17 [95% CI, 0.04-0.76], p = 0.02). The utilization of POCUS, versus not, was associated with greater use of resuscitation fluid, and reductions in VIS and pediatric logistic organ dysfunction (PELOD-2) score at 24 hours after MV and PICU discharge. CONCLUSIONS: In our experience of pediatric patients with profound DSS and undergoing MV (2013-2021), POCUS use was associated with lower odds of death, a higher volume of resuscitation fluid, and improvements in the blood lactate levels, VIS, and PELOD-2 score.

DCAF14 regulates CDT2 to promote SET8-dependent replication fork protection.

DDB1- and CUL4-associated factors (DCAFs) CDT2 and DCAF14 are substrate receptors for Cullin4-RING E3 ubiquitin ligase (CRL4) complexes. CDT2 is responsible for PCNA-coupled proteolysis of substrates CDT1, p21, and SET8 during S-phase of cell cycle. DCAF14 functions at stalled replication forks to promote genome stability, but the mechanism is unknown. We find that DCAF14 mediates replication fork protection by regulating CRL4CDT2 activity. Absence of DCAF14 causes increased proteasomal degradation of CDT2 substrates. When forks are challenged with replication stress, increased CDT2 function causes stalled fork collapse and impairs fork recovery in DCAF14-deficient conditions. We further show that stalled fork protection is dependent on CDT2 substrate SET8 and does not involve p21 and CDT1. Like DCAF14, SET8 blocks nuclease-mediated digestion of nascent DNA at remodeled replication forks. Thus, unregulated CDT2-mediated turnover of SET8 triggers nascent strand degradation when DCAF14 is absent. We propose that DCAF14 controls CDT2 activity at stalled replication forks to facilitate SET8 function in safeguarding genomic integrity.

An Undetected Pheochromocytoma Leading to Fulminant Adrenergic Myocarditis Complicated by Cardiogenic Shock.

Pheochromocytomas are rare catecholamine-secreting neuroendocrine tumors. Their episodic nature is correlated with abrupt catecholamine release and clinical manifestations that mimic other vascular conditions, leading to delayed diagnosis and potentially life-threatening complications, such as acute myocarditis and pheochromocytoma crises. In this report, we described the case of fulminant adrenergic myocarditis-induced cardiogenic shock requiring extracorporeal membrane oxygenation support in a Vietnamese middle-aged man with a 5-year history of Brugada syndrome, hypertension, and previously undiagnosed pheochromocytoma. After stabilization, the patient was medically treated with a combination of α- and ß-blockers before undergoing laparoscopic right adrenalectomy.

Pain is common in early onset Parkinson's disease and pain severity is associated with age and worsening of motor and non-motor symptoms.

The consequences of pain in early onset Parkinson's disease (EOPD) remain under appreciated even though pain may exert an increasingly negative impact on patient quality of life as motor and non-motor symptoms worsen. In this prospective study, we investigate the prevalence and severity of pain in 135 Vietnamese patients with EOPD from three medical centers using the King's PD Pain Scale (KPPS), the Mini Mental Status Exam (MMSE), the Unified Parkinson's Disease Rating Scale (UPDRS) and the Non-Motor Symptoms Scale (NMSS). Pain was reported by 79.3%. The most common subtype of pain was musculoskeletal (70.1%), followed by nocturnal (43.9%), radicular (43.0%), chronic (42.1%), fluctuation-related (34.6%) and orofacial pain (16.8%). Most patients (74.8%) experienced more than one pain subtype. Fluctuation-related pain and orofacial pain were significantly more prevalent among patients with higher Hoehn & Yahr (H&Y) stages (3-5) versus lower H&Y stages (1-2). Pain subtype and severity were not significantly related to gender or age of PD onset. Patients with H&Y stages 3-5 had statistically significantly higher KPPS scores for fluctuation-related pain (p = 0.018) and radicular pain (p = 0.026). Independent associations were found between pain severity and age (p = 0.028), depression severity (p = 0.018), perceptual problems/hallucinations (p = 0.033) and sexual function (p = 0.024). Patients with depression and higher H&Y stages (3-5) had statistically significantly higher mean KPPS scores versus patients without depression and at lower H&Y stages (1-2). Pain may be more common and severe in EOPD patients than previously appreciated. Older age, depression, perceptual problems/hallucinations and sexual dysfunction were independently associated with higher pain severity.

The therapeutically actionable long non-coding RNA 'T-RECS' is essential to cancer cells' survival in NRAS/MAPK-driven melanoma.

Finding effective therapeutic targets to treat NRAS-mutated melanoma remains a challenge. Long non-coding RNAs (lncRNAs) recently emerged as essential regulators of tumorigenesis. Using a discovery approach combining experimental models and unbiased computational analysis complemented by validation in patient biospecimens, we identified a nuclear-enriched lncRNA (AC004540.4) that is upregulated in NRAS/MAPK-dependent melanoma, and that we named T-RECS. Considering potential innovative treatment strategies, we designed antisense oligonucleotides (ASOs) to target T-RECS. T-RECS ASOs reduced the growth of melanoma cells and induced apoptotic cell death, while having minimal impacton normal primary melanocytes. Mechanistically, treatment with T-RECS ASOs downregulated the activity of pro-survival kinases and reduced the protein stability of hnRNPA2/B1, a pro-oncogenic regulator of MAPK signaling. Using patient- and cell line- derived tumor xenograft mouse models, we demonstrated that systemic treatment with T-RECS ASOs significantly suppressed the growth of melanoma tumors, with no noticeable toxicity. ASO-mediated T-RECS inhibition represents a promising RNA-targeting approach to improve the outcome of MAPK pathway-activated melanoma.

A Combination of Blue Light at 460 nm and H2O2 for the Safe and Effective Eradication of Staphylococcus aureus in an Infected Mouse Skin Abrasion Model.

Antibiotic-free approaches are more important than ever to address the rapidly growing problem of the antibiotic resistance crisis. The photolysis of the bacterial virulence factor staphyloxanthin using blue light at 460 nm (BL460 nm) has been found to effectively attenuate Staphylococcus aureus to chemical and physical agents. However, phototherapy using BL640 nm still needs to be investigated in detail for its safety in eradicating Staphylococcus aureus in vitro and in vivo. In this study, we employed a 460 nm continuous-wavelength LED source and a low concentration of hydrogen peroxide to treat S. aureus under a culturing condition and a wound abrasion mouse model. The results demonstrated the safety of the combined therapy when it did not modify the bacterial virulence factors or the susceptibility to widely used antibiotics. In addition, the results of the mouse model also showed that the combined therapy was safe to apply to mouse skin since it did not cause adverse skin irritation. More importantly, the therapy can aid in healing S. aureus-infected wounds with an efficacy comparable to that of the topical antibiotic Fucidin. The aforementioned findings indicate that the concurrent application of BL460 nm and hydrogen peroxide can be used safely as an alternative or adjunct to antibiotics in treating S. aureus-infected wounds.