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Importance: Glaucoma is the leading cause of irreversible blindness worldwide and, in the US, disproportionately affects people from racial and ethnic minority groups. Glaucoma prevalence has not been estimated for the US in more than a decade, and state- and county-level estimates are not available., Objective: To estimate glaucoma and vision-affecting glaucoma prevalence by demographic factors and US state and county for the Centers for Disease Control and Prevention's Vision and Eye Health Surveillance System (VEHSS)., Data Sources: This meta-analysis used data from the National Health and Nutrition Examination Survey (2005-2008), Medicare fee-for-service claims (2019), IBM MarketScan commercial insurance claims (2016), population-based studies of eye disease (1985-2003), and 2022 population estimates from the US Census Bureau., Study Selection: PubMed was searched for population-based studies of glaucoma prevalence published between 1991 and 2016., Data Extraction and Synthesis: Bayesian meta-regression methods were used to estimate the prevalence of glaucoma and vision-affecting glaucoma stratified by age, undifferentiated sex/gender (a measure that captures an unclear mix of aspects of sex and or gender), race and ethnicity, and US county and state., Main Outcomes and Measures: Prevalence of any type of glaucoma (open or closed angle) among people 18 years or older and vision-affecting glaucoma, defined as glaucoma and a visual field abnormality., Results: For 2022, an estimated 4.22 million people (95% uncertainty interval [UI], 3.46 million to 5.23 million) in the US were living with glaucoma, with a prevalence of 1.62% (UI, 1.33%-2.00%) among people 18 years or older and 2.56% (UI, 2.10%-3.16%) among people 40 years or older. An estimated 1.49 million people (UI, 1.17 million to 1.90 million) were living with vision-affecting glaucoma, with a prevalence of 0.57% (UI, 0.45%-0.73%) among people 18 years or older and 0.91% (UI, 0.71%-1.16%) among people 40 years or older. Prevalence of glaucoma among people 18 years or older ranged from 1.11% (UI, 0.89%-1.40%) in Utah to 1.95% (UI, 1.57%-2.39%) in Mississippi. Black adults had a prevalence of 3.15% (UI, 2.32%-4.09%) compared with 1.42% (UI, 1.10%-1.85%) among White adults; adults in the Hispanic and all other racial and ethnic categories combined had a prevalence of 1.56% (UI, 1.13%-2.06%)., Conclusions and Relevance: This meta-analysis found that an estimated 2.56% of people 40 years or older have glaucoma, slightly more than estimated by previous studies. Black individuals are disproportionately affected. Prevalence estimates at the state and county level can help guide public health planning.

We present an enhancer AAV toolbox for accessing and perturbing striatal cell types and circuits. Best-in-class vectors were curated for accessing major striatal neuron populations including medium spiny neurons (MSNs), direct and indirect pathway MSNs, as well as Sst-Chodl, Pvalb-Pthlh, and cholinergic interneurons. Specificity was evaluated by multiple modes of molecular validation, three different routes of virus delivery, and with diverse transgene cargos. Importantly, we provide detailed information necessary to achieve reliable cell type specific labeling under different experimental contexts. We demonstrate direct pathway circuit-selective optogenetic perturbation of behavior and multiplex labeling of striatal interneuron types for targeted analysis of cellular features. Lastly, we show conserved in vivo activity for exemplary MSN enhancers in rat and macaque. This collection of striatal enhancer AAVs offers greater versatility compared to available transgenic lines and can readily be applied for cell type and circuit studies in diverse mammalian species beyond the mouse model.

Adaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (FPl). Our results indicate that FPl holds previous causal choices in a "pending" state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making., Competing Interests: Declaration of Interests The authors declare no competing interests.

Introduction: To minimize unused outpatient opioids while providing adequate pain control, we sought to create a model to predict outpatient opioid use following the minimally invasive repair of pectus excavatum with cryoablation MIRPE-C., Methods: A retrospective review was conducted at a single center from May 2023 to January 2024 among patients <21 years who underwent MIPRE-C. Demographic and clinical data, including inpatient and outpatient opioid use were reviewed. Patients completed opioid use questionnaires at their first postoperative visit. Simple linear regression was employed to create a model for outpatient opioid use., Results: Sixty-eight patients underwent MIRPE-C: 84% were male (mean age of 15.2 ± 1.7 years, and median Haller index 4.2[IQR:3.7-5.7]). Daily mean inpatient opioid requirement and daily opioid doses were 0.3 ± 0.2 OME/day/kg and 2 ± 1.2 opioid doses/day. At the first outpatient follow-up visit, patients reported using a median of five 5-mg oxycodone tablets [IQR:1.6-10] for 5 days [IQR:2-7] with 22% of patients needing an opioid refill. On linear regression, inpatient opioid use had a significant relationship with the number of outpatient doses taken, while patient factors were not associated with outpatient opioid use. A simple equation for predicting opioid need based on best fit (R 2  = 0.211) was developed: #OUTPATIENT OPIOID TABLETS = 3 TABLETS + (0.82 x #INPATIENT OPIOID RECIEVED)., Conclusion: The proposed outpatient opioid prescription model is simple to calculate and tailors the prescription to individual patient need. This model has the potential to provide effective pain control and avoid prescription refills, while minimizing over-prescription of opioids., Level of Evidence: Treatment study Level III., Competing Interests: Conflict of interest Dr. Padilla is an education consultant for Atricure. The other authors have no relevant financial or non-financial interests to disclose. No funding was received for conducting this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We argue that a diverse and dynamic pool of agents mitigates proxy failure. Proxy modularity plays a key role in the ongoing production of diversity. We review examples from a range of scales.

The genus Achyranthes belong to the family Amaranthaceae which constitutes an important group of herbs and shrubs with immense medicinal value. The present research work was conducted to investigate the anticancer potential of Achyranthes aspera L. leaves by focusing on the antioxidant, aniproliferative and antimitotic activities of leaf extracts. Plant extraction was carried out by soxhelt method with different solvents. Phytochemical characterization of the plants extracts using chemical methods identified the presence of cardiac glycosides, saponins, coumarins, proteins, tannins, flavonoids and triterpenes. Alkaloid was present in methanolic and ethanolic extract. High performance liquid chromatography showed presence of different concentration of myricetin, quercetin and kaempferol in different extracts with the highest concentration of myricetin (84.53 μg/mL) in n-butanolic extract. The extracts were then tested for antioxidant activity using 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging assay by spectrophotometric method. In DPPH radical scavenging assay, antioxidant activity of A. aspera ranged between 79.78 ± 0.034% and 58.63 ± 0.069%. Highest antioxidant activity was observed for methanolic extract and lowest for acetone. Antimitotic activity was determined by using Allium cepa assay in which microscopic investigation was carried out to observe normal and abnormal phases of mitosis. In this assay, n-butanolic extract had highest antimitotic activity with minimum mitotic index at 2 mg/mL (57 ± 0.0351%). The plant extracts also caused chromosomal and mitotic aberrations which were clearly observed under 40× and 100× magnification of compound microscope. Antiproliferative activity was determined by using yeast cell model in which light microscope with hemocytometer was used for cell counting. In case of Antiproliferative activity, the ethyl acetate extract of A. aspera had highest antiproliferative activity with lowest cell viability (22.14 ± 0.076%) at highest extract concentration (2 mg/mL) while methanol extract of A. aspera had highest antiproliferative activity with lower cell viability (24.24 ± 0.057%) at lowest extract concentration (0.25 mg/mL). The results of the study indicated that the leaves extract of A. aspera have strong potential to be used as a source of anti-cancer agent. RESEARCH HIGHLIGHTS: Achyranthes aspera L. leaves have various phytochemicals which contribute to its medicinal properties Various extracts of the leaves of A. aspera L. possess antioxidant, antimitotic and antiproliferative potential The results of the study indicated that the leaves extract of A. aspera have strong potential to be used as a source of anti-cancer agent., (© 2024 Wiley Periodicals LLC.)

Background: Despite cardiovascular disease being the leading cause of death in India, limited data exist regarding the factors associated with outcomes in patients with diabetes who suffer acute myocardial infarction (AMI)., Methods: We examined 21,374 patients with AMI enrolled in the ACS QUIK trial. We compared in-hospital and 30-day major adverse cardiac events including death, re-infarction, stroke, or major bleeding in those with and without diabetes. The associations between diabetes and cardiac outcomes were adjusted for presentation and in-hospital management using logistic regression., Results: Mean ± SD age was 60.1 ± 12.0 years, 24.3% were females, and 44.4% had diabetes. Those with diabetes were more likely to be older, female, hypertensive, and have higher Killip class but less likely to present with STEMI. Patients with diabetes had longer symptoms onset-to-arrival (median 225 vs 290 min; P < 0.001) and, in case of STEMI, longer door-to-balloon times (median, 75 vs 91 min; P < 0.001). Diabetes was independently associated with higher in-hospital death (adjusted odds ratio [aOR], 1.46; 95% CI, 1.12-1.89), in-hospital reinfarction (aOR, 1.52; 95% CI, 1.15-2.02), 30-day MACE (aOR, 1.33; 95% CI, 1.14-1.55) and 30-day death (aOR, 1.40; 95%CI, 1.16-1.69) but not 30-day stroke or 30-day major bleeding., Conclusion: Among patients presenting with AMI in Kerala, India, a considerable proportion has diabetes and are at increased risk for in-hospital and 30-day adverse cardiovascular outcomes. Increased awareness of the increased cardiovascular risk and attention to the implementation of established cardiovascular therapies are indicated for patients with diabetes in lower-middle-income countries who develop AMI., Clinical Trial Registration: ClinicalTrials.gov Unique identifier: NCT02256658., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)

Ethnopharmacological Relevance: Snake bites are a critical health issue in many parts of the world particularly in Asian countries lacking efficient health facilities in rural areas. Cobra is the most common snake type in Asia and is responsible for a large number of mortalities particularly in rural areas. Plants are usually considered the most effective and easy-to-approach treatment for snake bites in rural areas of various countries. Vitex negundo L. is an important medicinal plant traditionally used to treat snake bite envenomation in many countries of Asia., Aim of the Study: From literature survey of plants traditionally used in the treatment of snake bites in Asian countries including India, Pakistan and Sri Lanka, roots of V. negundo were selected for the present study. Anti-snake venom potential of its roots was assessed through various in vitro assays targeting the phospholipase A 2 enzyme., Materials and Methods: V. negundo roots were sequentially extracted in different organic solvents to get fractions and in methanol to get total extract. The extracts were evaluated for phospholipase A 2 (PLA 2 ) inhibitory potential through inhibition of venom-induced hemolysis, ADP-induced platelet aggregation, PLA 2 -induced fatty acid hydrolysis and anticoagulant effect of cobra venom. Antioxidant power was determined using DPPH and superoxide radical scavenging assays. GC-MS and HPLC analysis was performed for the total methanol extract., Results: Strong PLA 2 inhibitory effect was observed for all the extracts. The ethyl acetate, acetone and methanol fractions significantly inhibited toxic effects of cobra venom under in vitro conditions. Radical scavenging potential of these fractions was also significantly high as compared to non-polar fractions in both DPPH and superoxide scavenging assays. Phytochemical analysis indicated high phenolic and flavonoid contents in these fractions. GC-MS and HPLC analysis of total methanol extract confirmed the presence of bis(2-ethylhexyl) phthalate, phenol, o-Guaiacol, palmitic acid-methyl ester, methyl stearate, quercetin and kaempferol in the plant., Conclusion: The study concluded that the roots of V. negundo, particularly their polar extracts, have strong PLA 2 inhibitory effect against cobra venom confirming their traditional use to manage snake bites. The roots of this plant can be further studied for isolation of plant-based antisera., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Islet autoantibodies form the foundation for type 1 diabetes (T1D) diagnosis and staging, but heterogeneity exists in T1D development and presentation. We hypothesized that autoantibodies can identify heterogeneity before, at, and after T1D diagnosis, and in response to disease-modifying therapies., Methods: We systematically reviewed PubMed and EMBASE databases (6/14/2022) assessing 10 years of original research examining relationships between autoantibodies and heterogeneity before, at, after diagnosis, and in response to disease-modifying therapies in individuals at-risk or within 1 year of T1D diagnosis. A critical appraisal checklist tool for cohort studies was modified and used for risk of bias assessment., Results: Here we show that 152 studies that met extraction criteria most commonly characterized heterogeneity before diagnosis (91/152). Autoantibody type/target was most frequently examined, followed by autoantibody number. Recurring themes included correlations of autoantibody number, type, and titers with progression, differing phenotypes based on order of autoantibody seroconversion, and interactions with age and genetics. Only 44% specifically described autoantibody assay standardization program participation., Conclusions: Current evidence most strongly supports the application of autoantibody features to more precisely define T1D before diagnosis. Our findings support continued use of pre-clinical staging paradigms based on autoantibody number and suggest that additional autoantibody features, particularly in relation to age and genetic risk, could offer more precise stratification. To improve reproducibility and applicability of autoantibody-based precision medicine in T1D, we propose a methods checklist for islet autoantibody-based manuscripts which includes use of precision medicine MeSH terms and participation in autoantibody standardization workshops., (© 2024. The Author(s).)

Alzheimer's disease (AD) is a neurodegenerative disorder that impairs mental ability and interrupts cognitive function. Heavy metal exposure like aluminum chloride is associated with neurotoxicity linked to neuro-inflammation, oxidative stress, accumulation of amyloid plaques, phosphorylation of tau proteins associated with AD like symptoms. The objective of the present investigation was to assess the effect 3-acetyl coumarin (3AC) in a rat model of AD. Preliminary screening was performed with SWISS ADME to check for the bioavailability of 3-AC and likeness score which proved favorable. 3-AC docked against Caspase 3, NF-κβ and tau protein kinase I exhibited good binding energies. Male rats were divided into six groups (n = 5). AlCl 3 (100 mg/kg BW) was administered for 28 days before starting treatment to induce AD. Normal control rats received vehicle. Treatment groups received 10, 20 and 30 mg/kg 3-AC for 28 days. Rivastigmine (2 mg/kg) was the standard. Behavioral tests (EPM, MWM) were performed at 7-day intervals throughout study period. Rats showed improved spatial memory and learning in treatment groups during behavioral tests. Rats were euthanized on day 28. Inflammatory markers (IL-1β, IL-16 and TNFα) exhibited significant improvement (p < 0.001) in treated rats. Oxidative stress enzymes (SOD, CAT, GSH, MDA) were restored. Caspase3 and NF-κβ quantified through qRT-PCR also decreased significantly (p < 0.001) when compared to disease control group. Levels of acetyl cholinesterase, dopamine and noradrenaline were also restored in treated rats significantly (p < 0.001). 3-AC treatment restored neuroprotection probably because of anti-inflammatory, anti-oxidant and anti-cholinesterase potential; hence, this can be considered a promising therapeutic potential alternative., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The prefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories center on learning the expectation of potential rewarding outcomes and explain a wealth of neural data in the prefrontal cortex. Distributional RL, on the other hand, learns the full distribution of rewarding outcomes and better explains dopamine responses. In the present study, we show that distributional RL also better explains macaque anterior cingulate cortex neuronal responses, suggesting that it is a common mechanism for reward-guided learning., (© 2024. The Author(s).)

Introduction: Globally, sexually transmissible infections (STIs) continue to disproportionately affect young people. Regular STI testing is an important public health strategy but remains low among this age group. Raising awareness of testing is an essential step and requires effective interventions designed for young people. To inform the development of effective interventions that promote STI testing among young people, we conducted a systematic literature review to describe the social marketing and visual design components commonly found in STI testing interventions and explore associations of these components with intervention effectiveness., Methods: We used a systemic review methodology to identify peer-reviewed articles that met pre-defined inclusion criteria. Social marketing and visual component analyses were conducted using structured data extraction tools and coding schemes, based on the eight key social marketing principles and 28 descriptive dimensions for visual analysis., Results: 18 studies focusing on 13 separate interventions met the inclusion criteria. Most interventions used photograph-based images, using conventionally attractive actors, positioned centrally and making direct eye contact to engage the viewer. The majority of interventions featured text sparingly and drew on a range of tones (e.g. serious, humorous, positive, reassuring, empowering and informative) and three interventions used sexualised content. Four articles explicitly stated that the interventions was informed by social marketing principles, with two explicitly referencing all eight principles. Around half of the articles reported using a formal theoretical framework, but most were considered to have theoretical constructs implicit in interventions materials. Four articles provided detailed information regarding developmental consumer research or pre-testing. All articles suggested segmentation and development of materials specifically for young people. Explicit consideration of motivation and competition was lacking across all articles. This study found that there were some design elements common to interventions which were considered more effective. High social marketing complexity (where interventions met at least seven of the 11 criteria for complexity) seemed to be associated with more effective interventions., Conclusions: Our findings suggest that the incorporation of social marketing principles, could be more important for intervention effectiveness than specific elements of visual design. Effective and systematic use of social marketing principles may help to inform future evidence-informed and theoretically based interventions and should be employed within sexual health improvement efforts., (© 2024. The Author(s).)

Human reasoning depends on reusing pieces of information by putting them together in new ways. However, very little is known about how compositional computation is implemented in the brain. Here, we ask participants to solve a series of problems that each require constructing a whole from a set of elements. With fMRI, we find that representations of novel constructed objects in the frontal cortex and hippocampus are relational and compositional. With MEG, we find that replay assembles elements into compounds, with each replay sequence constituting a hypothesis about a possible configuration of elements. The content of sequences evolves as participants solve each puzzle, progressing from predictable to uncertain elements and gradually converging on the correct configuration. Together, these results suggest a computational bridge between apparently distinct functions of hippocampal-prefrontal circuitry and a role for generative replay in compositional inference and hypothesis testing., Competing Interests: Declaration of interests Z.K.-N. and M.B. are employed by DeepMind Technologies Limited., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Overexploitation, habitat fragmentation, and flow alteration are major threats to freshwater biodiversity that can lead to fisheries collapse and species extinction. These threats are particularly alarming in poorly monitored ecosystems where resource use supports the livelihoods of numerous people. The Tonle Sap Lake in Cambodia is such an ecosystem, supporting one of the world's largest freshwater fisheries. Tonle Sap Lake fishes are the focus of indiscriminate harvest affecting species stocks, community composition and food-web structure. Changes in the magnitude and timing of the seasonal flood pulse have also been linked to declines in fish stocks. Yet, changes in fish abundance and species-specific temporal trends remain poorly documented. Analyzing 17 years' time series of fish catch data for 110 species, we show that fish populations have declined by 87.7 %, owing to a statistically significant decline for >74 % species, particularly the largest ones. Despite large variations in species-specific trends - going from locally extinct to >1000 % increase - declines were found across most migratory behaviors, trophic positions or IUCN threat categories, though uncertainty regarding the magnitude of effect precluded us drawing conclusions in some cases. These results, reminiscent of alarming declines in fish stocks in many marine fisheries, provide unequivocal evidence that Tonle Sap fish stocks are increasingly depleted. The consequences of this depletion on ecosystem function are unknown but will undoubtedly affect the livelihoods of millions of people, stressing the need to set-up management strategies aimed to protect both the fishery and its associated diversity. Flow alteration, habitat degradation / fragmentation - especially deforestation of seasonally inundated areas and overharvest - have been reported as major drivers in population dynamics and community structure, highlighting the need for management efforts aimed at preserving the natural flood pulse, protecting flooded forest habitats, and reducing overfishing., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zeb Hogan reports financial support was provided by USAID. Gael Grenouillet reports financial support was provided by French National Research Agency., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: Diabetic retinopathy (DR) is a common microvascular complication of diabetes and a leading cause of blindness among working-age adults in the US., Objective: To update estimates of DR and vision-threatening diabetic retinopathy (VTDR) prevalence by demographic factors and US county and state., Data Sources: The study team included data from the National Health and Nutrition Examination Survey (2005 to 2008 and 2017 to March 2020), Medicare fee-for-service claims (2018), IBM MarketScan commercial insurance claims (2016), population-based studies of adult eye disease (2001 to 2016), 2 studies of diabetes in youth (2021 and 2023), and a previously published analysis of diabetes by county (2012). The study team used population estimates from the US Census Bureau., Study Selection: The study team included relevant data from the US Centers for Disease Control and Prevention's Vision and Eye Health Surveillance System., Data Extraction and Synthesis: Using bayesian meta-regression methods, the study team estimated the prevalence of DR and VTDR stratified by age, a nondifferentiated sex and gender measure, race, ethnicity, and US county and state., Main Outcomes and Measures: The study team defined individuals with diabetes as those who had a hemoglobin A1c level at 6.5% or more, took insulin, or reported ever having been told by a physician or health care professional that they have diabetes. The study team defined DR as any retinopathy in the presence of diabetes, including nonproliferative retinopathy (mild, moderate, or severe), proliferative retinopathy, or macular edema. The study team defined VTDR as having, in the presence of diabetes, severe nonproliferative retinopathy, proliferative retinopathy, panretinal photocoagulation scars, or macular edema., Results: This study used data from nationally representative and local population-based studies that represent the populations in which they were conducted. For 2021, the study team estimated 9.60 million people (95% uncertainty interval [UI], 7.90-11.55) living with DR, corresponding to a prevalence rate of 26.43% (95% UI, 21.95-31.60) among people with diabetes. The study team estimated 1.84 million people (95% UI, 1.41-2.40) living with VTDR, corresponding to a prevalence rate of 5.06% (95% UI, 3.90-6.57) among people with diabetes. Prevalence of DR and VTDR varied by demographic characteristics and geography., Conclusions and Relevance: US prevalence of diabetes-related eye disease remains high. These updated estimates on the burden and geographic distribution of diabetes-related eye disease can be used to inform the allocation of public health resources and interventions to communities and populations at highest risk.

Objective: Our aim was to assess central and peripheral retinal and choroidal diseases using novel simultaneous multiwavelength-ultra-widefield (MW-UWF) fundus fluorescein angiography (FFA)/indocyanine green angiography (ICGA) with navigated central and peripheral swept-source optical coherence tomography (SS-OCT) technology., Methods: Retrospective evaluation was carried out of 30 consecutive patients (60 eyes) who underwent UWF red/green (RG), infrared (IR), FFA and ICGA with simultaneous navigated SS-OCT using Optos Silverstone (Optos PLC). Angiographic retinal and choroidal findings in vascular pathologies and their relationship with the vitreoretinal interface (VRI) were assessed., Results: Simultaneous FFA with navigated SSOCT was performed in all patients and simultaneous FFA-ICGA with SS-OCT in 18 eyes (30%). Cross-sectional central and peripheral changes in the retina, choroid, and VRI corresponding with angiographic findings in several diseases were imaged., Conclusion: First-in-human study of a new technology providing UWF RG/FFA/ICGA with simultaneous navigated central and peripheral SS-OCT can guide clinical management and provide new insights and understanding of central and peripheral retinal and choroidal disease. [ Ophthalmic Surg Lasers Imaging Retina 2023;54:401-410.] .

Objective: This study was undertaken to assess and evaluate adherence to secondary prevention recommendations and risk factor modifications among a patient cohort at a single-tertiary centre in Ireland, following coronary artery bypass grafting (CABG)., Methods: This is a retrospective observational study analysing patients who had CABG from 2015 to 2020, identified via the Adult Cardiac Surgery Database. Patients were asked a number of questions either over the phone or via postal survey, regarding blood pressure, cholesterol control, adherence to medication, attendance at cardiac-rehab and lifestyle factors. Any repeat interventions following CABG were noted., Results: A total of 540 patients were invited to take part in this study. One hundred seventy-three patients consented to participate, ranging from 47 to 86 years old. Postoperatively, 59% of participants attended cardiac rehab. 90.2% of patients report taking a statin, 91.3% report taking an antiplatelet, 77.4% report taking a β-blocker and 75.7% take an antihypertensive. 93.1% of patients questioned in this study reported full compliance with their daily medications. Sixteen patients continue to have hypertension despite their current regimen. Thirteen patients continue to have hypercholesterolemia despite their current prescription. 62.4% of participants have quit smoking with only 4.6% remaining current smokers. No patients required re-operation, and eight patients required stenting. Compliance with diet and exercise modifications was suboptimal., Conclusion: In this patient population, adherence to medication and control of risk factors is acceptable. However, there is room for improvement in terms of attendance at cardiac rehab (59%) and maintenance of a healthy lifestyle post-CABG., (© 2022. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

The Androgen Receptor (AR) gene plays a key role in castration-resistant prostate cancer (CRPC). Controlling the progression of CRPC by inhibiting AR gene expression is one of the core directions for prostate cancer (Pca) drug development. A 23-amino acids retention, named exon 3a, into the DNA binding domain of the splice variant AR23 has been shown to prevent AR from entering the nucleus and restore the sensitivity of cancer cells to related therapies. In this study, we conducted a preliminary investigation of the splicing modulation of the AR gene in order to develop a splice-switching therapy for Pca by promoting exon 3a inclusion. Using mutagenesis-coupled RT-PCR with AR minigene and over-expression of certain splicing factors, we found that serine/arginine-rich (SR) proteins are key factors facilitating the recognition of the 3' splice site of exon 3a (L-3' SS), while the deletion or blocking of the polypyrimidine tract (PPT) region of the original 3' splice site of exon 3 (S-3' SS) could strongly enhance exon 3a splicing without affecting the function of any SR protein. Furthermore, we designed a series of antisense oligonucleotides (ASOs) to screen drug candidates, and ASOs targeting S-3' SS and its PPT region or the exonic region of exon 3 turned out to be most effective in rescuing exon 3a splicing. A dose-response test indicated ASO12 as the lead candidate drug significantly promoting the inclusion of exon 3a to more than 85%. MTT assay confirmed that the cell proliferation was significantly inhibited after ASO treatment. Our results provide the first glance to AR splicing regulation. With several promising therapeutic ASO candidates obtained here, further development of ASO drugs to treat CRPC is strongly encouraged., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Purpose: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM)., Methods: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index., Results: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments., Conclusions: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769)., Competing Interests: Conflict of Interest M.D.B. discloses research support from Viacyte and Dexcom, DSMB membership for Insulet, and advisory board for Ariel Precision Medicine. Y.C.K. reports research support from Dexcom and advisory Board for Novo Nordisk Inc. K.M. is currently employed by Eli Lilly and Company. His contribution to this work preceded, and was independent of, this employment. None of the other authors have potential conflicts., (Published by Oxford University Press on behalf of the Endocrine Society 2022.)

Imposing an external periodic electrostatic potential to the electrons confined in a quantum well makes it possible to engineer synthetic two-dimensional band structures, with electronic properties different from those in the host semiconductor. Here we report the fabrication and study of a tunable triangular artificial lattice on a GaAs/AlGaAs heterostructure where it is possible to transform from the original GaAs band structure and a circular Fermi surface to a new band structure with multiple artificial Fermi surfaces simply by altering a gate bias. For weak electrostatic modulation magnetotransport measurements reveal multiple quantum oscillations and commensurability oscillations due to the electron scattering from the artificial lattice. Increasing the strength of the modulation reveals new commensurability oscillations of the electrons from the artificial Fermi surface scattering from the triangular artificial lattice. These results show that low disorder gate-tunable lateral superlattices can be used to form artificial two-dimensional crystals with designer electronic properties.

Introduction: Delay discounting (DD), the preference for smaller and sooner rewards over larger and later ones, is an important behavioural phenomenon for daily functioning of increasing interest within psychopathology. The neurobiological mechanisms behind DD are not well understood and the literature on structural correlates of DD shows inconsistencies., Methods: Here we leveraged a large openly available dataset (n = 1196) to investigate associations with memory performance and gray and white matter correlates of DD using linked independent component analysis., Results: Greater DD was related to smaller anterior temporal gray matter volume. Associations of DD with total cortical volume, subcortical volumes, markers of white matter microscopic organization, working memory, and episodic memory scores were not significant after controlling for education and income., Conclusion: Effects of size comparable to the one we identified would be unlikely to be replicated with sample sizes common in many previous studies in this domain, which may explain the incongruities in the literature. The paucity and small size of the effects detected in our data underscore the importance of using large samples together with methods that accommodate their statistical structure and appropriate control for confounders, as well as the need to devise paradigms with improved task parameter reliability in studies relating brain structure and cognitive abilities with DD., (© The Author(s) 2022. Published by Oxford University Press.)

Replay in the brain has been viewed as rehearsal or, more recently, as sampling from a transition model. Here, we propose a new hypothesis: that replay is able to implement a form of compositional computation where entities are assembled into relationally bound structures to derive qualitatively new knowledge. This idea builds on recent advances in neuroscience, which indicate that the hippocampus flexibly binds objects to generalizable roles and that replay strings these role-bound objects into compound statements. We suggest experiments to test our hypothesis, and we end by noting the implications for AI systems which lack the human ability to radically generalize past experience to solve new problems., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Summary: Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism triggered by precipitants that increase the activity of the sodium-potassium pump in the skeletal muscle. In our case study, a previously healthy 34-year-old male presented to the emergency department with new onset thyrotoxicosis, secondary to Graves' disease. Given the severity of his triiodothyronine (T3) thyrotoxicosis, he was admitted and started on a high dose of beta-blocker, thioamides, and intravenous hydrocortisone. On the second day of his hospitalization, he developed acute flaccid paralysis of his lower extremities. Subsequent stroke workup was negative, and his electrolytes revealed severe hypokalemia and hyperglycemia consistent with TPP. He was treated with potassium and had a complete recovery of his paralysis and hypokalemia within hours. The patient has not had any recurrence since this singular episode in the hospital. This case highlights the scenario where the treatment of hyperthyroidism with high-dose corticosteroids to reduce the conversion of thyroxine to T3 inadvertently resulted in TPP. Clinicians should be aware of this potentially rare but serious consequence of using steroids to manage hyperthyroidism., Learning Points: High-dose steroids used to treat hyperthyroidism in hospitalized patients may rarely precipitate thyrotoxic periodic paralysis (TPP) by inducing hypokalemia and hyperglycemia. TPP should be included in the differential diagnosis for acute flaccid paralysis in hospitalized patients with hyperthyroidism. Since TPP is associated with trans-cellular shifts in potassium instead of total body potassium depletion, conservative repletion of potassium is recommended to avoid rebound hyperkalemia.

This study evaluated whether different colour intensities of ribeye steaks from dark-cutting (B4 grade) beef carcasses (Dark-B4DK/Moderate-B4MD) were similar in appearance and eating quality to steaks from normal (N) carcasses of lower marbling grades (AA or A) as assessed by consumers. The B4MDAAA and B4DK/MDAA had similar raw appearance and eating quality to N carcasses with a one quality downgrade for marbling (P > 0.1), potentially supporting a B4MDAAA and B4DK/MDAA re-class to NAA and NA grades, respectively. Cooked B4DKAAA steaks had greater juiciness and tenderness acceptability (P < 0.01) and similar appearance, flavour and overall acceptability and purchase intent compared to NAA steaks (P > 0.1). However, consumers perceived greater marbling and lower colour acceptability (P < 0.01) in raw B4DKAAA compared to NAA steaks, lowering the purchase intent scores of B4DKAAA steaks (P < 0.01). These results suggest merit for continuing a B4DKAAA segregated grade, unless the superior eating quality of B4DKAAA could offset its poorer raw appearance through consumer education or modified atmosphere packaging., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the frequent bacterial pathogens causing blood stream infections in various age brackets, and to discover their antibiotic susceptibility pattern., Methods: The retrospective, descriptive, observational, cross-sectional study was conducted at the microbiology laboratory of Patel Hospital, Karachi, and comprised positive blood culture bacterial isolates analysed between July 1, 2018, and June 30, 2019. Standard microbiological techniques were employed for the identification and antimicrobial susceptibility testing. Data was analysed using SPSS 20., Results: Of the 3450 specimen, 1243(36%) were positive; 668(53.7%) from male and 575(46.3%) from female subjects, and 771(62%) were gram-positive whereas 472(38%).were gram-negative. Salmonella typhi was the most common pathogen 139(11.1) among gram-negative organisms, followed by Acinetobacter species 103(8.2%), Escherichia coli 96(7.7%) and Klebsiella species 42(3.4%). Among gram-positive bacteria, the predominant isolates were staphylococcus epidermidis 650(52%), staphylococcus aureus 67(5.4%) and enterococci 28(2.3%). Linezolid (99.8%), vancomycin (99%) and chloramphenicol (69%) were found to be the most sensitive antibiotics among gram-positive cocci. Meropenem (60%), amikacin (46%) and gentamicin (40%) were the most sensitive antibiotics for multidrug resistant gram-negative bacteria., Conclusions: The identification of frequent bacterial pathogens in blood cultures of patients may guide clinicians in proper empirical selection of antibiotics in patients with bacteraemia.

Importance: Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness. AMD prevalence has not been estimated for the US in over a decade and early-stage AMD prevalence estimates are scarce and inconsistently measured., Objective: To produce estimates of early- and late-stage AMD prevalence overall and by age, gender, race and ethnicity, county, and state., Design, Setting, and Participants: The study team conducted a bayesian meta-regression analysis of relevant data sources containing information on the prevalence of AMD among different population groups in the US., Data Sources: We included data from the American Community Survey (2019), the National Health and Nutrition Examination Survey (2005-2008), US Centers for Medicare & Medicaid Services claims for fee-for-service beneficiaries (2018), and population-based studies (2004-2016)., Study Selection: We included all relevant data from the US Centers for Disease Control and Prevention's Vision and Eye Health Surveillance System., Data Extraction and Synthesis: The prevalence of early- and late-stage AMD was estimated and stratified when possible by factors including county, age group, gender, and race and ethnicity. Data analysis occurred from June 2021 to April 2022., Main Outcomes or Measures: The prevalence of early- (defined as retinal pigment epithelium abnormalities or the presence of drusen 125 or more microns in diameter in either eye) and late-stage (defined as choroidal neovascularization and/or geographic atrophy in either eye) manifestations of AMD., Results: This study used data from nationally representative and local population-based studies that represent the populations in which they were conducted. For 2019, we estimated that there were 18.34 million people 40 years and older (95% uncertainty interval [UI], 15.30-22.03) living with early-stage AMD, corresponding to a crude prevalence rate of 11.64% (95% UI, 9.71-13.98). We estimated there were 1.49 million people 40 years and older (95% UI, 0.97-2.15) living with late-stage AMD, corresponding to a crude prevalence rate of 0.94% (95% UI, 0.62-1.36). Prevalence rates of early- and late-stage AMD varied by demographic characteristics and geography., Conclusions and Relevance: We estimated a higher prevalence of early-stage AMD and a similar prevalence of late-stage AMD as compared with earlier studies. State-level and county-level AMD estimates may help guide public health practice.

Periodic lattices in hyperbolic space are characterized by symmetries beyond Euclidean crystallographic groups, offering a new platform for classical and quantum waves, demonstrating great potential for a new class of topological metamaterials. One important feature of hyperbolic lattices is that their translation group is nonabelian, permitting high-dimensional irreducible representations (irreps), in contrast to abelian translation groups in Euclidean lattices. Here we introduce a general framework to construct wave eigenstates of high-dimensional irreps of infinite hyperbolic lattices, thereby generalizing Bloch's theorem, and discuss its implications on unusual mode counting and degeneracy, as well as bulk-edge correspondence in hyperbolic lattices. We apply this method to a mechanical hyperbolic lattice, and characterize its band structure and zero modes of high-dimensional irreps.

Background: Mass medical migration from Pakistan to more developed counties pose a threat to the professional resources of Pakistan. The aim of our study is to assess magnitude of the brain drain and to assess reasons behind it., Methods: A Cross-sectional study, using convenience non-probability sampling, with sample of 201 Ayub Medical College graduates. A simple questionnaire was designed on Google Forms, comprising of three sections including bio data, intentions to emigrate and the last part evaluating work environment, training and personal factors associated with the desire to train abroad. Data was analysed using SPSS version 20.0, descriptive statistics were calculated and Chi square test was used to determine association between various groups of push and pull factors and the intention to train abroad. A significance level (p-value) of less than 0.05 was used., Results: Over half (63.68%) of our participants wanted to emigrate, and out of the remaining 71.6% would consider it in the future if given the opportunity. Overall, more males wanted to train overseas as compared to females, and the United Kingdom was the most popular destination. The leading factor push factors behind wanting to move abroad were quality of training and a poor work environment. While family commitments and costly examinations were the main reasons to stay in Pakistan., Conclusions: A significant number of young doctors are planning on pursue training/careers abroad. If this large-scale brain drain is not addressed on time, it can have various implications in the future. Hence the Government and Medical authorities must take action in order to prevent further loss.

Context: Lymphocytic hypophysitis (LyHy) is characterized by inflammation of the pituitary and or neuroinfundibulum and is uncommon. Treatment options include observation, high-dose glucocorticoids (HD-GCs) or surgery. Optimal first-line management strategy, however, remains unknown., Objective: This work aimed to assess response to first-line treatment options (observation, HD-GCs, or surgery) of clinically relevant outcomes (symptomatic, hormonal, and radiographic improvement) among patients with LyHy., Methods: A systematic review was conducted in 6 databases through 2020. Meta-analysis was conducted when feasible using a random-effects model., Results: We included 33 studies reporting on 591 patients (423 women, 72%) with LyHy. Improvement/resolution of anterior pituitary dysfunction was highest when HD-GCs was first-line treatment. Surgery was associated with the greatest proportion of patients who had regression on imaging. Subgroup analysis comparing HD-GCs to observation showed the odds of anterior pituitary hormone recovery (OR 3.41; 95% CI, 1.68-6.94) or radiographic regression (OR 3.13; 95% CI, 1.54-6.36) were higher with HD-GCs, but so was the need for additional forms of treatment (OR 4.37; 95% CI, 1.70-11.22). No statistically significant difference was seen in recovery of diabetes insipidus (OR 0.9; 95% CI, 0.26-3.10). Certainty in these estimates was very low., Conclusion: Observation and use of HD-GCs both are successful first-line management strategies in LyHy. Although use of HD-GCs was associated with increased recovery of anterior pituitary hormone deficit, it also was associated with greater likelihood of additional treatment after withdrawal. Optimal dosing and duration of HD-GCs remains unknown., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8-11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration's Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.

Global freshwater biodiversity is declining dramatically, and meeting the challenges of this crisis requires bold goals and the mobilisation of substantial resources. While the reasons are varied, investments in both research and conservation of freshwater biodiversity lag far behind those in the terrestrial and marine realms. Inspired by a global consultation, we identify 15 pressing priority needs, grouped into five research areas, in an effort to support informed stewardship of freshwater biodiversity. The proposed agenda aims to advance freshwater biodiversity research globally as a critical step in improving coordinated actions towards its sustainable management and conservation., (© 2021 The Authors. Ecology Letters published by John Wiley & Sons Ltd.)

Understanding how and why the size of populations varies is critical knowledge for conservation and management. While considerable work has explored how different demographic parameters affect population growth, less is known the drivers of variability in these parameters. Long-term time series tracking population size that are coupled with empirical data to examine the relative importance of different drivers are rare, especially in freshwater systems. Even rarer are studies that collect this information concurrently from multiple species with contrasting life history strategies in the same system to assess whether population size and the relative importance of drivers also vary. We studied changes in the abundance and size structure of four native freshwater fish species in the Murray River, southeastern Australia, over a continuous 19-yr period. Two species with traits typical of "equilibrium" species (Murray cod Maccullochella peelii and trout cod Maccullochella macquariensis) and two with traits of "periodic" species (golden perch Macquaria ambigua and silver perch Bidyanus bidyanus) were sampled annually and capture-mark-recapture modeling was used to ask (1) how did population size change during this period, (2) how were changes in population size related to variability in hydrology, and (3) how were changes in population size driven by different processes (local recruitment or migration events)? Populations of all four species varied throughout the study, and our results are consistent with the notion that local recruitment is an important driver of this variability for Murray cod and trout cod, whereas immigration is more important for the two other species. Increases in spring river discharge strongly influenced these responses for trout cod and golden perch. Our study provides fundamental insights into the population dynamics of these valued species, and how management strategies might differ based on their life histories. Management should focus on allowing connectivity for golden and silver perch, and on promoting local scale recruitment and survival for Murray cod and trout cod. More generally, our study highlights the importance of understanding the processes underpinning population persistence, how these processes may vary for different species, and ultimately how this knowledge can inform targeted management actions., (© 2021 by the Ecological Society of America.)

Directional or stabilising selection should drive the expression of a dominant movement phenotype within a population. Widespread persistence of multiple movement phenotypes within wild populations, however, suggests that individuals that move (movers) and those that do not (residents) can have commensurate performance. The costs and benefits of mover and resident phenotypes remain poorly understood. Here, we explored how the presence and timing of movements are correlated with annual somatic growth rates, a useful proxy for performance because it is easily measured and rapidly reflects environmental changes. We used otolith growth measurements and stable isotope analyses to recreate growth and among-reach movement histories of a partially migrating, long-lived freshwater fish, golden perch Macquaria ambigua. We compared the association between movement and growth at two temporal scales: (a) short-term (annual) differences in growth, in the years preceding, during or following movement; and (b) long-term (lifetime) differences in growth. Overall, 59% of individuals performed at least one among-reach movement, with these individuals subsequently more likely to move repeatedly throughout their lives. Movers grew faster than residents, with this difference most pronounced in the juvenile and early adult stages, when most movements occurred. Annual growth did not, however, change immediately prior to or following a specific movement event. Among-individual variation in growth was initially higher for residents than for movers but decreased with age, at a faster rate for residents than for movers, such that levels conformed after 5 years of age. Our results indicate that lifetime movement is linked to faster growth in the early years of a fish's life. These faster growing movers are likely to be larger at a given age, leading to numerous potential benefits. However, the persistence of resident phenotypes suggests that there is likely a cost-benefit trade-off to moving. The presence of multiple movement phenotypes may contribute to the resilience of populations by buffering against naturally and anthropogenically exacerbated environmental variability., (© 2021 British Ecological Society.)

A dislike of waiting for pain, aptly termed 'dread', is so great that people will increase pain to avoid delaying it. However, despite many accounts of altruistic responses to pain in others, no previous studies have tested whether people take delay into account when attempting to ameliorate others' pain. We examined the impact of delay in 2 experiments where participants (total N = 130) specified the intensity and delay of pain either for themselves or another person. Participants were willing to increase the experimental pain of another participant to avoid delaying it, indicative of dread, though did so to a lesser extent than was the case for their own pain. We observed a similar attenuation in dread when participants chose the timing of a hypothetical painful medical treatment for a close friend or relative, but no such attenuation when participants chose for a more distant acquaintance. A model in which altruism is biased to privilege pain intensity over the dread of pain parsimoniously accounts for these findings. We refer to this underestimation of others' dread as a 'Dread Empathy Gap'., (© 2021 The Authors. Journal of the Experimental Analysis of Behavior published by Wiley Periodicals LLC on behalf of Society for the Experimental Analysis of Behavior.)

Context: There is little information about fatty liver in prediabetes as it transitions to early diabetes., Objective: This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP)., Methods: We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed., Results: There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence., Conclusion: Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Population genetic analyses can evaluate how evolutionary processes shape diversity and inform conservation and management of imperiled species. Taimen (Hucho taimen), the world's largest freshwater salmonid, is threatened, endangered, or extirpated across much of its range due to anthropogenic activity including overfishing and habitat degradation. We generated genetic data using high throughput sequencing of reduced representation libraries for taimen from multiple drainages in Mongolia and Russia. Nucleotide diversity estimates were within the range documented in other salmonids, suggesting moderate diversity despite widespread population declines. Similar to other recent studies, our analyses revealed pronounced differentiation among the Arctic (Selenge) and Pacific (Amur and Tugur) drainages, suggesting historical isolation among these systems. However, we found evidence for finer-scale structure within the Pacific drainages, including unexpected differentiation between tributaries and the mainstem of the Tugur River. Differentiation across the Amur and Tugur basins together with coalescent-based demographic modeling suggests the ancestors of Tugur tributary taimen likely diverged in the eastern Amur basin, prior to eventual colonization of the Tugur basin. Our results suggest the potential for differentiation of taimen at different geographic scales, and suggest more thorough geographic and genomic sampling may be needed to inform conservation and management of this iconic salmonid., (© 2021. The Author(s).)

Several muscles from mature beef carcasses have been identified as failing to provide adequate tenderness required for a satisfactory consumer eating experience. Postmortem processing strategies can help improve the tenderness and subsequent eating quality of mature beef muscles. The current study was undertaken to investigate the impact of processing strategies (blade tenderization [BT], pretumbling [PT], and moisture enhancement [ME]), alone and in combination, on processing yield and eating quality-related parameters of selected loin and hip muscles (gluteus medius [GM], longissimus lumborum [LL], semimembranosus [SM], and biceps femoris [BF]) from youthful and mature beef cattle. Results indicate that muscles from mature beef were inherently less tender ( P < 0.05), but some tenderization procedures produced meat that was similar in tenderness to that of youthful cattle. Of the different tenderization strategies evaluated, BT followed by ME (injection of a salt/phosphate solution) was the most effective strategy for improving ( P < 0.05) tenderness of tougher muscle cuts such as BF and SM. Moisture enhancement alone improved tenderness ( P < 0.05) and juiciness ( P < 0.01) of SM, GM and LL, but with the exception of samples tenderized prior to injection, was not effective ( P > 0.05) in BF muscles. No additional tenderization of GM and LL samples was observed ( P > 0.05) by combining PT or BT with ME. Combining PT or BT with ME; however, was effective ( P < 0.05) to control the increased purge loss observed following ME treatment in SM and LL muscles. Pretumbling as a single treatment was ineffective ( P > 0.05) in all of the muscles, and only treatments that included BT were sufficient to effect an increase ( P < 0.05) in tenderness of BF., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society of Animal Science.)

Background: Owing to recent changes in consumer eating behaviours as well as potential cost savings for processors, pulse ingredients are finding more application in the meat processing industry. In this study, pea ingredients (pea fibre, FB; pea starch, ST; pea flour, PF) and chickpea flour (CF) were used, at 4% addition level, as fat replacers in low-fat breakfast sausages. The impact of these substitutions on processing and sensory characteristics of breakfast sausage was evaluated., Results: While reduction in fat content in breakfast sausage resulted in some detrimental changes in cooking as well as textural characteristics of the product, addition of binders significantly improved these attributes in low-fat breakfast sausages. Overall, treatment formulation did not significantly affect the pH and the instrumental colour attributes of cooked breakfast sausage. Addition of all binders resulted in reduced cooking loss and increased moisture retention in low-fat breakfast sausage (P < 0.05), whereas, FB and ST were significantly more effective in improving water holding capacity of low-fat breakfast sausage. Furthermore, while both FB and ST increased the hardness, cohesiveness and chewiness parameters of low-fat breakfast sausage (P < 0.05), PF and CF had no impact. Generally, the consumer overall liking and flavour acceptability of FB and ST in low-fat breakfast sausage were significantly higher than those of PF and CF., Conclusion: The use of ST or FB as a fat replacer in breakfast sausages offers processors improved cook yield without negatively impacting the important sensory attributes of breakfast sausages. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Electrochemical CO 2 reduction reaction (CO 2 RR) provides a promising approach to curbing harmful emissions contributing to global warming. However, several challenges hinder the commercialization of this technology, including high overpotentials, electrode instability, and low Faradic efficiencies of desirable products. Several materials have been developed to overcome these challenges. This mini-review discusses the recent performance of various cobalt (Co) electrocatalysts, including Co-single atom, Co-multi metals, Co-complexes, Co-based metal-organic frameworks (MOFs), Co-based covalent organic frameworks (COFs), Co-nitrides, and Co-oxides. These materials are reviewed with respect to their stability of facilitating CO 2 conversion to valuable products, and a summary of the current literature is highlighted, along with future perspectives for the development of efficient CO 2 RR.

An ability to build structured mental maps of the world underpins our capacity to imagine relationships between objects that extend beyond experience. In rodents, such representations are supported by sequential place cell reactivations during rest, known as replay. Schizophrenia is proposed to reflect a compromise in structured mental representations, with animal models reporting abnormalities in hippocampal replay and associated ripple activity during rest. Here, utilizing magnetoencephalography (MEG), we tasked patients with schizophrenia and control participants to infer unobserved relationships between objects by reorganizing visual experiences containing these objects. During a post-task rest session, controls exhibited fast spontaneous neural reactivation of presented objects that replayed inferred relationships. Replay was coincident with increased ripple power in hippocampus. Patients showed both reduced replay and augmented ripple power relative to controls, convergent with findings in animal models. These abnormalities are linked to impairments in behavioral acquisition and subsequent neural representation of task structure., Competing Interests: Declaration of interests Z.K.-N. is an employee of Deepmind Technologies Ltd. The remaining authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Empagliflozin is a selective inhibitor of sodium glucose co-transporter II, given as mono therapy or an add-on treatment to reduce the glycated hemoglobin levels in type 2 diabetes. This work deals with designing, formulating and optimizing empagliflozin (10mg) immediate release (IR) tablets by direct compression technique using different excipients. Through central composite rotatable design (CCRD), total nine formulations (EF1-EF9) were generated by changing the composition of binder avicel PH 102® (X1) and superdisintegrant acdisol⌖ (X2). Formulation runs with in suitable weight range and powder properties were subjected to compression. The influence of interaction of excipients on friability (Y1), hardness (Y2) and disintegration (Y3) were analyzed by fitting the polynomial quadratic model with response surface methodology (RSM). Trials EF2, EF7, EF8 and EF9 exhibited acceptable tablet attributes upon physico-chemical testing. Different dissolution models were applied to observe the in vitro drug release pattern in phosphate buffer of pH 6.8. The cumulative drug release of IR tablet batches followed the Weibull kinetics with regression coefficient (r2) values of 0.983-0.992. Empagliflozin trials were exposed to accelerated storage conditions (40±2°C/ 75±5% RH) for stability testing. Shelf life period of exposed formulations were computed in range of 22 to 25 months. Keeping in view of the results, it is concluded that the employed technique of preparation and optimization are observed to be excellent for developing immediate release empagliflozin (10mg) tablets.

Anthropogenic alterations to river flow regimes threaten freshwater biodiversity globally, with potentially disproportionate impacts on species that rely on flow cues to trigger critical life history processes, such as migration for diadromous fishes. This study investigates the influence of river discharge on the abundance of juvenile fish moving into rivers by four temperate catadromous or amphidromous species (common galaxias Galaxias maculatus, spotted galaxias Galaxias truttaceus, climbing galaxias Galaxias brevipinnis and the threatened Australian grayling Prototroctes maraena). Fyke netting or fishway trapping was used to catch juvenile fish moving from estuaries into freshwater in five coastal waterways in south-eastern Australia during the spring migratory period. There was a positive relationship between the probability of high catch rates and mean discharge in September. We also found a positive relationship between discharge and the number of recruits captured 22-30 days later in a flow stressed system. In addition, day-of-year had a strong influence on catch rates, with the peak abundance of juveniles for three species most likely to occur midway through the sampling period (spotted galaxias in October, climbing galaxias in late October and Australian grayling in late October and early November). Our study shows that higher magnitudes of river discharge were associated with increased catches of juvenile catadromous and amphidromous fishes. With a limited supply of environmental water, environmental flows used to enhance immigration of these fishes may be best targeted to maintain small amounts of immigration into freshwater populations in waterways or years when discharges are low and stable. When there are natural, large discharge volumes, relatively large numbers of juvenile fish can be expected to enter coastal waterways and during these times environmental flows may not be required to promote immigration., (© 2021 Commonwealth of Australia. Journal of Fish Biology © 2021 Fisheries Society of the British Isles.)

There are rich structures in off-task neural activity which are hypothesized to reflect fundamental computations across a broad spectrum of cognitive functions. Here, we develop an analysis toolkit - temporal delayed linear modelling (TDLM) - for analysing such activity. TDLM is a domain-general method for finding neural sequences that respect a pre-specified transition graph. It combines nonlinear classification and linear temporal modelling to test for statistical regularities in sequences of task-related reactivations. TDLM is developed on the non-invasive neuroimaging data and is designed to take care of confounds and maximize sequence detection ability. Notably, as a linear framework, TDLM can be easily extended, without loss of generality, to capture rodent replay in electrophysiology, including in continuous spaces, as well as addressing second-order inference questions, for example, its temporal and spatial varying pattern. We hope TDLM will advance a deeper understanding of neural computation and promote a richer convergence between animal and human neuroscience., Competing Interests: YL, RD, CH, HP, MW, HÓ, CB No competing interests declared, ZK Zeb Kurth-Nelson is affiliated with DeepMind. The author has no other competing interests to declare. TB Senior editor, eLife, (© 2021, Liu et al.)

Objectives: This paper reports results of an evaluation of 17 holiday clubs located throughout North East England that ran during the summer of 2017, designed to reduced summertime food insecurity., Study Design: Questionnaire administed to parents/caregivers of children who attended a holiday club., Methods: Ordinary Least Squares regression models were used to predict Warwick-Edinburg Mental Wellbeing scale scores measuring parental mental wellbeing., Results: We find that after a summer of attending a holiday club, the most important factor associated with higher parental wellbeing scores is the reduction in social isolation and increased relationships that the parent and their children build while children attend holiday clubs., Conclusions: Our results suggest that reducing social isolation for parents and families during summertime is a likely a latent function of holiday clubs. These are important findings in that the benefits of holiday club appear to extend beyond access to food and reductions in household food insecurity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

The limiting factor in the utilization of herbal medicine is the risk of replacement or substitution of their plant resources. Therefore, the authentication of medicinal plants before its use in herbal medicines is essentially required. Hence, the prime objective of this study was to provide some reliable morpho-anatomical and morpho-palynological tools for the identification of nine traditional therapeutic plants of district Lahore. For this study, scanning electron microscopic and light microscopic approaches has been employed. Results reported great variations in qualitative and quantitative morpho-anatomical features of the epidermal cell, stomatal complexes, trichomes, silica bodies and oil droplets. For example, Aegle marmelos L. can be distinguished from Cestrum diurnum L. based on epidermal cell shapes, as irregular cells in former and lobed cells shape in later one. Similarly unicellular, bicellular, and multicellular trichomes could be an identification basis for Cynodon dactylon L., Lantana camara L., and Pongamia pinnata L., respectively. In combination with these morpho-anatomical characters, SEM-based morpho-palynological characterization also reported diagnostic value. Both the Aegle marmelos and Lantana camara possessed similar cell shape (irregular) but can be delimited based on their pollen morphology as spheroidal pollen was reported in Aegle marmelos whereas prolate in Lantana camara. Moreover, quantitative characters also aid well for species delimitation, such as prolate pollen found in both Cestrum diurnum and Terminalia chebula Retz. but both of these varied in their P/E ratio, that is, 0.97 and 0.88, respectively. The leaf epidermal characters in correlation with morph-palynological traits showed potential for taxonomic resolution at the species level. RESEARCH HIGHLIGHTS: This study provides valuable morpho-anatomical and morpho-palynological tools for the nine traditional therapeutic plants of the district, Lahore, Pakistan. Light and scanning electron microscopic studies provided useful systematic data for the identification of studied plants. This systematic data include moprho-anatomical and morpho-palynological keys for the studied plants. This data can be used for future identification purposes., (© 2020 Wiley Periodicals LLC.)

Our brains at rest spontaneously replay recently acquired information, but how this process is orchestrated to avoid interference with ongoing cognition is an open question. Here we investigated whether replay coincided with spontaneous patterns of whole-brain activity. We found, in two separate datasets, that replay sequences were packaged into transient bursts occurring selectively during activation of the default mode network (DMN) and parietal alpha networks. These networks are believed to support inwardly oriented attention and inhibit bottom-up sensory processing and were characterized by widespread synchronized oscillations coupled to increases in high frequency power, mechanisms thought to coordinate information flow between disparate cortical areas. Our data reveal a tight correspondence between two widely studied phenomena in neural physiology and suggest that the DMN may coordinate replay bursts in a manner that minimizes interference with ongoing cognition., Competing Interests: Declaration of interests Z.K.-N. is employed by DeepMind Technologies Limited., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)