Setting research priorities for global pandemic preparedness: An international consensus and comparison with ChatGPT's output.

Background: In this priority-setting exercise, we sought to identify leading research priorities needed for strengthening future pandemic preparedness and response across countries. Methods: The International Society of Global Health (ISoGH) used the Child Health and Nutrition Research Initiative (CHNRI) method to identify research priorities for future pandemic preparedness. Eighty experts in global health, translational and clinical research identified 163 research ideas, of which 42 experts then scored based on five pre-defined criteria. We calculated intermediate criterion-specific scores and overall research priority scores from the mean of individual scores for each research idea. We used a bootstrap (n = 1000) to compute the 95% confidence intervals. Results: Key priorities included strengthening health systems, rapid vaccine and treatment production, improving international cooperation, and enhancing surveillance efficiency. Other priorities included learning from the coronavirus disease 2019 (COVID-19) pandemic, managing supply chains, identifying planning gaps, and promoting equitable interventions. We compared this CHNRI-based outcome with the 14 research priorities generated and ranked by ChatGPT, encountering both striking similarities and clear differences. Conclusions: Priority setting processes based on human crowdsourcing - such as the CHNRI method - and the output provided by ChatGPT are both valuable, as they complement and strengthen each other. The priorities identified by ChatGPT were more grounded in theory, while those identified by CHNRI were guided by recent practical experiences. Addressing these priorities, along with improvements in health planning, equitable community-based interventions, and the capacity of primary health care, is vital for better pandemic preparedness and response in many settings.

The impact of COVID-19 on health of the older persons in Bangladesh.

The COVID-19 is impacting the health of the population, including older persons. Available evidence shows that older people are highly vulnerable and more likely to have adverse health outcomes. In Bangladesh, the older population is rapidly increasing, living with various disadvantaged socio-economic conditions, including inadequate access and healthcare services. These disparities are likely to increase during the COVID-19, resulting in high morbidity and mortality among them. Thus, we have examined the health vulnerabilities of older persons due to the COVID-19 pandemic using content analysis. We have analyzed 102 content collected from various online and printed articles published in newspapers, journals, and other relevant sources. The study has found increased health risks, deteriorated mental health, and poor health system functioning during the pandemic and its impact on older persons in Bangladesh. Strengthening health systems through an integrated model with capacity development of existing health care providers to deal with elderly health problems, including mental health and psychosocial wellbeing; promoting preventive measures, facilitating access to healthcare is required. Bangladesh can learn the Chinese experience to adopt innovative, specialized, and advanced systems to efficiently fight against the COVID-19.

Designing and Evaluating Multimodal Interactions for Facilitating Visual Analysis With Dashboards.

Exploring and analyzing data using visualizations is at the heart of many decision-making tasks. Typically, people perform visual data analysis using mouse and touch interactions. While such interactions are often easy to use, they can be inadequate for users to express complex information and may require many steps to complete a task. Recently natural language interaction has emerged as a promising technique for supporting exploration with visualization, as the user can express a complex analytical question more easily. In this paper, we investigate how to synergistically combine language and mouse-based direct manipulations so that the weakness of one modality can be complemented by the other. To this end, we have developed a novel system, named Multimodal Interactions System for Visual Analysis (MIVA), that allows user to provide input using both natural language (e.g., through speech) and direct manipulation (e.g., through mouse or touch) and presents the answer accordingly. To answer the current question in the context of past interactions, the system incorporates previous utterances and direct manipulations made by the user within a finite-state model. The uniqueness of our approach is that unlike most previous approaches which typically support multimodal interactions with a single visualization, MIVA enables multimodal interactions with multiple coordinated visualizations of a dashboard that visually summarizes a dataset. We tested MIVA's applicability on several dashboards including a COVID-19 dashboard that visualizes coronavirus cases around the globe. We further empirically evaluated our system through a user study with twenty participants. The results of our study revealed that MIVA system enhances the flow of visual analysis by enabling fluid, iterative exploration and refinement of data in a dashboard with multiple-coordinated views.

Mobile Apps for Foot Measurement in Pedorthic Practice: Scoping Review.

BACKGROUND: As the use of smartphones increases globally across various fields of research and technology, significant contributions to the sectors related to health, specifically foot health, can be observed. Numerous smartphone apps are now being used for providing accurate information about various foot-related properties. Corresponding to this abundance of foot scanning and measuring apps available in app stores, there is a need for evaluating these apps, as limited information regarding their evidence-based quality is available. OBJECTIVE: The aim of this review was to assess the measurement techniques and essential software quality characteristics of mobile foot measurement apps, and to determine their potential as commercial tools used by foot care health professionals, to assist in measuring feet for custom shoes, and for individuals to enhance their awareness of foot health and hygiene to ultimately prevent foot-related problems. METHODS: An electronic search across Android and iOS app stores was performed between July and August 2020 to identify apps related to foot measurement and general foot health. The selected apps were rated by three independent raters, and all discrepancies were resolved by discussion among raters and other investigators. Based on previous work on app rating tools, a modified rating scale tool was devised to rate the selected apps. The internal consistency of the rating tool was tested with a group of three people who rated the selected apps over 2-3 weeks. This scale was then used to produce evaluation scores for the selected foot measurement apps and to assess the interrater reliability. RESULTS: Evaluation inferences showed that all apps failed to meet even half of the measurement-specific criteria required for the proper manufacturing of custom-made footwear. Only 23% (6/26) of the apps reportedly used external scanners or advanced algorithms to reconstruct 3D models of a user's foot that could possibly be used for ordering custom-made footwear (shoes, insoles/orthoses), and medical casts to fit irregular foot sizes and shapes. The apps had varying levels of performance and usability, although the overall measurement functionality was subpar with a mean of 1.93 out of 5. Apps linked to online shops and stores (shoe recommendation) were assessed to be more usable than other apps but lacked some features (eg, custom shoe sizes and shapes). Overall, the current apps available for foot measurement do not follow any specific guidelines for measurement purposes. CONCLUSIONS: Most commercial apps currently available in app stores are not viable for use as tools in assisting foot care health professionals or individuals to measure their feet for custom-made footwear. Current apps lack software quality characteristics and need significant improvements to facilitate proper measurement, enhance awareness of foot health, and induce motivation to prevent and cure foot-related problems. Guidelines similar to the essential criteria items introduced in this study need to be developed for future apps aimed at foot measurement for custom-made or individually fitted footwear and to create awareness of foot health.

Adolescent motherhood in Bangladesh: Trends and determinants.

BACKGROUND: While studies on fertility and contraceptives issues are available, until recently adolescent motherhood has not received enough attention among policy makers in understanding adolescent motherhood in Bangladesh. We aimed to examine the trends and determinants of adolescent motherhood among women aged 15-49 years. METHODS: For trend analysis we used all the 7 waves of Bangladesh Demographic and Health Survey (BDHS, 1993-2014) data but for multivariate analysis 4 waves of BDHS (2004-2014). Two separate analyses were carried out on ever married women aged 15-49: (1) teenage girls aged 15-19 and (2) adult women aged 20 and above. RESULTS: The prevalence of adolescent motherhood had declined to a slower pace from 1993 to2014 (from 33.0% to 30.8%). Lower spousal age gap and higher education were found to be associated with lower likelihood of adolescent motherhood both among teenage girls [OR 0.447 (0.374-0.533)] and adult women [OR 0.451 (0.420-0.484)]. Teenage girls in the poorest wealth quintile [OR 1.712 [1.350-2.173] were more likely to experience adolescent motherhood than the richest wealth quintile. Teenage girls who had no education were found to have 2.76 times higher odds of adolescent motherhood than their counterparts who had higher than secondary education. Concerning the time effect, the odds of adolescent motherhood among adult women was found to decline overtime. CONCLUSIONS: Despite substantial decrease in total fertility rate in Bangladesh adolescent motherhood is still highly prevalent though declining from 1993 to 2014. Social policies including those addressing poverty, ensuring greater emphasis on education for women; and adolescent mothers in rural areas are needed.

Use of reproductive health care services among urban migrant women in Bangladesh.

BACKGROUND: Recent internal migration flows from rural to urban areas pose challenges to women using reproductive health care services in their migratory destinations. No studies were found which examined the relationship between migration, migration-associated indicators and reproductive health care services in Bangladesh. METHODS: We analyzed the 2006 Bangladesh Urban Health Survey (data made publically available in June 2013) of 14,191 ever-married women aged 10-59 years. Cross tabulations and logistic regression were conducted. RESULTS: Migrants and non-migrants did not differ significantly in their use of modern contraceptives and treatment for STI but were less likely to receive ANC even after controlling for a range of variables. Compared to non-migrants, more migrants had home births, did not take vitamin A after delivery, and had no medical exam post-birth. Migrant women being village-born (rather than urban-born) were associated with risk of diminished: use of ANC; treatment for STI; medical exam post-birth; vitamin A post-birth. Migrating for work or education (rather than other reasons) was associated with risk of diminished: use of ANC; use of modern facilities for birth; and medical exam post-birth. Each additional year lived in urban areas was associated with a greater likelihood of receiving ANC. CONCLUSIONS: Women who migrated to urban areas in Bangladesh were significantly less likely than non-migrants to use reproductive health care services related to pregnancy care. Pro-actively identifying migrant women, especially those who originated from villages or migrated for work or education may be warranted to ensure optimal use of pregnancy-related services.

Interaction between glutamate dehydrogenase (GDH) and L-leucine catabolic enzymes: intersecting metabolic pathways.

Branched-chain amino acids (BCAAs) catabolism follows sequential reactions and their metabolites intersect with other metabolic pathways. The initial enzymes in BCAA metabolism, the mitochondrial branched-chain aminotransferase (BCATm), which deaminates the BCAAs to branched-chain α-keto acids (BCKAs); and the branched-chain α-keto acid dehydrogenase enzyme complex (BCKDC), which oxidatively decarboxylates the BCKAs, are organized in a supramolecular complex termed metabolon. Glutamate dehydrogenase (GDH1) is found in the metabolon in rat tissues. Bovine GDH1 binds to the pyridoxamine 5'-phosphate (PMP)-form of human BCATm (PMP-BCATm) but not to pyridoxal 5'-phosphate (PLP)-BCATm in vitro. This protein interaction facilitates reamination of the α-ketoglutarate (αKG) product of the GDH1 oxidative deamination reaction. Human GDH1 appears to act like bovine GDH1 but human GDH2 does not show the same enhancement of BCKDC enzyme activities. Another metabolic enzyme is also found in the metabolon is pyruvate carboxylase (PC). Kinetic results suggest that PC binds to the E1 decarboxylase of BCKDC but does not effect BCAA catabolism. The protein interaction of BCATm and GDH1 promotes regeneration of PLP-BCATm which then binds to BCKDC resulting in channeling of the BCKA products from BCATm first half reaction to E1 and promoting BCAA oxidation and net nitrogen transfer from BCAAs. The cycling of nitrogen through glutamate via the actions of BCATm and GDH1 releases free ammonia. Formation of ammonia may be important for astrocyte glutamine synthesis in the central nervous system. In peripheral tissue association of BCATm and GDH1 would promote BCAA oxidation at physiologically relevant BCAA concentrations.

Branched-chain amino acid metabolon: interaction of glutamate dehydrogenase with the mitochondrial branched-chain aminotransferase (BCATm).

The catabolic pathway for branched-chain amino acids includes deamination followed by oxidative decarboxylation of the deaminated product branched-chain alpha-keto acids, catalyzed by the mitochondrial branched-chain aminotransferase (BCATm) and branched-chain alpha-keto acid dehydrogenase enzyme complex (BCKDC). We found that BCATm binds to the E1 decarboxylase of BCKDC, forming a metabolon that allows channeling of branched-chain alpha-keto acids from BCATm to E1. The protein complex also contains glutamate dehydrogenase (GDH1), 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1, pyruvate carboxylase, and BCKDC kinase. GDH1 binds to the pyridoxamine 5'-phosphate (PMP) form of BCATm (PMP-BCATm) but not to the pyridoxal 5'-phosphate-BCATm and other metabolon proteins. Leucine activates GDH1, and oxidative deamination of glutamate is increased further by addition of PMP-BCATm. Isoleucine and valine are not allosteric activators of GDH1, but in the presence of 5'-phosphate-BCATm, they convert BCATm to PMP-BCATm, stimulating GDH1 activity. Sensitivity to ADP activation of GDH1 was unaffected by PMP-BCATm; however, addition of a 3 or higher molar ratio of PMP-BCATm to GDH1 protected GDH1 from GTP inhibition by 50%. Kinetic results suggest that GDH1 facilitates regeneration of the form of BCATm that binds to E1 decarboxylase of the BCKDC, promotes metabolon formation, branched-chain amino acid oxidation, and cycling of nitrogen through glutamate.

Structural insights into the enzymatic mechanism of serine palmitoyltransferase from Sphingobacterium multivorum.

Serine palmitoyltransferase (SPT) is a key enzyme of sphingolipid biosynthesis and catalyses the pyridoxal 5'-phosphate (PLP)-dependent decarboxylative condensation reaction of l-serine with palmitoyl-CoA to generate 3-ketodihydrosphingosine. The crystal structure of SPT from Sphingobacterium multivorum GTC97 complexed with l-serine was determined at 2.3 A resolution. The electron density map showed the Schiff base formation between l-serine and PLP in the crystal. Because of the hydrogen bond formation with His138, the orientation of the Calpha-H bond of the PLP-l-serine aldimine was not perpendicular to the PLP-Schiff base plane. This conformation is unfavourable for the alpha-proton abstraction by Lys244 and the reaction is expected to stop at the PLP-l-serine aldimine. Structural modelling of the following intermediates indicated that His138 changes its hydrogen bond partner from the carboxyl group of l-serine to the carbonyl group of palmitoyl-CoA upon the binding of palmitoyl-CoA, making the l-serine Calpha-H bond perpendicular to the PLP-Schiff base plane. These crystal and model structures well explained the observations on bacterial SPTs that the alpha-deprotonation of l-serine occurs only in the presence of palmitoyl-CoA. This study provides the structural evidence that directly supports our proposed mechanism of the substrate synergism in the SPT reaction.

Molecular characterization of membrane-associated soluble serine palmitoyltransferases from Sphingobacterium multivorum and Bdellovibrio stolpii.

Serine palmitoyltransferase (SPT) is a key enzyme in sphingolipid biosynthesis and catalyzes the decarboxylative condensation of l-serine and palmitoyl coenzyme A (CoA) to form 3-ketodihydrosphingosine (KDS). Eukaryotic SPTs comprise tightly membrane-associated heterodimers belonging to the pyridoxal 5'-phosphate (PLP)-dependent alpha-oxamine synthase family. Sphingomonas paucimobilis, a sphingolipid-containing bacterium, contains an abundant water-soluble homodimeric SPT of the same family (H. Ikushiro et al., J. Biol. Chem. 276:18249-18256, 2001). This enzyme is suitable for the detailed mechanistic studies of SPT, although single crystals appropriate for high-resolution crystallography have not yet been obtained. We have now isolated three novel SPT genes from Sphingobacterium multivorum, Sphingobacterium spiritivorum, and Bdellovibrio stolpii, respectively. Each gene product exhibits an approximately 30% sequence identity to both eukaryotic subunits, and the putative catalytic amino acid residues are conserved. All bacterial SPTs were successfully overproduced in Escherichia coli and purified as water-soluble active homodimers. The spectroscopic properties of the purified SPTs are characteristic of PLP-dependent enzymes. The KDS formation by the bacterial SPTs was confirmed by high-performance liquid chromatography/mass spectrometry. The Sphingobacterium SPTs obeyed normal steady-state ordered Bi-Bi kinetics, while the Bdellovibrio SPT underwent a remarkable substrate inhibition at palmitoyl CoA concentrations higher than 100 microM, as does the eukaryotic enzyme. Immunoelectron microscopy showed that unlike the cytosolic Sphingomonas SPT, S. multivorum and Bdellovibrio SPTs were bound to the inner membrane of cells as peripheral membrane proteins, indicating that these enzymes can be a prokaryotic model mimicking the membrane-associated eukaryotic SPT.

A novel branched-chain amino acid metabolon. Protein-protein interactions in a supramolecular complex.

The catabolic pathways of branched-chain amino acids have two common steps. The first step is deamination catalyzed by the vitamin B(6)-dependent branched-chain aminotransferase isozymes (BCATs) to produce branched-chain alpha-keto acids (BCKAs). The second step is oxidative decarboxylation of the BCKAs mediated by the branched-chain alpha-keto acid dehydrogenase enzyme complex (BCKD complex). The BCKD complex is organized around a cubic core consisting of 24 lipoate-bearing dihydrolipoyl transacylase (E2) subunits, associated with the branched-chain alpha-keto acid decarboxylase/dehydrogenase (E1), dihydrolipoamide dehydrogenase (E3), BCKD kinase, and BCKD phosphatase. In this study, we provide evidence that human mitochondrial BCAT (hBCATm) associates with the E1 decarboxylase component of the rat or human BCKD complex with a K(D) of 2.8 microM. NADH dissociates the complex. The E2 and E3 components do not interact with hBCATm. In the presence of hBCATm, k(cat) values for E1-catalyzed decarboxylation of the BCKAs are enhanced 12-fold. Mutations of hBCATm proteins in the catalytically important CXXC center or E1 proteins in the phosphorylation loop residues prevent complex formation, indicating that these regions are important for the interaction between hBCATm and E1. Our results provide evidence for substrate channeling between hBCATm and BCKD complex and formation of a metabolic unit (termed branched-chain amino acid metabolon) that can be influenced by the redox state in mitochondria.

Human mitochondrial branched chain aminotransferase isozyme: structural role of the CXXC center in catalysis.

Mammalian branched chain aminotransferases (BCATs) have a unique CXXC center. Kinetic and structural studies of three CXXC center mutants (C315A, C318A, and C315A/C318A) of human mitochondrial (hBCATm) isozyme and the oxidized hBCATm enzyme (hBCATm-Ox) have been used to elucidate the role of this center in hBCATm catalysis. X-ray crystallography revealed that the CXXC motif, through its network of hydrogen bonds, plays a crucial role in orienting the substrate optimally for catalysis. In all structures, there were changes in the structure of the beta-turn preceding the CXXC motif when compared with wild type protein. The N-terminal loop between residues 15 and 32 is flexible in the oxidized and mutant enzymes, the disorder greater in the oxidized protein. Disordering of the N-terminal loop disrupts the integrity of the side chain binding pocket, particularly for the branched chain side chain, less so for the dicarboxylate substrate side chain. The kinetic studies of the mutant and oxidized enzymes support the structural analysis. The kinetic results showed that the predominant effect of oxidation was on the second half-reaction rather than the first half-reaction. The oxidized enzyme was completely inactive, whereas the mutants showed limited activity. Model building of the second half-reaction substrate alpha-ketoisocaproate in the pyridoxamine 5'-phosphate-hBCATm structure suggests that disruption of the CXXC center results in altered substrate orientation and deprotonation of the amino group of pyridoxamine 5'-phosphate, which inhibits catalysis.

Binding of C5-dicarboxylic substrate to aspartate aminotransferase: implications for the conformational change at the transaldimination step.

The mechanism for the reaction of aspartate aminotransferase with the C4 substrate, l-aspartate, has been well established. The binding of the C4 substrate induces conformational change in the enzyme from the open to the closed form, and the entire reaction proceeds in the closed form of the enzyme. On the contrary, little is known about the reaction with the C5 substrate, l-glutamate. In this study, we analyzed the pH-dependent binding of 2-methyl-l-glutamate to the enzyme and showed that the interaction between the amino group of 2-methyl-l-glutamate and the pyridoxal 5'-phosphate aldimine is weak compared to that between 2-methyl-l-aspartate and the aldimine. The structures of the Michaelis complexes of the enzyme with l-aspartate and l-glutamate were modeled on the basis of the maleate and glutarate complex structures of the enzyme. The result showed that l-glutamate binds to the open form of the enzyme in an extended conformation, and its alpha-amino group points in the opposite direction of the aldimine, while that of l-aspartate is close to the aldimine. These models explain the observations for 2-methyl-l-glutamate and 2-methyl-l-aspartate. The crystal structures of the complexes of aspartate aminotransferase with phosphopyridoxyl derivatives of l-glutamate, d-glutamate, and 2-methyl-l-glutamate were solved as the models for the external aldimine and ketimine complexes of l-glutamate. All the structures were in the closed form, and the two carboxylate groups and the arginine residues binding them are superimposable on the external aldimine complex with 2-methyl-l-aspartate. Taking these facts altogether, it was strongly suggested that the binding of l-glutamate to aspartate aminotransferase to form the Michaelis complex does not induce a conformational change in the enzyme, and that the conformational change to the closed form occurs during the transaldimination step. The hydrophobic residues of the entrance of the active site, including Tyr70, are considered to be important for promoting the transaldimination process and hence the recognition of the C5 substrate.

Reaction of aspartate aminotransferase with C5-dicarboxylic acids: comparison with the reaction with C4-dicarboxylic acids.

The reaction of Escherichia coli aspartate aminotransferase (AspAT) with glutamate and other C5-dicarboxylates was analyzed in order to compare its mechanism of action toward C5 substrates with that toward C4 substrates, which had been extensively characterized. The association of the amino-group protonated and unprotonated forms of glutamate (SH(+) and S, respectively) with the Schiff-base protonated and unprotonated forms of the enzyme (E(L)H(+) and E(L), respectively) yields at least three forms of the Michaelis complex, whereas in the case of aspartate, only two species of this complex exist, E(L).SH(+) and E(L)H(+).S. The reaction of AspAT with 2-methylglutamate can be explained only when we consider all the protonation states of the Michaelis complex. Based on the previous crystallographic studies [Miyahara et al. (1994) J. Biochem. 116, 1001-1012], we consider that glutamate binds to the open form of AspAT and takes an extended conformation in the Michaelis complex, with the alpha-amino group of glutamate oriented in the opposite direction to the Schiff base. This is in contrast to the Michaelis complex of aspartate, in which a strong interaction of the alpha-amino group of aspartate and the Schiff base excludes the presence of the species E(L)H(+).SH(+). It is concluded that AspAT recognizes the two types of dicarboxylates with different chain lengths by changing the gross conformation of the enzyme protein.

Strain and catalysis in aspartate aminotransferase.

The notion of "ground-state destabilization" has been well documented in enzymology. It is the unfavourable interaction (strain) in the enzyme-substrate complex, and increases the k(cat) value without changing the k(cat)/K(m) value. During the course of the investigation on the reaction mechanism of aspartate aminotransferase (AAT), we found another type of strain that is crucial for catalysis: the strain of the distorted internal aldimine in the unliganded enzyme. This strain raises the energy level of the starting state (E+S), thereby reducing the energy gap between E+S and ES(++) and increasing the k(cat)/K(m) value. Further analysis on the reaction intermediates showed that the Michaelis complex of AAT with aspartate contains strain energy due to an unfavourable interaction between the main chain carbonyl oxygen and the Tyr225-aldimine hydrogen-bonding network. This belongs to the classical type of strain. In each case, the strain is reflected in the pK(a) value of the internal aldimine. In the historical explanation of the reaction mechanism of AAT, the shifts in the aldimine pK(a) have been considered to be the driving forces for the proton transfer during catalysis. However, the above findings indicate that the true driving forces are the strain energy inherent to the respective intermediates. We describe here how these strain energies are generated and are used for catalysis, and show that variations in the aldimine pK(a) during catalysis are no more than phenomenological results of adjusting the energy levels of the reaction intermediates for efficient catalysis.