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Non-communicable diseases (NCDs) are a leading health and development challenge worldwide. Since 2015, WHO and the United Nations Development Programme have provided support to governments to develop national NCD investment cases to describe the socioeconomic dimensions of NCDs. To assess the impact of the investment cases, semistructured interviews and a structured process for gathering written feedback were conducted between July and October 2022 with key informants in 13 countries who had developed a national NCD investment case between 2015 and 2020. Investment cases describe: (1) the social and economic costs of NCDs, including their distribution and projections over time; (2) priority areas for scaled up action; (3) the cost and returns from investing in WHO-recommended measures to prevent and manage NCDs; and (4) the political dimensions of NCD responses. While no country had implemented all the recommendations set out in their investment case reports, actions and policy changes attributable to the investment cases were identified, across (1) governance; (2) financing; and (3) health service access and delivery. The pathways of these changes included: (1) stronger collaboration across government ministries and partners; (2) advocacy for NCD prevention and control; (3) grounding efforts in nationally owned data and evidence; (4) developing mutually embraced ‘language’ across health and finance; and (5) elevating the priority accorded to NCDs, by framing action as an investment rather than a cost. The assessment also identified barriers to progress on the investment case implementation, including the influence of some private sector entities on sectors other than health, the impact of the COVID-19 pandemic, and changes in senior political and technical government officials. The results suggest that national NCD investment cases can significantly contribute to catalysing the prevention and control of NCDs through strengthening governance, financing, and health service access and delivery.

Objective. To synthesize learnings from four national tobacco control investment cases conducted in the Americas (Colombia, Costa Rica, El Salvador, Suriname) under the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) 2030 project, to describe results and how national health authorities have used the cases, and to discuss implications for the role of investment cases in advancing tobacco control. Methods. We draw on findings from four national investment cases that included 1) a cost-of-illness analysis calculating the health and economic burden of tobacco use, 2) a return-on-investment analysis of implementing key tobacco control demand reduction measures, and 3) a subsidiary analysis of one tobacco control topic of national interest (e.g., equity implications of cigarette taxation). Co-authors reported how cases have been used to advance tobacco control. Results. In Colombia, Costa Rica, El Salvador, and Suriname, tobacco use causes social and economic losses equivalent to between 1.0 to 1.8 percent of GDP. Across these countries, implementing WHO FCTC demand reduction measures would save an average of 11 400 lives per year over the next 15 years. Benefits of the measures would far outweigh the costs of implementation and enforcement. Governments are using the cases to advance tobacco control, including to improve tobacco control laws and their enforcement, strengthen tobacco taxation, prioritize tobacco control planning, coordinate a multisectoral response, and engage political leaders. Conclusions. National investment cases can help to strengthen tobacco control in countries, including by increasing public and political support for implementation of the WHO FCTC and by informing effective planning, legislation, coordination and financing.

Purpose - The purpose of this study is to examine how the leadership competencies of frontline managers influence the organizational commitment of their subordinates. The study further examines the relationship between the dominant (strongest) competency and organizational commitment and how this relationship is mediated by leadership consistency. Design - Data were collected from employees in seven hotels in two cities using a multilevel scale for competencies and standardized scales for leadership consistency and commitment. Construct validity of the hospitality leadership competency model (HLCM) was tested by confirmatory factor analysis. A stepwise analysis was run to identify dominant competencies (predictors). Finally, a moderated mediation model was tested. Methodology - This research adopted a quantitative approach to collect and analyse the data. Findings - All competencies were highly and positively related to organizational commitment, with team leadership being the dominant competency and predictor. A moderated mediation mechanism analysis shows that leadership consistency mediated the relationship between team leadership and organizational commitment, but this relationship was slightly attenuated by team size. Originality - The study contributes to (1) validating the HLCM at the frontline level and from the employees’ perspective, (2) quantifying the relationships between organizational commitment and leadership competencies, especially team leadership under the mediating effect of leadership consistency, and (3) creating several evidence-based implications for hospitality educators, employers, and managers.

BackgroundNon-communicable diseases (NCDs) are increasingly recognized as a significant threat to health and development globally, and United Nations (UN) Member States adopted the Political Declaration of the Third High-level Meeting (HLM) on the prevention and control of NCDs in 2018. The negotiation process for the Declaration included consultations with Member States, intergovernmental organizations (IGOs), and non-state actors such as non-governmental organizations (NGOs) and the private sector. With NCD responses facing charges of inadequacy, it is important to scrutinize the governance process behind relevant high-level global decisions and commitments. MethodsThrough a review of 159 documents submitted by stakeholders during the negotiation process, we outline a typology of policy positions advocated by various stakeholders in the development of the Declaration. We document changes in text from the draft to the final version of the Declaration to analyse the extent to which various positions and their proponents were influential. ResultsNGOs and low- and middle-income countries (LMICs) generally pursued ‘stricter’ governance of NCD risk factors including stronger regulation of unhealthy products and improved management of conflicts of interest that arise when health-harming industries are involved in health policy-making. The private sector and high-income countries generally opposed greater restrictions on commercial factors. The pattern of changes between the draft and final Declaration indicate that advocated positions tended to be included in the Declaration if there was no clear opponent, whereas opposed positions were either not included or included with ambiguous language. ConclusionMany cost-effective policy options to address NCDs, such as taxation of health-harming products, were opposed by high-income countries and the private sector and not well-represented in the Declaration. To ensure robust political commitments and action on NCDs, multi-stakeholder governance for NCDs must consider imbalances in power and influence amongst constituents as well as biases and conflicts in positioning.

Abstract Background Addressing the social and other non-biological determinants of health largely depends on policies and programmes implemented outside the health sector. While there is growing evidence on the effectiveness of interventions that tackle these upstream determinants, the health sector does not typically prioritise them. From a health perspective, they may not be cost-effective because their non-health outcomes tend to be ignored. Non-health sectors may, in turn, undervalue interventions with important co-benefits for population health, given their focus on their own sectoral objectives. The societal value of win-win interventions with impacts on multiple development goals may, therefore, be under-valued and under-resourced, as a result of siloed resource allocation mechanisms. Pooling budgets across sectors could ensure the total multi-sectoral value of these interventions is captured, and sectors’ shared goals are achieved more efficiently. Under such a co-financing approach, the cost of interventions with multi-sectoral outcomes would be shared by benefiting sectors, stimulating mutually beneficial cross-sectoral investments. Leveraging funding in other sectors could off-set flat-lining global development assistance for health and optimise public spending. Although there have been experiments with such cross-sectoral co-financing in several settings, there has been limited analysis to examine these models, their performance and their institutional feasibility. Aim This study aimed to identify and characterise cross-sectoral co-financing models, their operational modalities, effectiveness, and institutional enablers and barriers. Methods We conducted a systematic review of peer-reviewed and grey literature, following PRISMA guidelines. Studies were included if data was provided on interventions funded across two or more sectors, or multiple budgets. Extracted data were categorised and qualitatively coded. Results Of 2751 publications screened, 81 cases of co-financing were identified. Most were from high-income countries (93%), but six innovative models were found in Uganda, Brazil, El Salvador, Mozambique, Zambia, and Kenya that also included non-public and international payers. The highest number of cases involved the health (93%), social care (64%) and education (22%) sectors. Co-financing models were most often implemented with the intention of integrating services across sectors for defined target populations, although models were also found aimed at health promotion activities outside the health sector and cross-sectoral financial rewards. Interventions were either implemented and governed by a single sector or delivered in an integrated manner with cross-sectoral accountability. Resource constraints and political relevance emerged as key enablers of co-financing, while lack of clarity around the roles of different sectoral players and the objectives of the pooling were found to be barriers to success. Although rigorous impact or economic evaluations were scarce, positive process measures were frequently reported with some evidence suggesting co-financing contributed to improved outcomes. Conclusion Co-financing remains in an exploratory phase, with diverse models having been implemented across sectors and settings. By incentivising intersectoral action on structural inequities and barriers to health interventions, such a novel financing mechanism could contribute to more effective engagement of non-health sectors; to efficiency gains in the financing of universal health coverage; and to simultaneously achieving health and other well-being related sustainable development goals.

[This corrects the article DOI: 10.1371/journal.pone.0223412.].

Noncommunicable diseases (NCDs) are a broad challenge for decision-makers. NCDs account for seven out of every 10 deaths globally, with 42 percent occurring prematurely in individuals under age 70. Despite their heavy toll, NCDs are underfunded, with only around two percent of global funding dedicated to the disease set. Country governments are responsible for funding targeted actions to reduce the NCD burden, but among other priorities, many have yet to invest in the health-system interventions and policy measures that can reduce the burden. This article examines "investment cases" as a potential mechanism for catalyzing attention to-and funding for-NCDs. In Jamaica, using the UN inter-agency OneHealth Tool, we conducted an economic analysis to estimate the return-on-investment from scaling up strategic clinical interventions, and from implementing or intensifying policy measures that target NCD risk factors. In addition, we conducted an institutional and context (ICA) analysis, interviewing stakeholders across sectors to take stock of promising policy pathways (e.g., areas of general consensus, political appetite and opportunity) as well as challenges to implementation. The economic analysis found that scaling up clinical interventions that target CVD, diabetes, and mental health disorders, and policy measures that target tobacco and alcohol use, would save over 6,600 lives between 2017-2032, and avert JMD 81.3 billion (USD 640 million) in direct and indirect economic costs that result from mortality and morbidity linked to NCDs. The ICA uncovered government economic growth targets and social priorities that would be aided by increased attention to NCDs, and it linked these targets and priorities to the economic analysis.

Background Cardiology has advanced guideline development and quality measurement. Recognizing the substantial benefits of guideline‐directed medical therapy, this study aims to measure and explain apparent deviations in heart failure (HF) guideline adherence by clinicians at hospital discharge and describe any impact on readmission rates. Methods and Results The extent of decongestion and prescription of neurohormonal therapy were recorded prospectively for 226 HF discharges, including 132 (58%) from an academic hospital and 94 (42%) from a community hospital. Among all discharges, 25% were discharged with residual congestion (30% academic versus 18% community, P=0.070). Among discharges of patients with HF with reduced ejection fraction, 37% (45% academic versus 18% community, P

Tuvalu is a small island developing state (SID) with least developed country (LDC) status. The island has gained international attention due to the threat to its land territory as a result of climate change and subsequent sea-level rises. At the United Nations Climate Change Conference, held in Copenhagen in December 2009, Tuvalu was described as being at serious risk of becoming the first state to become uninhabitable due to the impacts of climate change. The majority of climate change scientists agree that a key driver of climate change is the burning of fossil fuels, predominantly for energy production. Energy security is multifaceted and connections can be drawn between the energy demands of the wealthier, industrialised states and the less developed states that are experiencing the detrimental impacts of the meeting of these demands. For Tuvalu, the lack of access to adequate, affordable, reliable, safe and environmentally benign energy is a severe development constraint. Currently, Tuvalu is close to being a totally oil dependent economy (83% of primary energy), whose energy security is dependent upon foreign aid to ensure its ability to pay international oil companies. Costs of all imported goods are exacerbated by its geographical isolation. This paper analyses the impact of international aid on energy security in Tuvalu and comments on the Tuvaluan Government’s commitment to 100% renewable energy – “being carbon neutral” – by 2020. Although this is a commendable aspiration it is clear that even if Tuvalu were to end reliance on fossil fuels it would still be at risk of disastrous inundation unless the industrialised states radically reduce their own dependency on such fuels and dramatically reduce the global levels of greenhouse gas emissions.

To enhance ammonium removal in wastewater treatment, a novel adsorbent, multilayered ionic cross-linked alginate-hydrogel-metal-coated zeolite (Al-H-M-Z), was synthesized. Essential divalent cations, 2.60 mmol of Ca 2+ and Mg 2+ , were incorporated into Al-H-M-Z (10 g) in a Ca 2+ :Mg 2+ ratio of 0.73:1.85, facilitating strong alginate-polymer interactions and significantly enhancing the adsorption efficiency. Langmuir and Freundlich isotherm analyses revealed that Al-H-M-Z had a maximum adsorption capacity of 56.5 ± 8.78 mg g -1 and an adsorption intensity of 0.703 ± 0.122, which were 7.24-fold and 1.59-fold higher than those of natural zeolite (7.80 ± 1.09 mg g -1 and 0.444 ± 0.254), respectively. These enhanced properties are attributed to the modified structural and surface chemistry. The Al-H-M-Z coating exhibited a 4.76-fold increase in surface area (3.91 m 2  g -1 ), an 8.94-fold increase in micropore volume (17.8 × 10 -3  cm 3  g -1 ), and a 4.22-fold increase in pore diameter (4.14 nm) when compared to the traditional Al-only coating. For applicability, Al-H-M-Z and Z achieved ammonium removal rates of 7.94% and 5.61%, respectively, in actual fish farm wastewater, representing a 1.41-fold improvement in adsorption efficiency after the coating process., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The cosmopolitan terrestrial slug, Deroceraslaeve (O. F. Müller, 1774), is reported in the Philippines for the first time and characterized through morphology, morphometrics, and cytochrome oxidase subunit I (COI) gene analysis. Slug samples were recovered from two administrative regions in Mindanao, Philippines. In Region X, there were two sites: Misamis Oriental (Gingoog, 664 m a.s.l.; Claveria, 937 m a.s.l.) with farms planted with cabbage ( Brassicaoleracea ), radish ( Raphanussativus) , and eggplant ( Solanummelongena ); and Bukidnon (Talakag, 1410 m a.s.l.) planted with cabbage. In Region XI, specimens were collected from potted ornamentals in five nurseries along the Kapatagan road, Davao del Sur, 1000-1200 m a.s.l. The external morphology of the specimens matched the published descriptions, and their identity was further confirmed by their partial COI sequences. The obtained COI sequence of the specimen in Region X showed 99-100% similarity with the voucher specimens from Mexico (KX959495, KX959496, KX959497, KX959498, and KX495499); while that of the specimen from Region XI is 100% identical to specimens collected from Japan (MW507142), Canada (MT680918 and MT941436), UK (KF894311), and Vietnam (MT941435 and MT941436). Moreover, D.laeve from Region X and Region XI shared 98% similarity with each other. Preliminary surveys show that slug occurrence is prevalent mainly in highland regions of the southern Philippines where specialty crops/high value crops like vegetables and ornamentals are cultivated. Further surveys are essential to confirm any damage that they may cause, their distribution, associated parasites, and pest status in the Philippines., Competing Interests: No conflict of interest to declare Disclaimer: This article is (co-)authored by any of the Editors-in-Chief, Managing Editors or their deputies in this journal., (Veronica B. Tañan, Loel B. Dalan, Sheryll Mae Roy, Augie Fuentes, Irma Tandingan De Ley, Nanette Hope N. Sumaya.)

Background: Inhibition of p38 alpha mitogen activated protein kinase (p38α) has shown great promise as a treatment for Alzheimer's disease (AD) in preclinical tests. However, previous preclinical studies were performed in "pure" models of AD pathology. A vast majority of AD patients have comorbid dementia-contributing pathologies, particularly some form of vascular damage. The present study therefore aimed to test the potential of p38α inhibition to address dysfunction in the context of comorbid amyloid and vascular pathologies., Methods: An amyloid overexpressing mouse strain (5xFAD) was placed on an 8-week long diet to induce the hyperhomocysteinemia (HHcy) model of small vessel disease. Mice were treated with the brain-penetrant small molecule p38α inhibitor MW150 for the duration of the HHcy diet, and subsequently underwent behavioral, neuroimaging, electrophysiological, or biochemical/immunohistochemical analyses., Results: MW150 successfully reduced behavioral impairment in the Morris Water Maze, corresponding with attenuation of synaptic loss, reduction in tau phosphorylation, and a partial normalization of electrophysiological parameters. No effect of MW150 was observed on the amyloid, vascular, or neuroinflammatory endpoints measured., Conclusions: This study provides proof-of-principle that the inhibition of p38α is able to provide benefit even in the context of mixed pathological contributions to cognitive impairment. Interestingly, the benefit was mediated primarily via rescue of neuronal function without any direct effects on the primary pathologies. These data suggest a potential use for p38 inhibitors in the preservation of cognition across contexts, and in particular AD, either alone or as an adjunct to other AD therapies ( i.e. anti-amyloid approaches). Future studies to delineate the precise neuronal pathways implicated in the benefit may help define other specific comorbid conditions amenable to this type of approach or suggest future refinement in pharmacological targeting., 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., (© 2024 The Authors.)

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team., (© 2024 Wiley Periodicals LLC.)

Organic aquaculture is a new approach in the modern farming system. As the capital investment is higher for setting up the organic aquaculture, it is essential to conduct an economic feasibility study with compare the conventional farming system. In the current study, economic feasibility of culturing Indian major carps (IMC) using conventional culture system and organic culture system (OCS) were evaluated. IMC was cultured for three consecutive years from 2017 to 2019 in experimental ponds of 0.015 hectare (ha) area each. The crude protein content of the organic and conventional feed was maintained at the same iso-nitrogenous level (32% crude protein) but the highest production to the tune of 19 tons per ha was obtained in OCS. Further, in case of OCS, apart from fish production, vermicomposting to the tune of 45,000 kg ha -1 in the first year, and 90,000 kg ha -1 from second year onward is achievable by installing a vermicomposting unit of 200 tons annual capacity. Economic analysis of the culture systems assuming a project period of 10 years showed that the highest net present value (NPV) of 1.06 million USD, a payback period of one year and nine months and an internal rate of return (IRR) of 51% are achievable per ha of fish culture pond for OCS. Sensitivity analysis of various costs performed for OCS revealed that profitability of the organic fish farming investment is most sensitive to the total fish production and sale price of the organic fishes. In terms of production of fish and economics of organic culture system is proved to be the best available technique., (© 2024. The Author(s).)

Aeration plays a crucial role in aquaculture to maintain adequate dissolved oxygen (DO) levels in water, which is essential for supporting aquatic life. However, traditional aeration systems such as paddlewheel aerators or diffused air aerators often come with high energy consumption, frequent maintenance, and greater operational costs. To address these challenges, this research paper presents the development and evaluation of a more sustainable and cost-effective aerator, named the perforated pooled circular stepped cascade aerator (PPCSC), for intensive aquaculture. Laboratory experiments were conducted in a masonry tank to assess the performance of the PPCSC aerator with different bottom radii (R b ) and discharges (Q). The results showed that the highest standard aeration efficiency (SAE) of 4.564 ± 0.6662 kg O 2 /kWh was achieved with a bottom radii (R b ) of 0.75 m and a discharge (Q) of 0.016 m 3 /s. A developed regression model was found to effectively evaluate the standard oxygen transfer rate (SOTR) and SAE for different R b and Q values used in the PPCSC system. Both R b and Q were found to significantly impact the SOTR and SAE of the PPCSC aerator. Overall, the PPCSC aerator is a promising option for small-scale tank-based intensive aquaculture due to its high performance and lower operational costs., 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., (© 2024 The Authors.)

India being the second largest nurse exporter to the Organisation for Economic Cooperation and Development (OECD) countries, currently faces a shortage of 2.4 million nurses. The problem of nurse shortage has been aggravated by the COVID pandemic. The young age at which the Indian nurses migrate, suggests that the decision to work overseas is made probably at the time of pursuing the studies or probably one pursues nursing because it opens the opportunity for working overseas. The objective of this study was to assess the intensions of nursing students to pursue overseas career on completion of their studies. The study used a cross-sectional survey design to collect data from 1408 nursing students from across four states of India namely, Karnataka, Kerala, Maharashtra and Rajasthan using a google survey form. The major finding of the study was that 54% of the respondents intended to migrate overseas. Better career advancement opportunities, better working conditions, higher pay, better lifestyle, were the reasons cited by those who had an intension to migrate. Establishing norms for nurse-patient ratios, and scope of work along with pay scales for nurses with various qualifications and experience could be the most strategic moves that the policy makers can consider to control brain drain in nursing and control nurse migration.

Background: Background: Neurodegenerative diseases manifest behavioral dysfunction with disease progression. Intervention with neuropsychiatric drugs is part of most multi-drug treatment paradigms. However, only a fraction of patients responds to the treatments and those responding must deal with drug-drug interactions and tolerance issues generally attributed to off-target activities. Recent efforts have focused on the identification of underexplored targets and exploration of improved outcomes by treatment with selective molecular probes., Objective: As part of ongoing efforts to identify and validate additional targets amenable to therapeutic intervention, we examined levels of the serotonin 5-HT2b receptor (5-HT2bR) in Alzheimer's disease (AD) brains and the potential of a selective 5-HT2bR antagonist to counteract synaptic plasticity and memory damage induced by AD-related proteins, amyloid-β, and tau., Methods: This work used a combination of biochemical, chemical biology, electrophysiological, and behavioral techniques. Biochemical methods included analysis of protein levels. Chemical biology methods included the use of an in vivo molecular probe MW071, a selective antagonist for the 5HT2bR. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated spatial memory and associative memory., Results: 5HT2bR levels are increased in brain specimens of AD patients compared to controls. 5HT2bR antagonist treatment rescued amyloid-β and tau oligomer-induced impairment of synaptic plasticity and memory., Conclusions: The increased levels of 5HT-2bR in AD patient brains and the attenuation of disease-related synaptic and behavioral dysfunctions by MW071 treatment suggest that the 5HT-2bR is a molecular target worth pursuing as a potential therapeutic target.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on the nonreducing end of heparan sulfate (HS-NRE) within lysosomes. Enzyme deficiency results in accumulation of partially degraded HS within lysosomes throughout the body, leading to a progressive severe neurological disease. Enzyme replacement therapy has been proposed, but further evaluation of the treatment strategy is needed. Here, we used Chinese hamster ovary cells to produce a highly soluble and fully active recombinant human sulfamidase (rhSGSH). We discovered that rhSGSH utilizes both the CI-MPR and LRP1 receptors for uptake into patient fibroblasts. A single intracerebroventricular (ICV) injection of rhSGSH in MPS IIIA mice resulted in a tissue half-life of 9 days and widespread distribution throughout the brain. Following a single ICV dose, both total HS and the MPS IIIA disease-specific HS-NRE were dramatically reduced, reaching a nadir 2 weeks post dose. The durability of effect for reduction of both substrate and protein markers of lysosomal dysfunction and a neuroimmune response lasted through the 56 days tested. Furthermore, seven weekly 148 μg doses ICV reduced those markers to near normal and produced a 99.5% reduction in HS-NRE levels. A pilot study utilizing every other week dosing in two animals supports further evaluation of less frequent dosing. Finally, our dose-response study also suggests lower doses may be efficacious. Our findings show that rhSGSH can normalize lysosomal HS storage and markers of a neuroimmune response when delivered ICV., Competing Interests: Conflict of interest The authors were employees of BioMarin Pharmaceutical Inc at the time of the studies. The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, but therapeutic options are lacking. Despite long being able to effectively treat the ill-effects of pathology present in various rodent models of AD, translation of these strategies to the clinic has so far been disappointing. One potential contributor to this situation is the fact that the vast majority of AD patients have other dementia-contributing comorbid pathologies, the most common of which are vascular in nature. This situation is modeled relatively infrequently in basic AD research, and almost never in preclinical studies. As part of our efforts to develop small molecule, anti-inflammatory therapeutics for neurological injury and disease, we have recently been exploring potentially promising treatments in preclinical multi-morbidity contexts. In the present study, we generated a mouse model of mixed amyloid and hyperhomocysteinemia (HHcy) pathology in which to test the efficacy of one of our anti-inflammatory compounds, MW151. HHcy can cause cerebrovascular damage and is an independent risk factor for both AD dementia and vascular contributions to cognitive impairment and dementia. We found that MW151 was able to partially rescue hippocampal-dependent spatial memory and learning deficits in this comorbidity context, and further, that the benefit is associated with a normalization of hippocampal metabolites detectable via magnetic resonance spectroscopy. These findings provide evidence that MW151 in particular, and potentially anti-inflammatory treatment more generally, may be beneficial in AD patients with comorbid vascular pathology., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LVE and DMW are inventors on the following patents covering MW151: “Pyridazine compound composition and method of use in medicine: 8063047, 8367672, 8933076, 9527819, 9663493” “Lead compounds for neurodegeneration and neuroinflammation: 8158627, 9408845”. LVE is a scientific founder of ImmunoChem Therapeutics (ICT), LLC, a small virtual biotech company that has licensed these patents from Northwestern University. No funding has been received from ICT. This also does not alter our adherence to PLOS ONE policies on sharing data and materials.

Selection of aerator is a very important aspect in aquaculture operations. The selected aerator must be economically efficient and should be able to fulfil the requirement of oxygen supply in the pond water. In the present study, economic feasibility of nine different types of aerators, namely, perforated pooled circular stepped cascade (PPCSC), pooled circular stepped cascade (PCSC), circular stepped cascade (CSC), paddle wheel (PWA), spiral aerator (SA), propeller-aspirator-pump (PAA), submersible (SUBA), impeller aerator (IA) and air-jet aerator (AJA) was assessed based on capitalization method, a life cycle costing (LCC) approach. The results revealed that the PPCSC aerator can be considered as the most suitable aerator when dissolved oxygen (DO) content in the pond water is less than equal to 3 mg/L, and pond water volume (V) is less than 2100 m 3 . In other situations, mostly when pond water volume is more, IA proves to be the most suitable aerator, followed by PWA, PPCSC, and other available aerators. The sensitivity analysis conducted by using varying stocking density and capital cost also showed the same trend with regard to selection of aerators. This life cycle costing approach for selection of aerator can be implemented for any types of cultured species at any prevailing environmental conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Numerous strategies have been developed to treat cancer conventionally. Most importantly, chemotherapy shows its huge promise as a better treatment modality over others. Nonetheless, the very complex behavior of the tumor microenvironment frequently impedes successful drug delivery to the tumor sites that further demands very urgent and effective distribution mechanisms of anticancer drugs specifically to the tumor sites. Hence, targeted drug delivery to tumor sites has become a major challenge to the scientific community for cancer therapy by assuring drug effects to selective tumor tissue and overcoming undesired toxic side effects to the normal tissues. The application of nanotechnology to the drug delivery system pays heed to the design of nanomedicine for specific cell distribution. Aiming to limit the use of traditional strategies, the adequacy of drug-loaded nanocarriers (i.e., nanomedicine) proves worthwhile. After systemic blood circulation, a typical nanomedicine follows three levels of disposition to tumor cells in order to exhibit efficient pharmacological effects induced by the drug candidates residing within it. As a result, nanomedicine propounds the assurance towards the improved bioavailability of anticancer drug candidates, increased dose responses, and enhanced targeted efficiency towards delivery and distribution of effective therapeutic concentration, limiting toxic concentration. These aspects emanate the proficiency of drug delivery mechanisms. Understanding the potential tumor targeting barriers and limiting conditions for nanomedicine extravasation, tumor penetration, and final accumulation of the anticancer drug to tumor mass, experiments with in vivo animal models for nanomedicine screening are a key step before it reaches clinical translation. Although the study with animals is undoubtedly valuable, it has many associated ethical issues. Moreover, individual experiments are very expensive and take a longer time to conclude. To overcome these issues, nowadays, multicellular tumor spheroids are considered a promising in vitro model system that proposes better replication of in vivo tumor properties for the future development of new therapeutics. In this review, we will discuss how tumor spheroids could be used as an in vitro model system to screen nanomedicine used in targeted drug delivery, aiming for better therapeutic benefits. In addition, the recent proliferation of mathematical modeling approaches gives profound insight into the underlying physical principles and produces quantitative predictions. The hierarchical tumor structure is already well decorous to be treated mathematically. To study targeted drug delivery, mathematical modeling of tumor architecture, its growth, and the concentration gradient of oxygen are the points of prime focus. Not only are the quantitative models circumscribed to the spheroid, but also the role of modeling for the nanoparticle is equally inevitable. Abundant mathematical models have been set in motion for more elaborative and meticulous designing of nanomedicine, addressing the question regarding the objective of nanoparticle delivery to increase the concentration and the augmentative exposure of the therapeutic drug molecule to the core. Thus, to diffuse the dichotomy among the chemistry involved, biological data, and the underlying physics, the mathematical models play an indispensable role in assisting the experimentalist with further evaluation by providing the admissible quantitative approach that can be validated. This review will provide an overview of the targeted drug delivery mechanism for spheroid, using nanomedicine as an advantageous tool., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Roy, Garg, Barman, Ghosh, Maity and Ghosh.)

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes were seen in vital signs, electrocardiograms, physical or neurological examinations, or safety laboratory results. PK analysis showed dose-proportional increases in plasma concentrations of MW189 after single or multiple doses, with approximately linear kinetics and no significant drug accumulation. Steady state was achieved by dose 3 for all dosing cohorts. A pilot pharmacodynamic study administering low-dose endotoxin to induce a systemic inflammatory response was done to evaluate the effects of a single intravenous dose of MW189 on plasma cytokine levels. MW189 treatment resulted in lower levels of the proinflammatory cytokine TNF-α and higher levels of the anti-inflammatory cytokine IL-10 compared with placebo treatment. The outcomes are consistent with the pharmacological mechanism of MW189. Overall, the safety profile, PK properties, and pharmacodynamic effect support further development of MW189 for patients with acute brain injury., (© 2020 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Context: The ketogenic diet is associated with progressive skeletal demineralization, hypercalciuria, and nephrolithiasis. Acute hypercalcemia has been described as a newly recognized complication of this treatment., Objective: To describe the clinical characteristics of acute hypercalcemia in children on the ketogenic diet through analysis of the presentation, response to treatment, and natural history in a large cohort of patients., Design: A multicenter case series was performed including children who developed acute hypercalcemia while treated with the ketogenic diet. Information on clinical presentation, treatment, and course of this complication was collated centrally., Results: There were 14 patients (median (range) age 6.3 (0.9 to 18) years) who developed hypercalcemia 2.1 (range, 0.2-12) years after starting the ketogenic diet. All had low levels of parathyroid hormone and levels of 1,25-dihydroxyvitamin D were low in all except one. Seven (50%) had impaired renal function at presentation. All except the 2 oldest had low alkaline phosphatase levels for age. Once normocalcemia was achieved, hypercalcemia recurred in only 2 of these patients over observation of up to 9.8 years. One patient discontinued the ketogenic diet prior to achieving normocalcemia while 4 more stopped the diet during follow-up after resolution of hypercalcemia., Conclusions: Ketotic hypercalcemia can occur years after starting the ketogenic diet, especially in the setting of renal impairment. The mechanism is unknown but appears to be due to reduced osteoblast activity and impaired bone formation. We recommend close attention to optimizing bone health in these children, and screening for the development of ketotic hypercalcemia., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Autosomal recessive mutations in the galactosidase β1 ( GLB1 ) gene cause lysosomal β-gal deficiency, resulting in accumulation of galactose-containing substrates and onset of the progressive and fatal neurodegenerative lysosomal storage disease, GM1 gangliosidosis. Here, an enzyme replacement therapy (ERT) approach in fibroblasts from GM1 gangliosidosis patients with recombinant human β-gal (rhβ-gal) produced in Chinese hamster ovary cells enabled direct and precise rhβ-gal delivery to acidified lysosomes. A single, low dose (3 nm) of rhβ-gal was sufficient for normalizing β-gal activity and mediating substrate clearance for several weeks. We found that rhβ-gal uptake by the fibroblasts is dose-dependent and saturable and can be competitively inhibited by mannose 6-phosphate, suggesting cation-independent, mannose 6-phosphate receptor-mediated endocytosis from the cell surface. A single intracerebroventricularly (ICV) administered dose of rhβ-gal (100 μg) resulted in broad bilateral biodistribution of rhβ-gal to critical regions of pathology in a mouse model of GM1 gangliosidosis. Weekly ICV dosing of rhβ-gal for 8 weeks substantially reduced brain levels of ganglioside and oligosaccharide substrates and reversed well-established secondary neuropathology. Of note, unlike with the ERT approach, chronic lentivirus-mediated GLB1 overexpression in the GM1 gangliosidosis patient fibroblasts caused accumulation of a prelysosomal pool of β-gal, resulting in activation of the unfolded protein response and endoplasmic reticulum stress. This outcome was unsurprising in light of our in vitro biophysical findings for rhβ-gal, which include pH-dependent and concentration-dependent stability and dynamic self-association. Collectively, our results highlight that ICV-ERT is an effective therapeutic intervention for managing GM1 gangliosidosis potentially more safely than with gene therapy approaches., Competing Interests: The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Chen et al.)

The feasibility of using colicins to create an antimicrobial lubricant to prevent extraluminal catheter contamination during urinary catheter insertion was assessed. Levels of resistance of uropathogenic Escherichia coli to antibiotics and colicins were compared. The results showed that antibiotics and colicins possess similar frequencies of resistance to a single drug, whereas colicins exhibit significantly lower levels of multidrug resistance (22%) than antibiotics (42%). Colicins and antibiotics showed complementary inhibitory activity, with each targeting different subsets of pathogenic isolates. The collateral impact of these two antimicrobials on genera that are members of the fecal/vaginal/urinary microbiome was assessed, with colicins showing significantly less collateral damage than antibiotics. Using a novel colicin, SR4, minimum inhibitory concentrations (MICs) for a panel of 30 uropathogenic isolates were determined and showed that SR4 achieved the same antimicrobial efficacy as gentamicin using 20-30% less drug. An SR4-impregnated catheter lubricant was created and its ability to prevent extraluminal urinary catheter contamination in vitro was demonstrated. These data indicate that a colicin-impregnated lubricant may provide a viable prophylactic option for preventing catheter-associated urinary tract infections., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The p38αMAPK is a serine/threonine protein kinase and a key node in the intracellular signaling networks that transduce and amplify stress signals into physiological changes. A preponderance of preclinical data and clinical observations established p38αMAPK as a brain drug discovery target involved in neuroinflammatory responses and synaptic dysfunction in multiple degenerative and neuropsychiatric brain disorders. We summarize the discovery of highly selective, brain-penetrant, small molecule p38αMAPK inhibitors that are efficacious in diverse animal models of neurologic disorders. A crystallography and pharmacoinformatic approach to fragment expansion enabled the discovery of an efficacious hit. The addition of secondary pharmacology screens to refinement delivered lead compounds with improved selectivity, appropriate pharmacodynamics, and efficacy. Safety considerations and additional secondary pharmacology screens drove optimization that delivered the drug candidate MW01-18-150SRM (MW150), currently in early stage clinical trials.

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

Objective: To assess whether body mass index (BMI) provides a better assessment of measured adiposity at age 1 month compared with weight-for-length (WFL)., Study Design: Participants were healthy term-born infants in the Infant Growth and Microbiome (n = 146) and the Baby Peas (n = 147) studies. Length, weight, and body composition by air displacement plethysmography were measured at 1 month. World Health Organization-based WFL and BMI z-scores were calculated. Within-cohort z-scores of percent fat-Z, fat mass-Z, fat mass/length 2 -Z, fat mass/length 3 -Z, fat-free mass-Z, and fat-free mass/length 2 -Z were calculated. Correlation and multiple linear regression (adjusted for birth weight) analyses tested the associations between body composition outcomes and BMI-Z vs WFL-Z. Quantile regression was used to test the stability of these associations across the distribution of body compositions., Results: The sample was 52% female and 56% African American. Accounting for birth weight, both BMI-Z and WFL-Z were strongly associated with fat mass-Z (coefficients 0.56 and 0.35, respectively), FM/L 2 -Z (0.73 and 0.51), and FM/L 3 -Z (0.79 and 0.58), with stronger associations for BMI-Z compared with WFL-Z (P < .05). Even after accounting statistically for birth weight, BMI-Z was persistently more strongly associated than WFL-Z with body composition outcomes across the distribution of body composition outcomes., Conclusions: We demonstrate in 2 distinct cohorts that BMI is a better indicator of adiposity in early infancy compared with WFL. Our findings support the preferred use of BMI for growth and nutritional status assessment in infancy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood., Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race., Design, Setting, and Participants: This investigation was a mixed longitudinal study with annual assessments for up to 7 years at 5 US clinical centers. Participants were healthy children, adolescents, and young adults. The study dates were July 2002 through March 2010. The dates of the analysis were June through December 2016., Main Outcomes and Measures: Anthropometrics, BMC, and body composition via dual-energy x-ray absorptiometry. The superimposition by translation and rotation (SITAR) analysis method was used to define the mean trajectories for height, WB lean soft tissue, appendicular lean soft tissue, and WB and skeletal site-specific BMC acquisition and to measure the age and magnitude of peak velocity for each parameter. The SITAR modeling was performed separately by sex and self-reported race., Results: Among 2014 healthy children, adolescents, and young adults (1022 [50.7%] female and 479 [23.8%] African American) aged 5 to 19 years at study entry, the mean age of peak height velocity was 13.1 years (95% CI, 13.0-13.2 years) in African American boys vs 13.4 years (95% CI, 13.3-13.4 years) in non-African American boys (difference, -0.3 years; 95% CI, -0.4 to -0.1 years) and 11.0 years (95% CI, 10.8-11.1 years) in African American girls vs 11.6 years (95% CI, 11.5-11.6 years) in non-African American girls (difference, -0.6 years; 95% CI, -0.7 to -0.5 years). Age of peak acquisition of WB BMC was 14.0 years (95% CI, 13.8-14.1 years) in African American boys vs 14.0 years (95% CI, 13.9-14.1 years) in non-African American boys (difference, -0.0 years; 95% CI, -0.2 to 0.2 years) and 12.1 years (95% CI, 12.0-12.3 years) in African American girls vs 12.4 years (95% CI, 12.3-12.5 years) in non-African American girls (difference, -0.3 years; 95% CI, -0.4 to -0.1 years). At age 7 years, children had acquired 69.5% to 74.5% of maximal observed height but only 29.6% to 38.1% of maximal observed WB BMC. Adolescents gained 32.7% to 35.8% of maximal observed WB BMC during the 2 years before and 2 years after peak height velocity. Another 6.9% to 10.7% of maximal observed WB BMC occurred after linear growth had ceased. In the group at highest risk for fracture, non-African American boys, peak fracture incidence occurred approximately 1 year before peak height velocity., Conclusions and Relevance: In this longitudinal study, height gains substantially outpaced gains in BMC during childhood, which could contribute to fracture risk. A significant proportion of bone is accrued after adult height is achieved. Therefore, late adolescence represents a potentially underrecognized window of opportunity to optimize bone mass.

Failure to achieve optimal bone mineral accretion during childhood and adolescence results in subsequent suboptimal peak bone mass, contributing to osteoporosis risk later in life. To identify novel genetic factors that influence pediatric bone mass at discrete skeletal sites, we performed a sex-stratified genomewide association study of areal bone mineral density (BMD) measured by dual-energy X-ray absorptiometry at the 1/3 distal radius, spine, total hip, and femoral neck in a cohort of 933 healthy European American children. We took forward signals with p < 5 × 10 -5 and minor allele frequency (MAF) >5% into an independent cohort of 486 European American children in search of replication. In doing so, we identified five loci that achieved genome wide significance in the combined cohorts (nearest genes: CPED1, IZUMO3, RBFOX1, SPBT, and TBPL2), of which the last four were novel and two were sex-specific (SPTB in females and IZUMO3 in males), with all of them yielding associations that were particularly strong at a specific skeletal site. Annotation of potential regulatory function, expression quantitative trait loci (eQTL) effects and pathway analyses identified several potential target genes at these associated loci. This study highlights the importance of sex-stratified analyses at discrete skeletal sites during the critical period of bone accrual, and identifies novel loci for further functional follow-up to pinpoint key genes and better understand the regulation of bone development in children. © 2017 American Society for Bone and Mineral Research., (© 2017 American Society for Bone and Mineral Research.)

Background: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations., Methods: We explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11-12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1β, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aβ40 and Aβ42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities., Results: Intervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1β and TNFα but not IL-6. MW150 treatment also increased the IBA1 + microglia within a 15 μm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aβ40 and Aβ42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells., Conclusions: Our results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.

Bacillus thuringiensis (Bt) is a soil bacterium that forms spores containing crystals comprising one or more Cry or Cyt proteins having potential and specific insecticidal activity. Different strains of Bt produce different types of toxins, affecting a narrow taxonomic group of insects. Therefore, it is used in non-chemical pest management, including inherent pest resistance through GM crops. The specificity of action of Bt toxins reduces the concern of adverse effects on non-target species, a concern which remains with chemical insecticides as well. To make use of Bt more sustainable, new strains expressing novel toxins are actively being sought globally. Since Bt is successfully used against many pests including the lepidopteran pests in different crop groups, the insecticidal activity against Samia cynthia (Drury) (Eri silkworm) and Antheraea assamensis Helfer (Muga silkworm) becomes a concern in the state of Assam in India which is a predominantly tea- and silk-producing zone. Though Bt can be used as an effective non-chemical approach for pest management for tea pests in the same geographical region, yet, it may potentially affect the silk industry which depends on silkworm. There is a need to identify the potentially lethal impact (through evaluating their mortality potential) of local Bt strains on key silkworm species in North Eastern India. This will allow the use of existing Bt for which the silkworms have natural resistance. Through this review, the authors aim to highlight recent progress in the use of Bt and its insecticidal toxins in tea pest control and the potential sensitivity for tea- and silk-producing zone of Assam in India.

More rapid skeletal maturation in African-American (AA) children is recognized and generally attributed to an increased prevalence of obesity. The objective of the present study was to evaluate the effects of population ancestry on relative skeletal maturation in healthy, non-obese children and adolescents, accounting for body composition and sexual maturation. To do this, we leveraged a multiethnic, mixed-longitudinal study with annual assessments for up to 7 years (The Bone Mineral Density in Childhood Study and its ancillary cohort) conducted at five US clinical centers. Participants included 1592 children, skeletally immature (45% females, 19% AA) who were aged 5 to 17 years at study entry. The primary outcome measure was relative skeletal maturation as assessed by hand-wrist radiograph. Additional covariates measured included anthropometrics, body composition by dual-energy X-ray absorptiometry (DXA), and Tanner stage of sexual maturation. Using mixed effects longitudinal models, without covariates, advancement in relative skeletal maturation was noted in self-reported AA girls (∼0.33 years, p < 0.001) and boys (∼0.43 years, p < 0.001). Boys and girls of all ancestry groups showed independent positive associations of height, lean mass, fat mass, and puberty with relative skeletal maturation. The effect of ancestry was attenuated but persistent after accounting for covariates: for girls, 0.19 years (ancestry by self-report, p = 0.02) or 0.29 years (ancestry by admixture, p = 0.004); and for boys, 0.20 years (ancestry by self-report, p = 0.004), or 0.29 years (ancestry by admixture, p = 0.004). In summary, we conclude that advancement in relative skeletal maturation was associated with AA ancestry in healthy, non-obese children, independent of growth, body composition, and puberty. Further research into the mechanisms underlying this observation may provide insights into the regulation of skeletal maturation. © 2016 American Society for Bone and Mineral Research., Competing Interests: All authors state that they have no conflicts of interest., (© 2016 American Society for Bone and Mineral Research.)

Background: Hyperphosphorylation and aggregation of tau protein are the pathological hallmarks of Alzheimer's disease and related tauopathies. We previously demonstrated that the microglial activation induces tau hyperphosphorylation and cognitive impairment via activation of p38 mitogen-activated protein kinase (p38 MAPK) in the hTau mouse model of tauopathy that was deficient for microglial fractalkine receptor CX3CR1., Method: We report an isoform-selective, brain-permeable, and orally bioavailable small molecule inhibitor of p38α MAPK (MW181) and its effects on tau phosphorylation in vitro and in hTau mice., Results: First, pretreatment of mouse primary cortical neurons with MW181 completely blocked inflammation-induced p38α MAPK activation and AT8 (pS199/pS202) site tau phosphorylation, with the maximum effect peaking at 60-90 min after stimulation. Second, treatment of old (~20 months of age) hTau mice with MW181 (1 mg/kg body weight; 14 days via oral gavage) significantly reduced p38α MAPK activation compared with vehicle-administered hTau mice. This also resulted in a significant reduction in AT180 (pT231) site tau phosphorylation and Sarkosyl-insoluble tau aggregates. Third, MW181 treatment significantly increased synaptophysin protein expression and resulted in improved working memory. Fourth, MW181 administration reduced phosphorylated MAPK-activated protein kinase 2 (pMK2) and phosphorylated activating transcription factor 2 (pATF2), which are known substrates of p38α MAPK. Finally, MW181 reduced the expression of interferon-γ and interleukin-1β., Conclusions: Taken together, these studies support p38α MAPK as a valid therapeutic target for the treatment of tauopathies.

A recent whole-genome sequencing study in search of variation associated with adult areal bone mineral density (aBMD) identified rare variants near EN1, with markedly large effect sizes, and a common variant near SOX6. To understand the developmental effects of these loci, we sought to determine if they were associated with pediatric dual-energy X-ray absorptiometry-derived aBMD and bone mineral content (BMC) and if the associations were modified by sex. Our sample comprised 733 females and 685 males of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (up to 7 annual study visits). Sex- and age-specific Z-scores, adjusted for height, were calculated for the total hip, femoral neck, spine, and distal radius. Total body less head (TBLH) BMC Z-scores were also calculated. The previously reported single nucleotide polymorphisms (SNPs) near EN1 and SOX6 were derived from our imputed data set. Linear mixed-effects models were used to test associations between each SNP and bone Z-scores, plus interactions with sex were explored. The rare T allele of lead EN1 SNP rs11692564 was associated with higher aBMD Z-score for total hip (beta = 0.62, p = 9.0 × 10(-4) ) and femoral neck (beta = 0.53, p = 0.010). In sex-stratified analyses, this variant was associated with higher bone Z-scores in females only, with the associations being strongest for total hip (sex interaction p = 1.9 × 10(-4) ; beta females = 0.86, p = 6.6 × 10(-6) ) and femoral neck (sex interaction p = 0.016; beta females = 0.73, p = 0.001). The common G allele of SOX6 SNP rs11024028 was associated with higher aBMD Z-score for total hip (beta = 0.12, p = 0.009), femoral neck (beta = 0.13, p = 0.003), and TBLH-BMC (beta = 0.09, p = 0.007); furthermore, this association strengthened in males in the sex-stratified analyses. Our findings reveal that rare genetic variation near EN1 and common variation near SOX6 operates in childhood and has implications for the lifelong risk of osteoporosis and fracture. The sex differences observed need to be independently replicated. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Both genetics and physical activity (PA) contribute to bone mineral density (BMD), but it is unknown if the benefits of physical activity on childhood bone accretion depend on genetic risk. We, therefore, aimed to determine if PA influenced the effect of bone fragility genetic variants on BMD in childhood. Our sample comprised US children of European ancestry enrolled in the Bone Mineral Density in Childhood Study (N = 918, aged 5 to 19 years, and 52.4% female). We used a questionnaire to estimate hours per day spent in total, high-, and low-impact PA. We calculated a BMD genetic score (% BMD lowering alleles) using adult genome-wide association study (GWAS)-implicated BMD variants. We used dual-energy X-ray absorptiometry to estimate femoral neck, total hip, and spine areal-BMD and total body less head (TBLH) bone mineral content (BMC) Z-scores. The BMD genetic score was negatively associated with each bone Z-score (eg, TBLH-BMC: estimate = -0.03, p = 1.3 × 10(-6) ). Total PA was positively associated with bone Z-scores; these associations were driven by time spent in high-impact PA (eg, TBLH-BMC: estimate = 0.05, p = 4.0 × 10(-10) ) and were observed even for children with lower than average bone Z-scores. We found no evidence of PA-adult genetic score interactions (p interaction > 0.05) at any skeletal site, and there was no evidence of PA-genetic score-Tanner stage interactions at any skeletal site (p interaction > 0.05). However, exploratory analyses at the individual variant level revealed that PA statistically interacted with rs2887571 (ERC1/WNT5B) to influence TBLH-BMC in males (p interaction = 7.1 × 10(-5) ), where PA was associated with higher TBLH-BMC Z-score among the BMD-lowering allele carriers (rs2887571 AA homozygotes: estimate = 0.08 [95% CI 0.06, 0.11], p = 2.7 × 10(-9) ). In conclusion, the beneficial effect of PA on bone, especially high-impact PA, applies to the average child and those genetically predisposed to lower adult BMD (based on GWAS-implicated BMD variants). Independent replication of our exploratory individual variant findings is warranted. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

India is the second largest producer of black tea in the world. The biggest challenge for tea growers of India nowadays is to combat pests and diseases. Tea crop in India is infested by not less than 720 insect and mite species. At least four sucking pests and six chewing pests have well established themselves as regular pests causing substantial damage to this foliage crop. Various synthetic pesticides are widely used for the management of tea pests in India. Applications of such large quantity of pesticides could cause various problems such as development of resistance, deleterious effects on non-target organisms such as insect predators and parasitoids, upsetting the ecological balance, and accumulation of pesticide residues on tea leaves. There is a growing demand for organic tea or at least pesticide residue free tea in the international market which affects the export price. There is also a higher emphasis of implementation of new regulations on internationally traded foods and implementation of Plant Protection Code (PPC) for tea by the Government of India. This necessitates a relook into the usage pattern of synthetic pesticides on this crop. There are various non-chemical interventions which are being worked out for their sustainability, compatibility, and eco-friendly properties which can gradually replace the use of toxic chemicals. The application of plant extracts with insecticidal properties provides an alternative to the synthetic pesticides. Botanical products, especially neem-based products, have made a relatively moderate impact in tea pest control. Research has also demonstrated the potential of 67 plant species as botanical insecticides against tea pests. The majority of plant products used in pest management of tea in India are in the form of crude extracts prepared locally in tea garden itself, and commercial standardized formulations are not available for most of the plants due to lack of scientific research in the area. Apart from systematic research in this area, to facilitate the simplified and trade friendly registration procedures with quality assurance of the products, there is an increasing need of regulatory authority and national norms in India.

Background: Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity., Methods: Anthropometrics were extracted from electronic medical records for well-child visits for 73 949 full-term infants from a large pediatric network. World Health Organization WFL and BMI z scores (WFL-z and BMI-z, respectively) were calculated up to age 24 months. Correlation analyses assessed the agreement between WFL-z and BMI-z and within-subject tracking over time. Logistic regression determined odds of obesity at 2 years on the basis of adiposity classification at 2 months., Results: Agreement between WFL-z and BMI-z increased from birth to 6 months and remained high thereafter. BMI-z at 2 months was more consistent with measurements at older ages than WFL-z at 2 months. Infants with high BMI (≥85th percentile) and reference WFL (5th-85th percentiles) at 2 months had greater odds of obesity at 2 years than those with high WFL (≥85th percentile) and reference BMI (5th-85th percentiles; odds ratio, 5.49 vs 1.40; P < .001). At 2 months, BMI had a higher positive predictive value than WFL for obesity at 2 years using cut-points of either the 85th percentile (31% vs 23%) or 97.7th percentile (47% vs 29%)., Conclusions: High BMI in early infancy is more strongly associated with early childhood obesity than high WFL. Forty-seven percent of infants with BMI ≥97.7th percentile at 2 months (versus 29% of infants with WFL ≥97.7th percentile at 2 months) were obese at 2 years. Epidemiologic studies focused on assessing childhood obesity risk should consider using BMI in early infancy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2016 by the American Academy of Pediatrics.)

Using adult identified bone mineral density (BMD) loci, we calculated genetic risk scores (GRS) to determine if they were associated with changes in BMD during childhood. Longitudinal data from the Bone Mineral Density in Childhood Study were analyzed (N = 798, 54% female, all European ancestry). Participants had up to 6 annual dual energy X-ray scans, from which areal BMD (aBMD) Z-scores for the spine, total hip, and femoral neck were estimated, as well as total body less head bone mineral content (TBLH-BMC) Z-scores. Sixty-three single-nucleotide polymorphisms (SNPs) were genotyped, and the percentage of BMD-lowering alleles carried was calculated (overall adult GRS). Subtype GRS that include SNPs associated with fracture risk, pediatric BMD, WNT signaling, RANK-RANKL-OPG, and mesenchymal stem cell differentiation were also calculated. Linear mixed effects models were used to test associations between each GRS and bone Z-scores, and if any association differed by sex and/or chronological age. The overall adult, fracture, and WNT signaling GRS were associated with lower Z-scores (eg, spine aBMD Z-score: βadult  = -0.04, p = 3.4 × 10(-7) ; βfracture = -0.02, p = 8.9 × 10(-6) ; βWNT  = -0.01, p = 3.9 × 10(-4) ). The overall adult GRS was more strongly associated with lower Z-scores in females (p-interaction ≤ 0.05 for all sites). The fracture GRS was more strongly associated with lower Z-scores with increasing age (p-interaction ≤ 0.05 for all sites). The WNT GRS associations remained consistent for both sexes and all ages (p-interaction > 0.05 for all sites). The RANK-RANKL-OPG GRS was more strongly associated in females with increasing age (p-interaction < 0.05 for all sites). The mesenchymal stem cell GRS was associated with lower total hip and femoral neck Z-scores, in both boys and girls, across all ages. No associations were observed between the pediatric GRS and bone Z-scores. In conclusion, adult identified BMD loci associated with BMD and BMC in the pediatric setting, especially in females and in loci involved in fracture risk and WNT signaling., (© 2015 American Society for Bone and Mineral Research.)

Necrolytic migratory erythema (NME) is a rare cutaneous finding characterized by painful, pruritic, scaly red patches and plaques, bullae, and superficial erosions. Typically NME is a paraneoplastic phenomenon associated with glucagonoma. We report the exceptional case of an infant who developed iatrogenic NME arising secondary to glucagon therapy for congenital hyperinsulinism., (© 2015 Wiley Periodicals, Inc.)

The detection of intracellular fluoride was achieved by a novel Schiff base chemosensor derived from vitamin B6 cofactor (L) using fluorescence imaging technique. The sensor L was synthesized by condensation of pyridoxal phosphate with 2-aminothiophenol. The anion recognition ability of L was explored by UV-Vis and fluorescence methods in DMSO and mixed DMSO-H2O system. The sensor L showed both naked-eye detectable color change from colorless to light green and remarkable fluorescence enhancement at 500 nm in the presence of F(-) and AcO(-). The anion recognition was occurred through the formation of hydrogen bonded complexes between these anions and L, followed by the partial deprotonation of L. The detection limit of L for the analysis of F(-) and AcO(-) was calculated to be 1.88 μM and 9.10 μM, respectively. Finally, the detection of cytoplasmic fluoride was tested using human cancer cell HeLa through fluorescence imaging., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.