Keeping Up With ChatGPT: Evaluating Its Recognition and Interpretation of Nuclear Medicine Images.

PURPOSE: The latest iteration of GPT4 (generative pretrained transformer) is a large multimodal model that can integrate both text and image input, but its performance with medical images has not been systematically evaluated. We studied whether ChatGPT with GPT-4V(ision) can recognize images from common nuclear medicine examinations and interpret them. PATIENTS AND METHODS: Fifteen representative images (scintigraphy, 11; PET, 4) were submitted to ChatGPT with GPT-4V(ision), both in its Default and "Advanced Data Analysis (beta)" version. ChatGPT was asked to name the type of examination and tracer, explain the findings and whether there are abnormalities. ChatGPT should also mark anatomical structures or pathological findings. The appropriateness of the responses was rated by 3 nuclear medicine physicians. RESULTS: The Default version identified the examination and the tracer correctly in the majority of the 15 cases (60% or 53%) and gave an "appropriate" description of the findings or abnormalities in 47% or 33% of cases, respectively. The Default version cannot manipulate images. "Advanced Data Analysis (beta)" failed in all tasks in >90% of cases. A "major" or "incompatible" inconsistency between 3 trials of the same prompt was observed in 73% (Default version) or 87% of cases ("Advanced Data Analysis (beta)" version). CONCLUSIONS: Although GPT-4V(ision) demonstrates preliminary capabilities in analyzing nuclear medicine images, it exhibits significant limitations, particularly in its reliability (ie, correctness, predictability, and consistency).

Fusion-fission-mitophagy cycling and metabolic reprogramming coordinate nerve growth factor (NGF)-dependent neuronal differentiation.

Neuronal differentiation is regulated by nerve growth factor (NGF) and other neurotrophins. We explored the impact of NGF on mitochondrial dynamics and metabolism through time-lapse imaging, metabolomics profiling, and computer modeling studies. We show that NGF may direct differentiation by stimulating fission, thereby causing selective mitochondrial network fragmentation and mitophagy, ultimately leading to increased mitochondrial quality and respiration. Then, we reconstructed the dynamic fusion-fission-mitophagy cycling of mitochondria in a computer model, integrating these processes into a single network mechanism. Both the computational model and the simulations are able to reproduce the proposed mechanism in terms of mitochondrial dynamics, levels of reactive oxygen species (ROS), mitophagy, and mitochondrial quality, thus providing a computational tool for the interpretation of the experimental data and for future studies aiming to detail further the action of NGF on mitochondrial processes. We also show that changes in these mitochondrial processes are intertwined with a metabolic function of NGF in differentiation: NGF directs a profound metabolic rearrangement involving glycolysis, TCA cycle, and the pentose phosphate pathway, altering the redox balance. This metabolic rewiring may ensure: (a) supply of both energy and building blocks for the anabolic processes needed for morphological reorganization, as well as (b) redox homeostasis.

Arsenic Contamination of Groundwater Is Determined by Complex Interactions between Various Chemical and Biological Processes.

At a great many locations worldwide, the safety of drinking water is not assured due to pollution with arsenic. Arsenic toxicity is a matter of both systems chemistry and systems biology: it is determined by complex and intertwined networks of chemical reactions in the inanimate environment, in microbes in that environment, and in the human body. We here review what is known about these networks and their interconnections. We then discuss how consideration of the systems aspects of arsenic levels in groundwater may open up new avenues towards the realization of safer drinking water. Along such avenues, both geochemical and microbiological conditions can optimize groundwater microbial ecology vis-à-vis reduced arsenic toxicity.

Microbial Ecosystems in Movile Cave: An Environment of Extreme Life.

Movile Cave, situated in Romania close to the Black Sea, constitutes a distinct and challenging environment for life. Its partially submerged ecosystem depends on chemolithotrophic processes for its energetics, which are fed by a continuous hypogenic inflow of mesothermal waters rich in reduced chemicals such as hydrogen sulfide and methane. We sampled a variety of cave sublocations over the course of three years. Furthermore, in a microcosm experiment, minerals were incubated in the cave waters for one year. Both endemic cave samples and extracts from the minerals were subjected to 16S rRNA amplicon sequencing. The sequence data show specific community profiles in the different subenvironments, indicating that specialized prokaryotic communities inhabit the different zones in the cave. Already after one year, the different incubated minerals had been colonized by specific microbial communities, indicating that microbes in Movile Cave can adapt in a relatively short timescale to environmental opportunities in terms of energy and nutrients. Life can thrive, diversify and adapt in remote and isolated subterranean environments such as Movile Cave.

'Social' versus 'asocial' cells-dynamic competition flux balance analysis.

In multicellular organisms cells compete for resources or growth factors. If any one cell type wins, the co-existence of diverse cell types disappears. Existing dynamic Flux Balance Analysis (dFBA) does not accommodate changes in cell density caused by competition. Therefore we here develop 'dynamic competition Flux Balance Analysis' (dcFBA). With total biomass synthesis as objective, lower-growth-yield cells were outcompeted even when cells synthesized mutually required nutrients. Signal transduction between cells established co-existence, which suggests that such 'socialness' is required for multicellularity. Whilst mutants with increased specific growth rate did not outgrow the other cell types, loss of social characteristics did enable a mutant to outgrow the other cells. We discuss that 'asocialness' rather than enhanced growth rates, i.e., a reduced sensitivity to regulatory factors rather than enhanced growth rates, may characterize cancer cells and organisms causing ecological blooms. Therapies reinforcing cross-regulation may therefore be more effective than those targeting replication rates.

Prognostic Value of the De Ritis Ratio for Overall Survival in Patients with Metastatic Castration-Resistant Prostate Cancer Undergoing [177Lu]Lu-PSMA-617 Radioligand Therapy.

The De Ritis ratio (=aspartate transaminase/alanine transaminase) has shown prognostic value in different cancer types. This is the first such analysis in prostate cancer patients undergoing radioligand therapy (RLT) with [177Lu]Lu-PSMA-617. This retrospective monocentric analysis included 91 patients with a median of 3 RLT cycles (range 1-6) and median cumulative activity of 17.3 GBq. Univariable Cox regression regarding overall survival (OS) included age, different types of previous treatment, metastatic patterns and different laboratory parameters before RLT. Based on multivariable Cox regression, a prognostic score was derived. Seventy-two patients (79%) died (median follow-up in survivors: 19.8 months). A higher number of previous chemotherapy lines, the presence of liver metastases, brain metastases, a higher tumor load on PSMA-PET, a higher prostate-specific antigen (PSA) level, lower red blood cell count, lower hemoglobin, higher neutrophil-lymphocyte ratio and higher De Ritis ratio were associated with shorter OS (each p < 0.05). In multivariable Cox, a higher number of chemotherapy lines (range, 0-2; p = 0.036), brain metastases (p < 0.001), higher PSA (p = 0.004) and higher De Ritis ratio before RLT (hazard ratio, 1.27 per unit increase; p = 0.023) remained significant. This prognostic score separated five groups with a significantly different median OS ranging from 4.9 to 28.1 months (log-rank test, p < 0.001). If validated independently, the De Ritis ratio could enhance multifactorial models for OS after RLT.

On paradoxes between optimal growth, metabolic control analysis, and flux balance analysis.

In Microbiology it is often assumed that growth rate is maximal. This may be taken to suggest that the dependence of the growth rate on every enzyme activity is at the top of an inverse-parabolic function, i.e. that all flux control coefficients should equal zero. This might seem to imply that the sum of these flux control coefficients equals zero. According to the summation law of Metabolic Control Analysis (MCA) the sum of flux control coefficients should equal 1 however. And in Flux Balance Analysis (FBA) catabolism is often limited by a hard bound, causing catabolism to fully control the fluxes, again in apparent contrast with a flux control coefficient of zero. Here we resolve these paradoxes (apparent contradictions) in an analysis that uses the 'Edinburgh pathway', the 'Amsterdam pathway', as well as a generic metabolic network providing the building blocks or Gibbs energy for microbial growth. We review and show that (i) optimization depends on so-called enzyme control coefficients rather than the 'catalytic control coefficients' of MCA's summation law, (ii) when optimization occurs at fixed total protein, the former differ from the latter to the extent that they may all become equal to zero in the optimum state, (iii) in more realistic scenarios of optimization where catalytically inert biomass is compensating or maintenance metabolism is taken into consideration, the optimum enzyme concentrations should not be expected to equal those that maximize the specific growth rate, (iv) optimization may be in terms of yield rather than specific growth rate, which resolves the paradox because the sum of catalytic control coefficients on yield equals 0, (v) FBA effectively maximizes growth yield, and for yield the summation law states 0 rather than 1, thereby removing the paradox, (vi) furthermore, FBA then comes more often to a 'hard optimum' defined by a maximum catabolic flux and a catabolic-enzyme control coefficient of 1. The trade-off between maintenance metabolism and growth is highlighted as worthy of further analysis.

Is distance from equilibrium a good indicator for a reaction's flux control?

By analysing a large set of models obtained from the JWS Online and Biomodels databases, we tested to what extent the disequilibrium ratio can be used as an estimator for the flux control of a reaction, a discussion point that was already raised by Kacser and Burns, and Heinrich and Rapoport in their seminal MCA manuscripts. Whereas no functional relation was observed, the disequilibrium ratio can be used as an estimator for the maximal flux control of a reaction step. We extended the original analysis of the relationship by incorporating the overall pathway disequilibrium ratio in the expression, which made it possible to make explicit expressions for flux control coefficients.

Gear Shifting in Biological Energy Transduction.

Confronted with thermodynamically adverse output processes, free-energy transducers may shift to lower gears, thereby reducing output per unit input. This option is well known for inanimate machines such as automobiles, but unappreciated in biology. The present study extends existing non-equilibrium thermodynamic principles to underpin biological gear shifting and identify possible mechanisms. It shows that gear shifting differs from altering the degree of coupling and that living systems may use it to optimize their performance: microbial growth is ultimately powered by the Gibbs energy of catabolism, which is partially transformed into Gibbs energy ('output force') in the ATP that is produced. If this output force is high, the cell may turn to a catabolic pathway with a lower ATP stoichiometry. Notwithstanding the reduced stoichiometry, the ATP synthesis flux may then actually increase as compared to that in a system without gear shift, in which growth might come to a halt. A 'variomatic' gear switching strategy should be optimal, explaining why organisms avail themselves of multiple catabolic pathways, as these enable them to shift gears when the growing gets tough.

Competitive, multi-objective, and compartmented Flux Balance Analysis for addressing tissue-specific inborn errors of metabolism.

The inborn error of metabolism phenylketonuria (PKU, OMIM 261600) is most often due to inactivation of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) into tyrosine (Tyr). The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux balance analysis (FBA) of a single-compartment model of PKU predicts that maximum growth rate should be reduced unless Tyr is supplemented. However, the PKU phenotype is lack of development of brain function specifically, and Phe reduction rather than Tyr supplementation cures the disease. Phe and Tyr cross the blood-brain barrier (BBB) through the aromatic amino acid transporter implying that the two transport reactions interact. However, FBA does not accommodate such competitive interactions. We here report on an extension to FBA that enables it to deal with such interactions. We built a three-compartment model, made the common transport across the BBB explicit, and included dopamine and serotonin synthesis as parts of the brain function to be delivered by FBA. With these ramifications, FBA of the genome-scale metabolic model extended to three compartments does explain that (i) the disease is brain specific, (ii) phenylpyruvate in urine is a biomarker, (iii) excess of blood-phenylalanine rather than shortage of blood-tyrosine causes brain pathology, and (iv) Phe deprivation is the better therapy. The new approach also suggests (v) explanations for differences in pathology between individuals with the same PAH inactivation, and (vi) interference of disease and therapy with the functioning of other neurotransmitters.

Recommendations for performing measurements of apparent equilibrium constants of enzyme-catalyzed reactions and for reporting the results of these measurements.

The measurement of values of apparent equilibrium constants K' for enzyme-catalyzed reactions involve a substantial number of critical details, neglect of which could lead to systematic errors. Here, interferences, impurities in the substances used, and failure to achieve equilibrium are matters of substantial consequence. Careful reporting of results is of great importance if the results are to have archival value. Thus, attention must be paid to the identification of the substances, specification of the reaction(s), the conditions of reaction, the definition of the equilibrium constant(s) and standard states, the use of standard nomenclature, symbols, and units, and uncertainties. This document contains a general discussion of various aspects of these equilibrium measurements as well as STRENDA (Standards for Reporting Enzymology Data) recommendations regarding the measurements and the reporting of results.

Committing Fallacies and the Appearance Condition.

This appearance condition of fallacies refers to the phenomenon of weak arguments, or moves in argumentation, appearing to be okay when really they aren't. Not all theorists agree that the appearance condition should be part of the conception of fallacies but this essay explores some of the consequences of including it. In particular, the differences between committing a fallacy, causing a fallacy and observing a fallacy are identified. The remainder of the paper is given over to discussing possible causes of mistakenly perceiving weak argumentation moves as okay. Among these are argument caused misperception, perspective caused misperception, discursive environment caused misperception and perceiver caused misperception. The discussion aims to be sufficiently general so that it can accommodate different models and standards of argumentation that make a place for fallacies.

Decision criteria for selecting essential medicines and their connection to guidelines: an interpretive descriptive qualitative interview study.

BACKGROUND AND OBJECTIVES: The World Health Organization Model List of Essential Medicines has led to at least 137 national lists. Essential medicines should be grounded in evidence-based guideline recommendations and explicit decision criteria. Essential medicines should be available, accessible, affordable, and the supporting evidence should be accompanied by a rating of the certainty one can place in it. Our objectives were to identify criteria and considerations that should be addressed in moving from a guideline recommendation regarding a medicine to the decision of whether to add, maintain, or remove a medicine from an essential medicines list. We also seek to explore opportunities to improve organizational processes to support evidence-based health decision-making more broadly. METHODS: We conducted a qualitative study with semistructured interviews of key informant stakeholders in the development and use of guidelines and essential medicine lists (EMLs). We used an interpretive descriptive analysis approach and thematic analysis of interview transcripts in NVIVO v12. RESULTS: We interviewed 16 key informants working at national and global levels across all WHO regions. We identified five themes: three descriptive/explanatory themes 1) EMLs and guidelines, the same, but different; 2) EMLs can drive price reductions and improve affordability and access; 3) Time lag and disconnect between guidelines and EMLs; and two prescriptive themes 4) An "evidence pipeline" could improve coordination between guidelines and EMLs; 5) Facilitating the link between the WHO Model List of Essential Medicines (WHO EML) and national EMLs could increase alignment. CONCLUSION: We found significant overlap and opportunities for alignment between guideline and essential medicine decision processes. This finding presents opportunities for guideline and EML developers to enhance strategies for collaboration. Future research should assess and evaluate these strategies in practice to support the shared goal of guidelines and EMLs: improvements in health.

Transarterial Yttrium-90 Radioembolization in Intrahepatic Cholangiocarcinoma Patients: Outcome Assessment Applying a Prognostic Score.

Radioembolization (RE) is a viable therapy option in patients with intrahepatic cholangiocarcinoma (ICC). This study delineates a prognostic score regarding overall survival (OS) after RE using routine pre-therapeutic parameters. A retrospective analysis of 39 patients (median age, 61 [range, 32−82] years; 26 females, 13 males) with ICC and 42 RE procedures was conducted. Cox regression for OS included age, ECOG, hepatic and extrahepatic tumor burden, thrombosis of the portal vein, ascites, laboratory parameters and dose reduction due to hepatopulmonary shunt. Median OS after RE was 8.0 months. Using univariable Cox, ECOG ≥ 1 (hazard ratio [HR], 3.8), AST/ALT quotient (HR, 1.86), high GGT (HR, 1.002), high CA19-9 (HR, 1.00) and dose reduction of 40% (HR, 3.8) predicted shorter OS (each p < 0.05). High albumin predicted longer OS (HR, 0.927; p = 0.045). Multivariable Cox confirmed GGT ≥ 750 [U/L] (HR, 7.84; p < 0.001), ECOG > 1 (HR, 3.76; p = 0.021), albumin ≤ 41.1 [g/L] (HR, 3.02; p = 0.006) as a three-point pre-therapeutic prognostic score. More specifically, median OS decreased from 15.3 months (0 risk factors) to 7.6 months (1 factor) or 1.8 months (≥2 factors; p < 0.001). The proposed score may aid in improved pre-therapeutic patient identification with (un-)favorable OS after RE and facilitate the balance between potential life prolongation and overaggressive patient selection.

Cyanine Dye Coupling Mediates Self-assembly of a pH Sensitive Peptide into Novel 3D Architectures.

Synthetic multichromophore systems are of great importance in artificial light harvesting devices, organic optoelectronics, tumor imaging and therapy. Here, we introduce a promising strategy for the construction of self-assembled peptide templated dye stacks based on coupling of a de novo designed pH sensitive peptide with a cyanine dye Cy5 at its N-terminus. Microscopic techniques, in particular cryogenic TEM (cryo-TEM) and cryo-electron tomography technique (cryo-ET), reveal two types of highly ordered three-dimensional assembly structures on the micrometer scale. Unbranched compact layered rods are observed at pH 7.4 and two-dimensional membrane-like assemblies at pH 3.4, both species displaying spectral features of H-aggregates. Molecular dynamics simulations reveal that the coupling of Cy5 moieties promotes the formation of both ultrastructures, whereas the protonation states of acidic and basic amino acid side chains dictates their ultimate three-dimensional organization.

Hydrocephalus Study Design: Testing New Hypotheses in Clinical Studies and Bench-to-Bedside Research.

In this article, we aimed to describe some of the currently most challenging problems in neurosurgical management of hydrocephalus and how these can be reasons for inspiration for and development of research. We chose 4 areas of focus: 2 dedicated to improvement of current treatments (shunt implant surgery and endoscopic hydrocephalus surgery) and 2 dedicated to emerging future treatment principles (molecular mechanisms of cerebrospinal fluid secretion and hydrocephalus genetics).

Sudden loss of smell and taste: clinical predictors of coronavirus disease 2019 infection.

OBJECTIVES: This study aimed: to evaluate the association between coronavirus disease 2019 infection and olfactory and taste dysfunction in patients presenting to the out-patient department with influenza-like illness, who underwent reverse transcription polymerase chain reaction testing for coronavirus; and to determine the sensitivity, specificity, and positive and negative predictive values of olfactory and taste dysfunction and other symptoms in these patients. METHODS: Patients presenting with influenza-like illness to the study centre in September 2020 were included in the study. The symptoms of patients who tested positive for coronavirus on reverse transcription polymerase chain reaction testing were compared to those with negative test results. RESULTS: During the study period, 909 patients, aged 12-70 years, presented with influenza-like illness; of these, 316 (34.8 per cent) tested positive for coronavirus. Only the symptoms of olfactory and taste dysfunction were statistically more significant in patients testing positive for coronavirus than those testing negative. CONCLUSION: During the pandemic, patients presenting to the out-patient department with sudden loss of sense of smell or taste may be considered as positive for coronavirus disease 2019, until proven otherwise.

Development of inclined plate honey moisture reduction system.

Honey is delicious, nutritious and has high medicinal value in comparison to other sweeteners. Honey is usually extracted from comb as immature product which results in high moisture which makes it more liable to be fermented by osmophilic yeasts. So, it needs to be processed for moisture reduction, to delay crystallization and to overcome the problem of fermentation. In the present investigation, a honey moisture reduction system was developed and tested to reduce the moisture content of honey to about 17%. The system consisted of a flat plate inclined at an angle. The plate was heated from the underside and honey for moisture reduction was re-circulated over it until desired moisture content was achieved. Experiments were conducted for honey moisture reduction at water temperature of 40-70 °C with plate inclinations of 30°-60° according to four level full factorial design of experiment. The results showed that the total reduction time required for reaching moisture content of about 17% varied with water temperature and angle of inclination. The moisture reduction time required for reaching a moisture content of 17 percent at 40 °C was about five times the time required at 70 °C. The energy cost of honey moisture content reduction from 21.5 to 17% was Rs. 4.7 to Rs. 12.5 per kg.