Design, Synthesis, and Mechanistic Studies of (R)-3-Amino-5,5-difluorocyclohex-1-ene-1-carboxylic Acid as an Inactivator of Human Ornithine Aminotransferase.

Human ornithine aminotransferase (hOAT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme, has been shown to play an essential role in the metabolic reprogramming and progression of hepatocellular carcinoma (HCC). HCC accounts for approximately 75% of primary liver cancers and is within the top three causes of cancer death worldwide. As a result of treatment limitations, the overall 5-year survival rate for all patients with HCC is under 20%. The prevalence of HCC necessitates continued development of novel and effective treatment methods. In recent years, the therapeutic potential of selective inactivation of hOAT has been demonstrated for the treatment of HCC. Inspired by previous increased selectivity for hOAT by the expansion of the cyclopentene ring scaffold to a cyclohexene, we designed, synthesized, and evaluated a series of novel fluorinated cyclohexene analogues and identified (R)-3-amino-5,5-difluorocyclohex-1-ene-1-carboxylic acid as a time-dependent inhibitor of hOAT. Structural and mechanistic studies have elucidated the mechanism of inactivation of hOAT by 5, resulting in a PLP-inactivator adduct tightly bound to the active site of the enzyme. Intact protein mass spectrometry, 19F NMR spectroscopy, transient state kinetic studies, and X-ray crystallography were used to determine the structure of the final adduct and elucidate the mechanisms of inactivation. Interestingly, despite the highly electrophilic intermediate species conferred by fluorine and structural evidence of solvent accessibility in the hOAT active site, Lys292 and water did not participate in nucleophilic addition during the inactivation mechanism of hOAT by 5. Instead, rapid aromatization to yield the final adduct was favored.

Post-loss speeding or post-win slowing? An empirical note on the interpretation of decision-making time as a function of previous outcome.

Differences in response time following previous losses relative to previous wins are robust observations in behavioural science, often attributed to an increased (or decreased) degree of cognitive control exerted after negative feedback, hence, post-loss slowing (or post-loss speeding). This presumes that the locus of this effect resides in the specific modulation of decision time following negative outcomes. Across two experiments, I demonstrate how the use of absolute rather than relative processing speeds, and the sensitivity of processing speeds in response to specific experimental manipulations (Experiment 1: win rate, Experiment 2: feedback), provide clarity as to the relative weighting of post-win and post-loss states in determining these behavioural effects. Both experiments show that the speeding or slowing of decision-time is largely due to the flexibility generated by post-win cognitive states. Given that post-loss speeding may actually represent post-win slowing, conclusions regarding the modulation of decision-making time as a function of previous outcomes need to be more carefully considered.

Unveiling the potential of cellulose nanofibre based nitrogen fertilizer and its transformative effect on Vigna radiata (Mung Bean): nanofibre for sustainable agriculture.

Introduction: Fertilizer management is crucial to maintaining a balance between environmental health, plant health, and total crop yield. Farmers are overutilizing fertilizers with a mind set to enhance the productive capacity of the field, which adversely impacts soil fertility and causes serious environmental hazards. To mitigate the issues of over-utilization of fertilizers, controlled-release fertilizers were developed using nitrogen fertilizer (ammonium chloride) loaded on cellulose nanofibres (named CNF*N). Methodology: In this study, the effects of CNF*N were compared with commercial nitrogen fertilizer (ammonium chloride) on Vigna radiata (Mung) under greenhouse conditions. The pot experiment was conducted using six treatments: first treatment was control, where the plant was cultivated (T1); second treatment was T2, where the plant was cultivated with CNF to determine the impact of CNF on the plant; third was T3 where commercial ammonium chloride (24 mg/ 2 kg soil) was added to the plant; fourth was T4, where the plant was loaded with CNF, viz. CNF*N contains 4.8 mg of nitrogen; fifth was T5 CNF*N pellet contains 12 mg of nitrogen, and the last sixth treatment (T6) where CNF*N pellet containing 24 mg of nitrogen. Results: It indicated that the growth parameters were best achieved in T6 treatment. Plant height was at its maximum in the T6 treatment (44.4 ±0.1cm) after the second harvest, whereas the minimum plant height was observed in T1, which was 39.1 ±0.1 cm. Root-to-shoot weight ratio was also maximum in T6 (0.183± 0.02) and minimum in T1 (0.07± 0.01) after second harvesting. The significant difference among the treatments was determined with Tukey's honestly significant difference (HSD). The nitrogen content (available and total) was significantly higher in the T4, T5, and T6 treatments (0.22, 0.25, and 0.28%) as compared to the control treatments (T1 (0.12%), T2 (0.13%), and T3 (0.14%) during the second harvesting stage (90 days), as nitrogen plays a crucial role in the development of vegetative growth in Vigna radiata. The rate of controlled-release nitrogen-fertilizer was found to be optimal in terms of plant growth and soil nutrients; hence, it could potentially play a crucial role in improving soil health and the yield of the crop.

A systematic review of antimicrobial therapy in children with tracheostomies.

Tracheostomies are indicated in children to facilitate long-term ventilatory support, aid in the management of secretions, or manage upper airway obstruction. Children with tracheostomies often experience ongoing airway complications, of which respiratory tract infections are common. They subsequently receive frequent courses of broad-spectrum antimicrobials for the prevention or treatment of respiratory tract infections. However, there is little consensus in practice with regard to the indication for treatment/prophylactic antimicrobial use, choice of antimicrobial, route of administration, or duration of treatment between different centers. Routine antibiotic use is associated with adverse effects and an increased risk of antimicrobial resistance. Tracheal cultures are commonly obtained from pediatric tracheostomy patients, with the aim of helping guide antimicrobial therapy choice. However, a positive culture alone is not diagnostic of infection and the role of routine surveillance cultures remains contentious. Inhaled antimicrobial use is also widespread in the management of tracheostomy-associated infections; this is largely based on the theoretical benefits of higher airway antibiotic concentrations. The role of prophylactic inhaled antimicrobial use for tracheostomy-associated infections remains largely unproven. This systematic review summarizes the current evidence base for antimicrobial selection, duration, and administration route in pediatric tracheostomy-associated infections. It also highlights significant variation in practice between centers and the urgent need for further prospective evidence to guide the management of these vulnerable patients.

How to do a single-stage perforator based nasolabial flap for reconstruction of early-stage tongue cancer.

Tongue cancers are one of the most common subsites of malignancy in the head and neck, of which the majority are squamous cell carcinoma (SCC). Reconstruction following ablative surgery is challenging because of the role of the tongue in articulation, deglutition and protection of the airway. Microvascular free flaps are the current gold standard of reconstruction but are not feasible in all patients. Local and regional flaps provide a less challenging, faster alternative and may be more appropriate in comorbid patients with high anaesthetic risk as well as those with previously irradiated neck and poor vasculature. Nasolabial flaps are not commonly used for tongue reconstruction, requiring a two-staged procedure to allow division of the pedicle. We submit a modification of nasolabial flap as an inferiorly based, islanded perforator flap. This allows for single-stage reconstruction of tongue and floor of the mouth defects following resection of early-stage tongue cancers.

Deliberately making miskates: Behavioural consistency under win maximization and loss maximization conditions.

We argue that the feedback traditionally used to indicate negative outcomes causes future detrimental performance because of the default goal of win maximization. In gaming paradigms where participants intentionally performed as well (win maximization) and as poorly (loss maximization) as possible, we showed a double dissociation where actions following wins were more consistent during win maximization, but actions following losses were more consistent during loss maximization. This broader distinction between goal-congruent and goal-incongruent feedback suggests that individuals are able to flexibly redefine their definition of 'success', and provide a reconsideration of the way we think about 'losing'.

Rice straw-derived cellulose: a comparative study of various pre-treatment technologies and its conversion to nanofibres.

Rice straw is a waste product generated after the harvesting of rice crops and is commonly disposed of by burning it off in open fields. This study explored the potential for the extraction and conversion of cellulose to cellulose nanofibres (CNFs) to be used as smart delivery systems for fertilizers applications. In this study, alkali, steam explosion, and organosolv treatments were investigated for cellulose extraction efficiency. The morphological characterization of cellulose showed smooth fibrillar structures. Fourier transform infrared spectroscopy represented significant removal of non-cellulosic components in treatments. The crystallinity increased from 52.2 to 65% in CNFs after fibrillation. Cellulose nanofibres (CNFs) had an average diameter of 37.4 nm and - 25.2 mV surface charges as determined by SEM and zeta potential, respectively, which have desired properties for holding fertilizers. Therefore, this study paves the way for value-added uses of rice straw as alternatives to current environmentally harmful practices.

Controlled release fertilizer delivery system derived from rice straw cellulose nanofibres: a circular economy based solution for sustainable development.

Recently, the development of sustainable and environmentally friendly biomaterials has gained the attention of researchers as potential alternatives to petroleum-based materials. Biomaterials are a promising candidate to mitigate sustainability issues due to their renewability, biodegradability, and cost-effectiveness. Thus, the purpose of this study is to explore a cost-effective biomaterial-based delivery system for delivering fertilizers to plants. To achieve this, rice straw (agro-waste) was selected as a raw material for the extraction of cellulose. The cellulose was extracted through alkali treatment (12% NaOH), followed by TEMPO-based oxidation. The cellulose nanofibers were characterized using Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy, and transmission electron microscopy. In scanning electron microscopy, a loosening of the fibrillar structure in cellulose nanofibers (CNFs) was observed with a diameter of 17 ± 4 nm. The CNFs were loaded with nitrogen-based fertilizer (ammonium chloride) in 1:1, 1:2, and 2:1 (w/w) proportions. The loading was estimated through surface charge variation; in the case of the 1:1 sample, maximum reductions in surface charge were seen from -42.0 mV to -12.8 mV due to the binding of positive ammonium ions. In the release kinetics study, a controlled release pattern was observed at 1:1, which showed a 58% cumulative release of ammonium ions within 8 days. Thus, the study paves the way for value-added uses of rice straw as an alternative to the current environmentally harmful practices.

Bio-based cellulose nanofibers (CNFs) from rice straw via circular economy approach.Controlled release fertilizers for sustainable agriculture.Nanotechnology for precision agriculture and decarbonization via agricultural waste management.

Adherence to unsupervised exercise in sedentary individuals: A randomised feasibility trial of two mobile health interventions.

Introduction: Adherence to unsupervised exercise is poor, yet unsupervised exercise interventions are utilised in most healthcare settings. Thus, investigating novel ways to enhance adherence to unsupervised exercise is essential. This study aimed to examine the feasibility of two mobile health (mHealth) technology-supported exercise and physical activity (PA) interventions to increase adherence to unsupervised exercise. Methods: Eighty-six participants were randomised to online resources (n = 44, females n = 29) or MOTIVATE (n = 42, females n = 28). The online resources group had access to booklets and videos to assist in performing a progressive exercise programme. MOTIVATE participants received exercise counselling sessions supported via mHealth biometrics which allowed instant participant feedback on exercise intensity, and communication with an exercise specialist. Heart rate (HR) monitoring, survey-reported exercise behaviour and accelerometer-derived PA were used to quantify adherence. Remote measurement techniques were used to assess anthropometrics, blood pressure, HbA1c and lipid profiles. Results: HR-derived adherence rates were 22 ± 34% and 113 ± 68% in the online resources and MOTIVATE groups, respectively. Self-reported exercise behaviour demonstrated moderate (Cohen's d = 0.63, CI = 0.27 to 0.99) and large effects (Cohen's d = 0.88, CI = 0.49 to 1.26) in favour of online resources and MOTIVATE groups, respectively. When dropouts were included, 84% of remotely gathered data were available, with dropouts removed data availability was 94%. Conclusion: Data suggest both interventions have a positive impact on adherence to unsupervised exercise but MOTIVATE enables participants to meet recommended exercise guidelines. Nevertheless, to maximise adherence to unsupervised exercise, future appropriately powered trials should explore the effectiveness of the MOTIVATE intervention.

Effectiveness of a probiotic combination on the neurodevelopment of the very premature infant.

Probiotics have shown a benefit in reducing necrotising enterocolitis in the premature infant, however the study of their effect on premature neonates' neurodevelopment is limited. The aim of our study was to elucidate whether the effect of Bifidobacterium bifidum NCDO 2203 combined with Lactobacillus acidophilus NCDO 1748 could positively impact the neurodevelopment of the preterm neonates. Quasi-experimental comparative study with a combined treatment of probiotics in premature infants < 32 weeks and < 1500 g birth weight, cared for at a level III neonatal unit. The probiotic combination was administered orally to neonates surviving beyond 7 days of life, until 34 weeks postmenstrual age or discharge. Globally, neurodevelopment was evaluated at 24 months corrected age. A total of 233 neonates were recruited, 109 in the probiotic group and 124 in the non-probiotic group. In those neonates receiving probiotics, there was a significant reduction in neurodevelopment impairment at 2 years of age RR 0.30 [0.16-0.58], and a reduction in the degree of impairment (normal-mild vs moderate-severe, RR 0.22 [0.07-0.73]). Additionally, there was a significant reduction in late-onset sepsis (RR 0.45 [0.21-0.99]). The prophylactic use of this probiotic combination contributed to improving neurodevelopmental outcome and reduced sepsis in neonates born at < 32 weeks and < 1500 g.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.Accepted.

Incidence of Epiretinal Membrane Formation After Pars Plana Vitrectomy for Giant Retinal Tear-Associated Retinal Detachment.

Objective: To report the incidence of postoperative epiretinal membrane (ERM) formation after primary pars plana vitrectomy (PPV) for giant retinal tear associated retinal detachment (GRT-RD) repair as well as its clinical characteristics and visual outcomes at a level one trauma and tertiary referral academic center. Patients and Methods: Patients with primary RD repair for GRT-RD at West Virginia University from September 2010 to July 2021 were identified using the ICD-10 codes (H33.031, H33.032, H33.033 and H33.039). Imaging studies including optical coherence tomography (OCT) were manually reviewed pre- and post-operatively for ERM formation after PPV for GRT-RD repair in patients who underwent PPV or combined PPV and scleral buckle (SB). Univariate analysis was performed to analyze clinical factors for ERM formation. Results: The study included 17 eyes of 16 patients who underwent PPV for GRT-RD. Postoperative ERM was observed in 70.6% (13 of 17 eyes) of the patients. Anatomic success was achieved in all patients. The mean (range) preoperative and final best corrected visual acuity (BCVA) in logMAR units by macula status was 0.19 (0-0.5) and 0.28 (0-0.5) for macula-on and 1.7 (0.5-2.3) and 0.7 (0.2-1.9) for macular-off GRT-RDs. Clinical variables including use of medium-term tamponade with perfluorocarbon liquid (PFCL), cryopexy, endodiathermy, number of tears or total clock hours of tears did not correlate with an increased risk of ERM formation. Conclusion: Post-vitrectomized eyes for GRT-RD repair have a significantly higher incidence of ERM formation, nearing 70% in our study. Surgeons may consider prophylactic ILM peel at the time of removal of tamponade agents or weigh in ILM peel at the time of primary repair, a more challenging surgical technique in our opinion.

Neural spiking for causal inference and learning.

When a neuron is driven beyond its threshold, it spikes. The fact that it does not communicate its continuous membrane potential is usually seen as a computational liability. Here we show that this spiking mechanism allows neurons to produce an unbiased estimate of their causal influence, and a way of approximating gradient descent-based learning. Importantly, neither activity of upstream neurons, which act as confounders, nor downstream non-linearities bias the results. We show how spiking enables neurons to solve causal estimation problems and that local plasticity can approximate gradient descent using spike discontinuity learning.

Thoracic aortic aneurysm and atrial fibrillation: clinical associations with the risk of stroke from a global federated health network analysis.

BACKGROUND: An association with aortic aneurysm has been reported among patients with atrial fibrillation (AF). The aims of this study were to investigate the prevalence of thoracic aorta aneurysm (TAA) among patients with AF and to assess whether the co-presence of TAA is associated with a higher risk of adverse clinical outcomes. METHODS AND RESULTS: Using TriNetX, a global federated health research network of anonymised electronic medical records, all adult patients with AF, were categorised into two groups based on the presence of AF and TAA or AF alone. Between 1 January 2017 and 1 January 2019, 874,212 people aged ≥ 18 years with AF were identified. Of these 17,806 (2.04%) had a TAA. After propensity score matching (PSM), 17,805 patients were included in each of the two cohorts. During the 3 years of follow-up, 3079 (17.3%) AF patients with TAA and 2772 (15.6%) patients with AF alone, developed an ischemic stroke or transient ischemic attack (TIA). The risk of ischemic stroke/TIA was significantly higher in patients with AF and TAA (HR 1.09, 95% CI 1.04-1.15; log-rank p value < 0.001) The risk of major bleeding was higher in patients with AF and TAA (OR 1.07, 95% CI 1.01-1.14), but not significant in time-dependent analysis (HR 1.04, 95% CI 0.98-1.10; log-rank p value = 0.187), CONCLUSION: This retrospective analysis reports a clinical concomitance of the two medical conditions, and shows in a PSM analysis an increased risk of ischemic events in patients affected by TAA and AF compared to AF alone.

Developing an Evidence-Based Surgical Curriculum: Learning from a Randomized Controlled Trial of Surgical Rehearsal in Virtual Reality.

BACKGROUND: Surgical rehearsal - patient-specific preoperative surgical practice - can be provided by virtual reality simulation. This study investigated the effect of surgical rehearsal on cortical mastoidectomy performance and procedure duration. METHODS: University students (n=40) were randomized evenly into a rehearsal and control group. After watching a video tutorial on cortical mastoidectomy, participants completed the procedure on a virtual reality simulator as a pre-test. Participants completed a further 8 cortical mastoidectomies on the virtual reality simulator as training before drilling two 3-dimensional (3D) printed temporal bones. The rehearsal group received 3D printed bones they had previously operated on in virtual reality, while the control group received 2 new bones. Cortical mastoidectomy was assessed by 3 blinded graders using the Melbourne Mastoidectomy Scale. RESULTS: There was high interrater reliability between the 3 graders (intraclass correlation coefficient, r=0.8533, P < .0001). There was no difference in the mean surgical performance on the two 3D printed bones between the control and rehearsal groups (P=.2791). There was no significant difference in the mean procedure duration between the control and rehearsal groups for both 3D printed bones (P=.8709). However, there was a significant decrease in procedure duration between the first and second 3D printed bones (P < .0001). CONCLUSION: In this study, patient-specific virtual reality rehearsal provided no additional advantage to cortical mastoidectomy performance by novice operators compared to generic practice on a virtual reality simulator. Further, virtual reality training did not improve cortical mastoidectomy performance on 3D printed bones, highlighting the impact of anatomical diversity and changing operating modalities on the acquisition of new surgical skills.

Tuning the microstructure and mechanical properties of lyophilized silk scaffolds by pre-freezing treatment of silk hydrogel and silk solution.

This work aims to understand how pre-freezing treatments (-20 °C, -80 °C or -196 °C (liquid nitrogen)) affect the microstructure, mechanical properties and secondary structure of silk scaffolds prepared from lyophilization of silk hydrogels and silk solutions. It is found that in comparison with silk solutions, silk hydrogels at the same silk fibroin concentrations produce scaffolds with more nanofibrous structures when they are pre-frozen at the different temperatures. Although pre-freezing with liquid nitrogen can produce nanofibrous scaffolds from either a silk solution (low concentration of 2%) or silk hydrogel (produced from 2 to 6% silk fibroin solutions), aligned macro-channels can be produced only from silk hydrogels. In addition, scaffolds obtained from silk hydrogels are dominated by ß-sheets due to the crystallization process for gel network formation, while scaffolds prepared from silk solutions are largely amorphous. The findings of this work are important to tune the microstructure and mechanical properties of silk scaffolds.

Magnetic resonance imaging features of isolated periventricular heterotopia in pediatric epilepsy: a comparative study

Objective: Periventricular nodular heterotopia is a neurodevelopmental disorder in which neurons fail to migrate to the cortical surface, forming discrete areas of grey matter adjacent to the lateral ventricles. Given that periventricular nodular heterotopia is seen as an incidental finding in patients without epilepsy, causality between periventricular nodular heterotopia and epilepsy cannot be assumed. Furthermore, the structural characteristics of periventricular nodular heterotopia in patients with epilepsy are poorly defined and can be misleading. In this article, we investigate whether structural radiological characteristics of heterotopia can predict epileptogenicity in pediatric patients. Methods: Pediatric patients with periventricular nodular heterotopia, but no other epilepsy-associated cortical abnormalities on magnetic resonance imaging, were identified and divided into two groups: with epilepsy and without epilepsy. Radiological characteristics of laterality, regionalization, largest dimension and number of nodules were compared between the two groups. Results: Only periventricular nodular heterotopia spreading across several regions was associated with a statistically higher chance of epilepsy. Other features including laterality, individual region, number and largest dimension did not reliably predict epileptogenicity. Significance: Most radiological characteristics of periventricular nodular heterotopia are similar in patients with and without epilepsy. The involvement of multiple periventricular regions with heterotopia was the only feature that inferred a higher risk of epilepsy. Periventricular nodular heterotopia requires a comprehensive work-up and should be interpreted in the context of each individual patient and not assumed to be directly causative of epilepsy, nor unrelated to it. Therefore, further studies using additional structural and functional imaging modalities are needed to determine the radiological features of epileptogenic periventricular nodular heterotopia.

Assessing behavioural profiles following neutral, positive and negative feedback.

Previous data suggest zero-value, neutral outcomes (draw) are subjectively assigned negative rather than positive valence. The combined observations of faster rather than slower reaction times, subsequent actions defined by shift rather than stay behaviour, reduced flexibility, and, larger rather than smaller deviations from optimal performance following draws all align with the consequences of explicitly negative outcomes such as losses. We further tested the relationships between neutral, positive and negative outcomes by manipulating value salience and observing their behavioural profiles. Despite speeded reaction times and a non-significant bias towards shift behaviour similar to losses when draws were assigned the value of 0 (Experiment 1), the degree of shift behaviour approached an approximation of optimal performance when the draw value was explicitly positive (+1). This was in contrast to when the draw value was explicitly negative (-1), which led to a significant increase in the degree of shift behaviour (Experiment 2). Similar modifications were absent when the same value manipulations were applied to win or lose trials (Experiment 3). Rather than viewing draws as neutral and valence-free outcomes, the processing cascade generated by draws produces a complex behavioural profile containing elements found in response to both explicitly positive and explicitly negative results.