Polymer mechanochemistry offers attractive opportunitiesfor usingmacroscopic forces to drive molecular-scale chemical transformations,but achieving efficient activation in bulk polymeric materials hasremained challenging. Understanding how the structure and topologyof polymer networks impact molecular-scale force distributions iscritical for addressing this problem. Here we show that in block copolymerelastomers the molecular-scale force distributions and mechanochemicalactivation yields are strongly impacted by the molecular weight distributionof the polymers. We prepare bidisperse triblock copolymer elastomerswith spiropyran mechanophores placed in either the short chains, thelong chains, or both and show that the overall mechanochemical activationof the materials is dominated by the short chains. Molecular dynamicssimulations reveal that this preferential activation occurs becausepinning of the ends of the elastically effective midblocks to theglassy/rubbery interface forces early extension of the short chains.These results suggest that microphase segregation and network stranddispersity play a critical role in determining molecular-scale forcedistributions and suggest that selective placement of mechanophoresin microphase-segregated polymers is a promising design strategy forefficient mechanochemical activation in bulk materials. However, yieldsof force-driven reactions in elastomeric polymer networks are typicallylow, even for mechanophores that exhibit high activation yields insolution sonication experiments.23 By changing which component of the blend contains mechanophores, we are effectively able to “label”and probe the activation of chains with different elastic strand lengthswithin otherwise equivalent networks. We find that activation occursprimarily in the short chains, which molecular dynamics (MD) simulationsreveal is driven in large part by pinning of the elastically effectivemidblock ends to the glassy/rubbery interface. These results suggestthat controlling both microphase segregation and network strand lengthdistributions is an important design strategy for directing molecular-scaleforce distributions and enabling efficient mechanochemical activationin bulk materials.Here, we use a combination of experimentsand computer simulationsto investigate how network strand dispersity impacts molecular-scaleforce distributions and mechanochemical activation in self-assembledtriblock copolymers. As illustrated in n-butyl acrylate) (PnBA) midblocks, as depicted in fPMMA ≈ 0.45) and narrow dispersities (Đ ≈ 1.2), but differed in overall molecular weight (Mn ≈ 60 or 150 kg/mol) and whether theycontained a spiropyran mechanophore in the center of the PnBA midblock.These parent polymers were then blended to prepare bidisperse sampleswith equal weight fractions of short and long chains, but with spiropyranmechanophores in different subpopulations of the chains. Samples labeledW-Sl contained mechanophores only in the short (S) chains; sampleslabeled W-sL contained mechanophores only in the long (L) chains;and samples labeled W-SL contained mechanophores in both the shortand the long (SL) chains. Here, the “W-” prefix is usedto indicate that the samples contained equal weight fractions of shortand long chains; complementary experiments on samples with equal numberfractions of short and long chains (“N-”) are reportedin the Supporting Information. Size exclusionchromatography confirmed that all three blended samples had similarnumber-average molecular weights and molecular weight distributions.Scanning transmission electron microscopy (STEM) images and small-angleX-ray scattering (SAXS) patterns of the self-assembled samples revealedthat all three polymer blends self-assembled into disordered, microphase-segregated materials with domain spacings onthe order of 30 nm, consistent with the disordered, bicontinuous morphologiesobserved in other polydisperse block copolymer systems.26We first synthesized four triblock copolymers withglassy poly(methylmethacrylate) (PMMA) end blocks and rubbery poly activated relativelyearly, with the onset of activation observed around ϵ ≈0.67 and σ ≈ 6 MPa. The W-sL samples, on the other hand,which only contained mechanophores in the long strands, activatedmuch later, with the onset of activation not observed until ϵ≈ 2.25 and σ ≈ 9 MPa. The total activation ofthe W-SL sample, which contained mechanophores in both the short andthe long chains, was also almost identical with that of the W-Sl sample,which contained mechanophores in only the short chains. Similar trendswere observed in samples containing equal number fractions of shortand long chains (see Supporting Information). Together, these results reveal that in block copolymer elastomersmechanochemical activation is almost entirely dominated by the shortchains (even when both populations of chains contain mechanophores),suggesting that the molecular-scale forces on these chains are muchhigher than those on their longer counterparts.The mechanical properties and mechanochemical activation profilesof the materials were then characterized by measuring changes in theiroptical absorption between 550 and 630 nm during uniaxial tensiledeformation.28 The PMMA and PnBAblock fractions were chosen to yield well-defined cylindrical morphologies,as shown in 30 and activationof the mechanophores in both the long and the short chains was quantifiedby monitoring changes in the bond length of a double-well unit inthe center of the chains. The resulting activation profiles for eachsubset of chains are shown in true ≈ 0.75) than the longchains did (ϵtrue ≈ 0.95). The overall activationalso closely tracked that of the short chains alone until relativelyhigh strains (ϵtrue > 1). While the simulationswererun on perfectly ordered, anisotropic morphologies and thus likelyoverestimate the overall response of more disordered and/or isotropicsamples, the close qualitative agreement of the simulation data withthe experimental results validates the simulation model and reinforcesthe conclusion that mechanochemical activation is much more efficientin the shorter chains.To understand the molecular-scale origins of thisresult, we carriedout coarse-grained molecular dynamics simulations on triblock copolymerswith bimodal molecular weight distributions designed to mimic theexperimental system.Supporting Information) additionallyreveals that activation is higher in chains that are well-alignedwith the pulling direction and that the short tie chains align moreeasily than the long tie chains do. As in the experimental systems,similar trends were also observed in samples containing equal numberfractions of short and long chains.Detailed analysis of the MD simulations providesinsights intothe molecular-scale features that promote this preferential activationof the short chains. As shown in Supporting Information). From a fundamental perspective, since the mechanophores act asmolecular-scale force probes, these results provide detailed new insightsinto how force is distributed in block copolymer elastomers. In particular,short tie chains carry much of the load, even when they constitutea minority of the tie chains in the material. Interestingly, thisresult is in contrast to the behavior observed in linear homopolymers,where activation is typically more pronounced in longer chains,32 and in both rubbery and glassy cross-linked networks, where it hasbeen shown that activation levels are essentially independent of thecross-linker length as long as the probe strands are shorter thanthe average strand length of the material.33 This suggests that pinning of the midblock ends to the hard/softinterface may be critical for directing force to the shorter strands.While similar effects might be expected to occur in covalently cross-linkedrubbers, relaxation of the junction points in these materials mayalso reduce the preferential stretching of the short chains,33 and further investigation will be needed tounderstand how network topology and strand dispersity affect mechanochemicalactivation in those materials. We note, however, that the absoluteactivation in the block copolymer samples appears to be higher thanin most elastomers reported to date.18 While thereis a small amount of uncertainty in the absolute activation arisingfrom the measurement of the extinction coefficient of the activatedmechanophores (see Supporting Information), this result suggests that pinning of the midblocks to the glassy/rubberyinterface may facilitate a more efficient force transfer overall.The observation that activation only occurs after the yield pointof the materials further highlights the importance of the glassy phase,with rearrangement of the glassy phase (which is not captured in thesimulations) necessary prior to stretching and mechanophore activationin the rubbery midblock strands.27Both the experimental and computational resultsreported in thiswork show that mechanochemical activation preferentially occurs inthe short tie chains in bidisperse triblock elastomers. Preferentialactivation of the short tie chains is so pronounced that the shortchains dominate the overall activation profile of the material, eventhough the short chains have a lower probability of forming tie chainsthan the long chains do (see From an applied perspective, this work also suggests that microphasesegregation, control of elastic strand dispersity, and carefully consideredplacement of mechanophores in different populations of the networkstrands can be used to optimize both the overall mechanochemical activationefficiencies in polymeric materials and the point at which activationoccurs during a macroscopic deformation. To facilitate early activation,mechanophores should be placed in the short strands of a triblockelastomer, while materials displaying delayed activation can be preparedby instead placing mechanophores in the long strands. Additionally,because the mechanophores in the long strands display a much loweroverall activation and are in some sense “wasted” mechanophores,the overall activation yield per mechanophore can be improved by placingthe mechanophores primarily in the short strands. Regardless of thetargeted activation profile, however, the formation of microphase-segregatedmorphologies and pinning of the elastic chain ends to the block interfaceappear to be critical for forcing early extension of the short midblocks,and we anticipate that controlling microphase segregation should bea powerful design parameter for enhancing mechanochemical activationin elastomeric networks.In summary, we showed that in microphase-segregatedtriblock elastomerswith bidisperse molecular weight distributions, mechanochemical activationoccurs primarily in the short chains. These results suggest that networkstrand dispersity plays an important role in determining molecular-scaleforce distributions in these materials and that selective placementof mechanophores in the highest-force or highest-extension strandscan be used to both control the onset of activation and improve overallactivation yields. Further investigation of how microphase segregation,network topology, dispersity, and defect content influence molecular-scaleforce distributions and mechanochemical activation yields promisesto be a fruitful avenue for achieving efficient mechanochemical activationin bulk polymer materials.


Intuitions about extending topic through a propositional language are generally straightforward for extensional cases. For a number of reasons, arriving at a compelling account of the subject-matter of intensional operators—such as intensional conditionals—is a more difficult task. In particular, the framework of topic-sensitive intentional modals (TSIMs) championed by Francesco Berto and his collaborators leave the topics of intensional formulae undefined, which artificially constricts the expressivity of the theory. This paper proposes an approach to fill in this lacuna, emphasizing an analogous problem in Parry-style containment logics. In this setting, the approach receives a proof-of-concept through the introduction of a natural and general family of subsystems of Parry’s Although logical settings are typically concerned with tracking  Berto  is nothing more than punctuation. To make the additional assumption of synonymy of Junctive Transparency holding of the material implication Now, to consider the former case of inadequate refinement, let us consider some of the formalism in more detail. The model theory of TSIMs incorporates a in Berto :Negationmentclass2pt{minimknowability relative to information . Without an account of the topic of the intensional counterfactual, a relatively simple truth 3In an act of imagination in which ‘had Sam gone home, she would have eaten dinner and gone to bed’ is true, one also imagines that ‘had Sam gone home, she would have eaten dinner’.Cannot be evaluated.This greatly curtails the scope and ultimately limits the utility of the framework. Consider the setting of in Berto  and its in Berto . In pracextensional information knowledge-constitutive, but intensional information—e.g. information expressing the metaphysical necessity of such-and-such a proposition—can serve to ground knowability. In other words, to capture the full breadth of knowability relative to information, a means should exist to evaluate sentences such as: 4Given the information that it is necessary that water is If the framework is to reach its full realization, it must be faithful to linguistic practice. If the framework is to be faithful to linguistic practice, the assignment of formulae to topics must not only be total but be extensible to a wide variety of intensional operators. Thus, we have a need to introduce a framework for the assignment of topics to intensional formulae.Similarly, return to the context of knowability relative to information described in Berto and Hawke ; not onlcompositional, one can imagine numerous ways in which the topic of any particular intensional conditional may differ from the mere fusion of the topics of its subformulae. Likewise, one can imagine that distinct types of intensional conditionals determine their topics in different ways. E.g., while an about the constituents of the actual world, the nature of a counterfactual conditional seems to require that its topic omits these inhabitants from its subject-matter. Given the justified true belief account, the topic of a TSIM modeling knowledge may include that of the corresponding TSIM modeling belief. Given the variety of intensional operators—and number of distinct topic-theoretic relationships holding between them—an appropriate general machinery should be weak enough to cover a maximal number of cases.Our proposal is a modest one. Even if the topic of an intensional conditional is properly extends the fusion of cases in which incommensurable with the fusion of cases in which cases in which the topics While compositional, different types of intensional conditionals may determine different accounts of topic; e.g., the topics of permissive to not force a theory of topic upon a conditional when unwarranted; but also demand of the framework that it be sufficiently modular to allow the representation of stronger, more detailed theories of topic corresponding to individual types of intensional conditionals.Ways in which we might characterize the topic-theoretic behavior of an intensional conditional imposing new constraints on the properties of To capture this intuition, we equip the topic semilattice with a binary function feature rather than a bug. Just as Kripke models are agnostic with respect to the model-theoretic characterization of necessity—R—so, too, shall we remain agnostic about the topic-theoretic characterization of intensional sentences. But the proposal is not vacuous; as we will discover, there is enough subtlety to allow a fine degree of control over allowing the representation of various intuitions about the behavior of the topics of such sentences.This agnosticism is thus recognizably a In the foregoing section, we briefly considered several dimensions along which the topic of an intensional conditional could differ from the fusion of the topics of its parts. In this section, we will examine each of these cases more closely.topic-theoretically ampliative, i.e., the implication operator plays a role in determining the overall subject-matter of the complex, whether the influence is additive or transformative. The most direct route to intensional conditionals’ ampliativity begins by taking note of a familiar characterization: it is common to describe intensional conditionals as expressing a relation between antecedent and consequent. The interpretation of conditionals as expressing a relation—of some kind—between statements is a well-established and frequently encountered idiom, pronounced not only in revisionary, intensional projects like Lewis and Langford  Such relations between propositions are as authentically relational as first-order relations between individuals. The implausibility of Constituent Equivalence in the case of intensional conditionals is illustrated by the severity of the incongruity between the topics of the following two conditionals: 9Were John to win the lottery, he would retire tomorrow.10Were John to retire tomorrow, he would win the lottery.Intuitively, [9] and [10] paint radically different pictures. The former is an unsurprising statement about the actions the subject John would take in case of a sudden windfall. In contrast, the latter sentence expresses an unusual claim about John—retirement is an event that most people reach without a windfall, so John must have some surprising quality that ensures a lottery win upon his retirement. Like Yablo’s first-order example, [10] is clearly about a more interesting topic than [9] and, consequently, a different topic.As we’ve mentioned, restrictor, i.e., the antecedent serves to restrict the set of worlds or states against which the consequent is to be evaluated, then this can be taken a step further. In [9], there is a sense in which a class of scenarios in which John wins the lottery is not only part of how to determine the truth of [9]; these states are part of what the sentence is about.We can strengthen this. If one adopts a view like that of Kratzer in  in whicha priori intersection between topics, an interlocutor who utters [9] has nevertheless veered off-topic in a way that an utterer of [10] does not. [10]addresses the question—if perhaps unrealistically—in virtue of its being about those situations in which John retires. [9], on the other hand, fails to reflect the restriction implicit in the question; it is primarily about lottery-winnings and only subordinately about retirements.To illustrate, consider a conversation in which one participant asks, “What do you think would happen if John were to retire tomorrow?” Despite an [9] and [10] nontrivially influence their respective topics.This only makes sense in case the intensional conditionals in analytic implicationanalysis. As discussed in Ferguson  not present in the antecedent. The definitive statement of this condition is the Proscriptive Principle thatNo formula with analytic implication as main relation holds universally if it has a free variable occurring in the consequent but not the antecedent. Parry, , p. 151Parry’s approach has had its share of criticism  while simultaneously describing analytic implication itself as a concept (Begriff):Another change, suggested by Parry [in Parry ], arisesApparently, this suggestion is not explicitly posed by Parry; rather, the modification sketched by Fine has its origins in Parry’s choice of terminology:Begriff) of logical consequence should have the specified property, since the conclusion cannot contain any concepts (Begriffe) other than the premises.[T]he concept  and analytic implication is itself a concept (Begriff), then the proscription ought to extend to preclude the introduction of this concept as well.Fine observes that Parry offers the Proscriptive Principle as a thesis about the inclusion of intensional conditionals—are often described as asserting that an entailment relationship holds between two propositions, however. Consequently, there seem to be cases in which the appearance of contribution to the complex sentence’s subject matter as the predicate “is married to” contributes to the subject-matter of “Jill is married to Pat.”Having acknowledged that relations expressed by intensional conditionals may have an ampliative or transformational effect on component subject-matter, Fine’s suggestion is clearly a step in the right direction. Conditionals—most importantly, coarse proposal, let us follow Fine in Fine :A7], that is:A8], there is nevertheless some clear intuitive appeal to [A7]. It admits an intuitive reading attesting to the analyticity of the hypothetical syllogism, according to which the inference introduces no subject-matter beyond that of its premises.A similarly plausible strengthening might be to embrace Parry’s axiom —corresponds to this property. Following the foregoing idioms, we can define the following:Interestingly, one of Parry’s axioms that had been used to illustrate the features of Then this extension axiomatizes the class of models in which this type of preservation is respected. We show this with the following characterization result (which will be proven in the appendices):topic-theoretic features of models to determine systems intermediate between R yields stronger modal logics than Again, this speaks to the flexibility of the proposal as the framework is extensible enough to model differing positions about topic. This—and the other above examples—shows that we can in practice exercise a fine degree of control over the demodalizeddemodalizer axiomBut the assignment of subject-matter is not the only dimension along which one might want to strengthen a logic. Recall, for example, Dunn’s In the present context, though, the stock demodalizer axiom collapses not only modal distinctions but collapses many topic-theoretic distinctions one may wish to preserve. The validity of strictly demodalized So to provide a This suffices to characterize the logic (a proof can be found in the appendix):R is the diagonal relation on W, i.e., singleton domain W. Thus, soundness and completeness with respect to single-pointed frames is also established. Reading such models as ones in which the actual world is the only possible world, the necessity of a proposition is equivalent to its truth. Nevertheless, no additional conditions on demodalizes the system without side-effects on its topic-theoretic machinery. Moreover, as the scheme I also note that A7]). Then between Theorems Consider extending the above naming conventions in the obvious ways (so that e.g. mentclass2pt{minimR. Fine’s remarks e.g. on axiomatizing Given that one can express necessity, further intermediate logics can be determined by including axioms cognate with the standard axioms or imposing characteristic frame conditions on  in Fine  can be eproof of concept, so to speak—by enriching Kit Fine’s model theory for In this paper, I have introduced machinery to allow fine-grained control over the subject-matter of an intensional conditional and have provided an initial implementation—a other intensional conditionals beyond Parry’s analytic implication. The reader should be able to intuit how additional accessibility relations added to the model (e.g., a universal accessibility relation The reader is reminded that Definition E.g., complementing the function beyond conditionals. Because one can define e.g. TSIMs themselves is available merely by adding new Of course, this opens the doors to theories of topic for intensional notions intensional conditionals in general and unary modal operators. These accounts will be directly embedded in the setting of TSIMs, which will provide an account of the topic of formulae in which TSIMs appear.The present paper is intended as the first in a sequence of several detailed examinations of topic-theoretic properties of intensional connectives and operators. In the planned sequel, the theory is extended to provide accounts of topic for


Healthcare professionals produce abounding textual data in their daily clinical practice. Text mining can yield valuable insights from unstructured data. Extracting insights from multiple information sources is a major challenge in computational medicine. In this study, our objective was to illustrate how combining text mining techniques with statistical methodologies can yield new insights and contribute to the development of neurological and neuromuscular-related health information. We demonstrate how to utilize and derive knowledge from medical text, identify patient groups with similar diagnostic attributes, and examine differences between groups using demographical data and past medical history (PMH). We conducted a retrospective study for all patients who underwent electrodiagnostic (EDX) evaluation in Israel's Sheba Medical Center between May 2016 and February 2022. The data extracted for each patient included demographic data, test results, and unstructured summary reports. We conducted several analyses, including topic modeling that targeted clinical impressions and topic analysis to reveal age- and sex-related differences. The use of suspected clinical condition text enriched the data and generated additional attributes used to find associations between patients' PMH and the emerging diagnosis topics. We identified 6096 abnormal EMG results, of which 58% (n = 3512) were males. Based on the latent Dirichlet allocation algorithm we identified 25 topics that represent different diagnoses. Sex-related differences emerged in 7 topics, 3 male-associated and 4 female-associated. Brachial plexopathy, myasthenia gravis, and NMJ Disorders showed statistically significant age and sex differences. We extracted keywords related to past medical history (n = 37) and tested them for association with the different topics. Several topics revealed a close association with past medical history, for example, length-dependent symmetric axonal polyneuropathy with diabetes mellitus (DM), length-dependent sensory polyneuropathy with chemotherapy treatments and DM, brachial plexopathy with motor vehicle accidents, myasthenia gravis and NMJ disorders with botulin treatments, and amyotrophic lateral sclerosis with swallowing difficulty. Summarizing visualizations were created to easily grasp the results and facilitate focusing on the main insights. In this study, we demonstrate the efficacy of utilizing advanced computational methods in a corpus of textual data to accelerate clinical research. Additionally, using these methods allows for generating clinical insights, which may aid in the development of a decision-making process in real-life clinical practice. Over the past few decades, the amount of available daily medical information has been consistently growing, particularly data generated by healthcare professionals in their daily practice2. Uncovering knowledge hidden in this massive unstructured information is essential to supporting the daily decision-making process of medical professionals. In this context, text mining (TM) encompasses advanced techniques used to elicit high-quality structured information from unstructured textual data3.Text mining is a process that allows extracting previously unknown valuable knowledge from textual data. It enables eliciting implicit knowledge from unstructured texts and presenting it explicitly6; (b) Text representation, where the unstructured data is converted into a representation model such as Bag-Of-Words (BOW) or word embeddings7 that allows efficient analysis in subsequent phases8; (c) Discovery, where specific methods and techniques such as topic modeling, classification, and clustering allow extracting unexpected and unknown valuable information from textual data collections9.The text mining process usually comprises several stages: (a) Preprocessing, where different natural language processing (NLP) techniques, such as tokenization and stemming, are used to standardize and clean unstructured textual input11.Healthcare information systems gather massive amounts of textual and numeric information about patients, such as visits, prescriptions, physician notes, and more. Utilizing the textual content accompanying electronic clinical records can potentially improve healthcare quality, support clinical and research initiatives, decrease medical errors, and reduce costs. However, the variations in complexity, length, and technical vocabulary of health record documents challenge knowledge elicitation12. Analyzing medical records is challenging, as they typically use unstructured plain texts and a specific technical vocabulary13. Moreover, physicians approach event or symptom descriptions differently, depending on their previous learning experiences and medical practices14.EMR mining can potentially establish new patient-stratification principles and reveal unknown disease correlationsIn the present work, our goal was to demonstrate the utilization of large volumes of medical text to extract knowledge and generate meaningful insights in neuromuscular settings. We concentrate on identifying patient groups with similar diagnostic attributes using unsupervised topic modeling. We also examine differences between groups using demographic data and past medical history (PMH) derived from electrodiagnostic (EDX) evaluation reports. We demonstrate how such analysis can reveal hidden knowledge and generate new hypotheses.15 reviewed 48 papers that use natural language processing (NLP) applications in clinical neurosciences. Although NLP and text mining are not identical, both aim to gain insights from unstructured data and share uses and techniques. The authors show that the NLP experience gained in the clinical neurosciences improved clinical data extraction, research literature synthesis, patient cohort identification, and clinical outcome prediction. A TM-based methodology developed by Kaya et al.16 allows the classification of predictable neuromuscular diseases concealed in the free medical history text of EMRs. They analyzed 150 PMH reports of five commonly encountered neuromuscular diseases—carpal tunnel syndrome (CTS), peripheral neuropathy (PNP), cervical radiculopathy (CRP), brachial plexus, and sciatic nerve injury. In their analysis, they compared a method they had developed, consisting of a keyword-based association algorithm with bi-grams, with the results of the Naïve Bayes algorithm. The comparison results showed an improved clinical decision support system (CDSS) in the pre-diagnostic period.Different researchers have used text-mining approaches in their medical studies, each according to the characteristics, guidelines, needs, way of action, and vocabulary of their field. Our focus was the rarely used text mining in neurology. Buchlak et al.17. They used TM methods for literature synthesis to explore the most frequent diseases and syndromes (DsSs), sort them into ten categories that reflect coinciding DsSs, and observe changes over time. They found that categories 3, 5, and 7 were most frequently discussed. The two most characteristic words of category 3 were dementia and atrophy, category 5—tremor and dystonia, and category 7—weakness and neuropathy.Diseases and syndromes from 65,000 neurology case reports were extracted from 66 PubMed journals19. Karhade et al.20 developed an algorithm that processed clinical notes of spine surgery patients to identify those who needed reoperation for wound infection within 90 days of surgery. Other studies25 used NLP to extract data and glean new features from clinical texts. Several studies28 show the benefits of topic modeling for extracting relevant topics from patient support community websites and research articles, using latent Dirichlet allocation (LDA) modeling.Numerous examples exist of text mining benefits for various medical purposes, specifically clinical practice. Various researchers used NLP to retrospectively identify patients for inclusion in their study30, and identifying patients with comparable diagnoses, treatment plans, medication utilization, and related factors. Furthermore, it holds the potential to unveil novel International Classification of Diseases (ICD) codes and emergent trends31. On the other hand, for diverse predictive tasks, the extracted topics are used as features for classification algorithms34.Topic modeling has been employed on clinical notes data for various objectives. On one hand, it serves the purpose of identifying clusters of patients who share common characteristics. This can aid in comprehending the extent of disease severity29.Topic modeling was used to uncover latent themes in clinical notes of patients with heart failure to help the clinical researchers infer the patient's severity of the disease, including related comorbidities. Before applying the topic modeling, a negation detection algorithm was used to create negated phrases. The topic modeling method was LDA to the tf–idf representation. To identify the theme for each topic, the representative notes that had a percent contribution of 0.80 or higher to the topic were used35. Furthermore, they implement topic modeling using LDA to assign relevant topics to the summary text. The MIMIC III dataset served as a source of clinical data. By that, they demonstrate they can shorten the text the clinician needs to read, eliminate noise, and extract knowledge from vast unstructured clinical data. Four temporal topic modeling techniques using clinical notes obtained from primary care electronic medical records were evaluated36. The evaluation methods were Nonnegative Matrix Factorization (NMF), Latent Dirichlet Allocation (LDA), Structural Topic Model (STM), and BERTopic. The study revealed that despite the heterogeneity in the statistical methodology of each model, the learned latent topical summarizations and their temporal evolution over the study period were consistently estimated.The application of Bio Clinical Bert in conjunction with Bert extractive summarizer was introduced to shorten clinical data33.Top2Vec was utilized to conduct topic modeling of Electronic Health Records (EHR) as a preliminary stage to generate features for a predictive model that was designed to identify individuals at higher fall risk. They demonstrate that the predictive performance of models that combine structured data with features derived from unstructured clinical notes outperformed those relying solely on structured data34.The behavior of 17 topic modeling algorithms was studied using OCTIS and FuzzyTM packages and was evaluated based on their interpretability and predictive performance. The study didn’t identify a single model that outperforms the other models in both interpretability and predictive performance. In their experiments on a clinical notes dataset, the FLSA-W (fcm) performed best for interpretability, whereas ProdLDA seems the best choice for predictive performanceWhile topic modeling has found application in electronic health records and has gained traction in recent years, we have not come across text-mining or NLP papers that analyze nerve-conduction studies or textual EMG evaluation reports.39. The report serves as a unique document that combines the results from various tests, combining machine-generated measurements with the neurologist's observations.Neurological electrodiagnosis is an evolving field. Nerve conduction studies (NCS) and needle electromyography (EMG) are strong diagnostic tools used to evaluate patients with neuromuscular (NM) diseases. A verbal free-text extension attached to the electrodiagnostic (EDX) evaluation report describes the reason for referral and the EDX results and conclusions and summarizes the NCSs and needle EMG for the referring physician and the patient40 and help understand the pathophysiological process and choose a treatment41. For example, females are more susceptible to multiple sclerosis and major depressive disorder than males and are at a greater risk of Alzheimer’s Disease in their lifetime. In contrast, males are more likely to be diagnosed with autism spectrum disorder, attention deficiency and hyperactivity disorder, and Parkinson’s Disease42.Few biological differences are associated with disease prevalence and incidence. Patient sex and age are the most important among them. Sex differences play a part in the etiology, manifestation, and treatment of disease43. Some diseases tend to be age-specific, while others occur at all ages. One such example is myasthenia gravis (MG) known to be more prevalent in young females and older males, with a general higher incidence in females44.Besides sex, age is another factor known to significantly impair nerve conduction, as age-related physiological changes in all organs and systems affect axonal health45. This study aims to determine the existence of associations between past medical history as phrased by the physician and unstructured diagnostic texts.A patient's past medical history (PMH) is a valuable diagnostic tool in medicine, as it can support or refute the need for further clinical laboratory or radiological testing. With the ongoing population growth, physicians must navigate a large volume of PMHs with detailed information about each condition. Therefore, simplifying the complexity of EMR-based decisions is crucial in many medical situations46 that looked into the medical history of 73 patients  with brachial plexopathy found that falls were the primary cause of their injuries. Other examples concern diabetes mellitus (DM), one of the most serious twenty-first century global healthcare problems47. Diabetic neuropathies (DNs) are the most common complications associated with diabetes mellitus50. DN cases differ in their clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement51. Other studies investigated associations between DM and carpal tunnel syndrome (CTS)55 obtaining different results. Whether the source of heterogeneity in the research findings was due to differences in the target population or unmeasured confounding variables is yet to be assessed. A finer division of CTS patients into groups with specific characteristics might yield additional insights.Previous research has explored the potential link between past medical conditions and future diagnoses. There are numerus examples in the literature linking medical history and diagnosis. One study56. Brachial plexopathy also emerges as a complication of motor vehicle accident (MVA) injuries58. Additionally, MVA's are a common cause of peripheral nerves injury (PNI)60.A common complication of breast cancer is brachial plexopathy, usually attributed to later effects of radiationIn the present study, we show how text-mining approaches with computational techniques yield meaningful clinical insights. Our proposed method has several advantages: (a) Identifying and grouping patients with similar characteristics. (b) Analyzing age differences and showing that different topics each representing a group of patients with similar diagnostic characteristics have a different age distribution. (c) Detecting gender differences regarding various diagnoses. (d) Identifying associations between textual PMHs and diagnosis topics. The advantages listed above can aid in the development of healthcare analytics systems that will assist in generating research hypotheses. It can also assist in enhancing a clinical decision support system (CDSS) and developing an alert system that includes additional questions the physician might wish to ask the patient about past events and medical history. Figure Sheba medical center (SMC) institution review board (9127-22-SMC) approved the study before its launch. The electronic medical record system at Sheba Medical Center served to identify patients who underwent comprehensive EMG/NCS tests between May 2016 and February 2022.Data retrieved from multiple data clouds were assembled to form one data warehouse. The resultant dataset included records from hospitalizations and outpatient clinic visits. Besides demographic variables such as patient age and sex, the data for each visit comprised the visit date and textual medical notes stating the reason for referral, a summary of findings, and the physician's test readout conclusions. Data preparation consisted of filtering to remove incomplete records and a primary text analysis to identify tests with normal/abnormal results. A record was defined as "normal" if the performing electromyographer's report stated that the NCS/EMG results were within the normal range. The present study engages only with the abnormal test population.We included patients who underwent a detailed electrophysiological evaluation after a neuromuscular specialist saw them in our EMG laboratory. Patients whose data  were incomplete were excluded. Multiple tests of the same patient on different dates were included in the topic modeling stage (as the summary notes for each visit were not the same). Only a patient's last visit participated in the statistical analysis to create independent records.Of the different textual medical notes' sections, we focused on the conclusions, which contain the main findings of the nerve conduction study (NCS) and EMG results and the reason for referral that comprises a brief medical history, and the tested medical condition. A text preprocessing stage performed to "clean" the text and prepare it for analysis, included lowercasing the text, deletion of stop words and a few words commonly used in this specific domain, and punctuation marks. Only numbers that were parts of letter-number combinations were kept. . The default function that creates the term document matrix deletes words of length one or two, we changed these settings and kept length 2 terms . Lemmatization was performed in the topic modeling stage with the LDA configuration. We benefited from the advantage that most reports had a similar structure. This allowed us to identify different sections , and define several regular-expression rules to identify past medical history and negation .62. In this study, we used keyword extraction techniques to enrich the data by creating additional features representing patients' past medical history.Keywords represent the central themes of a text collection whose volume is too large to analyze manually. Keyword extraction stands for an automatic identification of key terms63 that provides a list of medical terms, their abbreviations, acronyms and similar concepts.The first stage of identifying keywords clinicians use to describe the past medical history of patients involved extracting texts appearing after the words “history of” in the reason for referral section. Although not all clinicians use the term “history of”, it was quite common, appearing in 3447 (56%) of the visit reports. For this purpose, we constructed a new dataset containing the text that starts with “history of" and ends with the string “complain”, which was the standard writing pattern, and promised to contain the keywords we were seeking. Another option, more generic, is to search the end of the sentence. Creating this smaller dataset allowed us to keep only terms in the context of past medical history. This dataset was used only for the keyword extraction stage. To reduce the number of terms in the dataset we removed sparse terms and kept only terms that appeared at least in ten documents. This step significantly reduced the number of terms. The standard preprocessing stages were performed to clean the data and normalize the terms , in addition we created several rules to normalize similar concepts. For example, bone marrow transplant can be written also as ‘bmt’, ‘bm transplantation’ and ‘bone marrow transplantation’. Normalizing concepts is important to find ‘not obvious’ associations because we might reveal an association or make it statistically significant only if we have enough support in the data by uniting terms that convey the same meaning. The list of normalized concepts appears in appendix 61, term frequency-inverse document frequency (TF-IDF)64, along with a bigram frequency analysis. TF-IDF  technique used for approximate inference in probabilistic models and is effective in handling high dimensional probabilistic models such as LDA73. However, LDA has several reported limitations. These include the necessity for data cleaning and pre-processing, the selection of model parameters, such as the number of topics, and challenges related to the interpretability and validation of the generated topics76. To tackle these limitations, in recent years, more advanced algorithms have been invented as an alternative technique for topic modeling, such as cluster analysis of document embeddings. Two notable advanced neural models techniques78 that offer automated pipelines for neural topic modeling are Top2Vec76 and BERTopic79. In their general pipelines, both methods begin with a collection of input texts. They then create document embeddings, followed by reducing the size of the embedding vectors through a dimensionality reduction algorithm. Subsequently, HDBSCAN is applied to cluster the reduced vectors and at the end they generate topic representations. There are two key distinctions between these two methods, the first is that BERTopic generates document embedding using pre-trained transformer-based language models. In contrast, Top2Vec, in addition to pre-trained embeddings, provides the option to train a doc2vec embedding model specifically on the given corpus. A second distinction arises in the way each algorithm generates the terms that characterize individual topics. BERTopic employs a class-based TF-IDF (C-TF-IDF) procedure while Top2Vec calculates the similarity of each term to the cluster centroid. Both algorithms automatically detect the number of topics and have an option to reduce the number of topics based on similarity between the generated topics.The primary purpose of topic modeling is to identify latent topics in a set of documents. Over the years, numerous topic modeling algorithms have been developed. Latent Dirichlet Allocation (LDA) stands out as the most widely used algorithm for topic modelling based on statistical analysis81. This measures a model’s ability to generalize and predict newly-presented documents, and is based on the model’s likelihood82. Lower perplexity values indicate improved model performance. Moreover, the ldatuning R library83 provides four indices to estimate the optimal number of topics, one of these indices is Griffiths2004, a prominent evaluation measure that computes the log likelihood (Log(P(W|T))84. A higher log likelihood indicates a better fit of the model to the data. The log likelihood measures how well a topic model fits the observed data, while perplexity, measures how well the model generalizes to unseen data. Additionally, a manual evaluation, which still remains critical80, was also carried out.When conducting LDA, the algorithm does not automatically detect the number of topics, and over the years, several evaluation measures have been developed to assist in determining the appropriate number of topics. External evaluation measures are applied when a ground truth exists, and the number of topics or classes is known beforehand. Internal measures, on the other hand, come into play when no ground truth is available. Among the most commonly used internal evaluation measure for topic modeling is the perplexity of a held-out dataset with respect to an inferred model86. Subsequently, once the range was established, we used the Griffiths2004 measure in conjunction with a manual evaluation to ascertain the definitive number of topics.In our study we examined the python packages BERTopic (version 0.15.0) using its default hyperparameters, Top2Vec (version 1.0.29) with both doc2vec embeddings and pre-trained universal-sentence-encoder embeddings. Additionally, we examined Gibbs-LDA from the R topicmodels package (0.2–14), with unigrams, bigrams and their combination. The inclusion of bigrams in the analysis introduces an extra semantic layer. For Gibbs LDA we conducted five-fold cross validation and computed the perplexity on each held-out set to evaluate a range for the number of topics spanning from 2 to 100. This process parallels the approach described inTo our knowledge, there are no papers that have previously employed topic modeling for Nerve Conduction Studies and EMG reports. In our research, we consider the conclusion text of the EDX reports as individual documents and employ topic modeling to form groups of patients with some similarities in clinical impressions and diagnoses.87. Visualizations intended to simplify the representation of a large amount of information play a central role in healthcare information systems.Data visualization plays an increasingly important role in analytical processes, complementing the statistical and data mining methods. It ranges from basic charts and graphs that elucidate trends, patterns, and outliers, to executive dashboards and guided analyticsWe used several visualization types to demonstrate prominent text characteristics in our extensive text collection. A normalized pyramid plot shows differences in the number of each word's occurrence among males or females. Because the number of male visits is higher, we calculated a proportional value. Furthermore, to validate the outcomes of the frequency analysis, we performed the Chi-Square test to ascertain the statistical significance of the observed variations.Two visualizations show topic and PMHs associations. In the first one, a topic-keyword association plot, a two-level X-axis displays topics and the keywords associated with them. A keyword appears under a topic if the standardized Pearson residuals (marked R) are greater than or equal to 2 (association indication). The Pearson residual score sorts out the keywords. A score higher than 4 indicates a strong association. At this point we added a target line, emphasizing all associations above 4. The second visualization, the keyword-topics association plot, provides another view of the same data, showing the topics associated with each keyword, each bar showing the associated topics. The length of a bar represents the strength of the association relative to other topics in the same bar. For example, if keyword 1 is associated with two topics, in one the R = 5 and in the other R = 10, 33.3% of the bar will show the color of topic 1 and 66.6% the color of topic 2. The visualizations were generated using both R and Excel.88. A Chi-square test examined the difference between two categorical variables. We used standardized Pearson residuals to show the strength and direction of the association between topic and sex. To show topic and PMH association, we first performed a chi-square test of each keyword with all the topics and kept only cases with a p-value < 0.05 and standardized Pearson residual >  = 2. A residual greater than |2| indicates an association, and a residual greater than |4| represents a high association. We used the R software version 4.1.289 for all the statistical analyses. The statistical significance (p) of all the tests was determined at p 0.05. Effect sizes of r 0.1– < 0.3 were considered a small effect, 0.3– < 0.5—a moderate effect, and >  = 0.5 a large effect.To avoid dependent observations in the statistical analysis, we kept only the last visit of each patient. Group differences were examined using Wilcoxon rank sum test, also known as Mann Whitney U test, which is a popular nonparametric test to compare outcomes between two independent groups. The effect size (r = z/√N) was calculated with the rstatix packageIn this work, we integrated several methods to acquire a unique incorporated analysis of EDX clinical notes. Figure Initially, we created an “abnormal cohort” by filtering out all the study reports with normal results. Next, we extracted the reason for referral and the visit's conclusions from the examination report. The reason for referral provided the patient's past medical history and a keyword extraction algorithm was applied to this sub-cohort (reports containing "history of…"). After creating a keyword list, we put together the new features (PMH indicators) on the “abnormal cohort”. In parallel, we grouped the patients according to the topic modeling of the conclusions text. Following the topic evaluation and initial interpretation, we merged the two datasets. The PMHs and demographical data together with the topics allowed us to perform a statistical analysis that yielded new insights and hypotheses. Additional visualizations summarized and displayed the results in a simple and clear way Figs. , 11.This study was reviewed and approved by the Sheba medical center (SMC) institution review board (9127-22-SMC). We confirm that all experiments were performed in accordance with relevant guidelines and regulations. The data was de-identified and therefore the IRB-Helsinki committee  waived the need for informed consent.In the present study, we identified 5601 patients who showed abnormal results in 6575 visits. After excluding visits for which there was no textual summary or conclusions, we were left with 6096 visits, of which 3512 (58%) were male patients and 2584 (42%) were female. Table 90.A primary text analysis performed on the textual visit summaries aimed to identify frequent words. Figure Next, we grouped the corpus by sex and analyzed the occurrence rates of identical words among males and females Fig. . This reAs detailed in the “Figure The topics' analysis followed patients’ demographic data and PMH, thus enhancing topic interpretation, knowledge discovery, and hypothesis generation.Age distribution: Initially, we analyzed topics by age groups to find the age distribution of each topic  with botulin and diplopia; topic 22 (Chronic Radiculopathy lumbar) with low back, lumbar discopathy, and back surgery; topic 7  with brachial plexopathy, fracture, MVA, and surgery; topic 6 (LDPN) with diabetes; topic 10  with GBS and CIDP; Topic 2 (CTS—mild) with CTR and CTS; topic 4  with Polio and low back; topic 18 (Myopathy) with Ckemia and edema; topic 19 (LDPN Sensory Polyneuropathy) with diabetes and chemotherapy; topic 21 (Sensory Neuropathy) with cut trauma, fracture; and topic 12 (ALS) with swallowing difficulty.Figure 91.In our cohort, 10% of the patients had a history of diabetes described in the examination report. It was the most frequent PMH item and therefore we examined those patients further against the different topics. Figure In this study, we evaluate the utility of text mining (TM) in clinical practice, specifically in the context of electronic medical record reports of EDX examinations. Our results demonstrate that implementing TM can facilitate a support framework for patients and healthcare providers in the settings of a neuromuscular lab, leading to improved quality of care, diagnosis accuracy, and disease prevention efforts.We propose a systematic methodology for analyzing EDX evaluation reports using a combination of TM techniques, statistical methods, and easy to capture visualizations. Keyword extraction enriched the data with relevant past medical history. To analyze the corpus as a whole and examine prominent sex differences we used frequency analysis and statistical tests. Topic modeling served to group together patients with similar diagnoses. Pearson Chi-Square Residuals Analysis found associations between topics and PMH, and a Wilcoxon test examined age and gender differences within topics.Our approach has several advantages Fig. . On the 92. Another one was myasthenia gravis (MG) and NMJ disorders (topic 20). MG is an autoimmune disease common in young females. Myopathy (Topic 18), a general term for a pathology in the skeletal muscles, displayed similar results; Two of the four main myopathies, polymyositis and dermatomyositis are more common in females93.In our study, 25 topics emerged, and each was labeled based on the ten top bigrams with the highest probability of association with this topic. The topics were analyzed against demographic data such as age and sex for a finer interpretation and additional insights. In several topics, sex emerged as a decisive factor. Four topics were associated with females and three with males. These associations matched other large-scale prevalence studies. For example, one of the female-related topics was carpal tunnel median neuropathy  which matched general population studies showing higher prevalence in females95.We also found clinical conditions that were more common in males, such as length-dependent polyneuropathy (LDPN) with axonal damage and denervation (topic 6) Fig. . Several96. Different conditions relate to different ages. For example, lumbar radiculopathy symptoms typically begin in midlife, with men often affected in their 40 s while women in their 50 s and 60 s98. Elderly people are the largest group with lumbar spine diseases99. Carpal tunnel syndrome (CTS) is the most frequent compression neuropathy, usually occurring after the age of 30; 76% of the patients become symptomatic between the age of 40–70100. In contrast, chronic inflammatory demyelinating polyneuropathy (CIDP) can occur throughout life from childhood to old age101.Reportedly, up to 7% of the overall neuropathy prevalence occurs in older patients102. Observing the age distribution of a specific topic can confirm previously known phenomena or reveal new hypotheses.Our age distribution analysis Fig.  showed t103. Myasthenia Gravis and NMJ Disorders (topic 20) also revealed differences (p < 0.05), showing that females suffer from myasthenia gravies at an earlier age than males. This agrees with the findings of Grob et al.44 who showed that myasthenia gravis is more common in younger females and older males.Age differences combined with the sex layer are particularly interesting as certain phenomena occur in females before they occur in males and vice versa. In this study, we found three topics Table  with staA patient’s past medical history is a powerful diagnostic tool. It should be given special consideration when seeking an appropriate balance between medical history and other diagnostics. Creating statistically adjusted combinations of information based on medical histories in daily practice is challenging. We have hypothesized that developing a rational approach to the use of medical history could improve diagnostic efficiency and clinical effectiveness, which would benefit the individual patient and the treating physician. To facilitate a better PMH investigation we performed a data enrichment process and extracted additional features from the examination report texts. Our keywords extraction method yielded keywords and binary features of selected keywords indicated whether a patient had a previous medical condition or not. Examination of the associations between topics and PMHs revealed previously known associations but also less obvious ones that require further investigation.104. Patients with diseases of the NMJ are clinically similar to MG patients, making it difficult to exclude MG in those patients based on an EDX examination. Weaker associations (2 <  = R < 4) were also found useful. One example was the association between breast cancer and brachial plexopathy (topic 7), also conforming to the literature106. The second topic associated with breast cancer is CTS, also mentioned in the literature107.Strong associations emerged between topics and PMHs see Fig. ,12. The 51 and this association is not surprising. The majority of patients in this topic were males (76.5%).Diabetes mellites was the most prevalent PMH in our dataset. Of the 25 topics, only 3 had a strong association with DM. The strongest association was with topic 6 (LDPN) Figs. , 11, 12.An association between Diabetes and CTS (R = 2.6) was found only in one out of the three CTS topics, topic 24 Figs. , 11. Thi108. On the other hand, Topic 6, which also comprises length-dependent polyneuropathy (LDPN) patients, had no association with chemotherapy, probably because chemotherapy affects sensory nerves more than motor nerves110. We also found a close association between topic 18, myopathy, and elevated serum creatine kinase (CK). Support for this finding appears in the literature which mentions that CK levels increase in cases of muscle pathology112.Topic 19, length dependent sensory neuropathy, showed a close association with chemotherapy and cancer, and is known as chemotherapy-induced peripheral neuropathy (CIPN)114. In our study, all participating physicians are affiliated with the same department and generally adhere to consistent technical terminology, although certain disparities persist. In situations where there is an abundance of data accessible, there are occurrences where physicians utilize various forms of the same term within a single report. For example, a word and its abbreviation could be enclosed within parentheses. This practice enhances the topic modeling algorithm's capability to detect consistent topics, even when diverse terminologies are used. This limitation diminishes even further when word embeddings are employed for topic modeling. Another limitation is that the study involved a single medical center. While all the textual reports followed the same format, this fact may impede generalizing the findings to other clinical reports, patient cohorts, and institutions. As part of this work's preprocessing stage, we defined several rules to correct often misspelled terms and uniform expressions to identify past medical history and negation . It will probably be necessary to adjust the preprocessing step for a different dataset and context.The study has several limitations. The first is a selection bias since physicians do not always write down the exact past medical history (PMH) for each of the patients or decide ad hoc what deserves documenting. Our dataset leans on the reports of several physicians, thus somewhat attenuating this drawback. Except for the differences in PMH documentation, each physician may use distinct terminology to depict identical phenomena. Demographics, geographical location, and even prior daily activities can affect their lexical preferencesTopic modeling is an unsupervised technique to classify patients. The classification is not deterministic and therefore harder to evaluate. It is recommended to test several techniques and parameters until a stable and desirable model is reached. Furthermore, labeling and interpreting the topics is also not deterministic. If we only consider the top words representing the topic, it's unclear whether these words convey the same theme related to a specific diagnosis, whether they emerge due to a patient having multiple diagnoses, or if the topic encompasses multiple merged sub-topics. To address this limitation, we recommend examining the documents within each topic and verifying the relevance of the words used to formulate the topic label, including checking the frequency of the top words.This study focuses on the analysis of the EDX report. A future study could include additional information sources and integrate past medical histories documented in the patient's medical records. Furthermore, in a future study, there could be an investigation into the evolution of topics, tracking their changes over time, identifying emerging phenomena, recognizing topics and PMHs that appear to become more frequent and identifying emerging trends. In this study, our focus was on the cohort with diagnosed abnormalities. Future research can encompass the entire population, extract past medical histories, and explore differences in sex and age among each cohort.The current study demonstrates that text mining is a useful tool for free-text data analysis, such as medical histories in electronic medical records (EMRs). It assists in making accurate diagnoses and developing hypotheses based on past medical history, taking into account age- and sex-related conditions. Despite certain limitations, the proposed method and findings can potentially enhance healthcare information systems in research scenarios and at the point of care.Supplementary Information.


Genes & Development through its formative years and, subsequently, through dramatic ongoing changes in molecular biology research and in the scientific publication landscape. Notably, Terri's contributions to science have extended well beyond G&D as a result of her own research and her diverse roles at Cold Spring Harbor Laboratory that have further served the biological research community. Most significant for those external to CSHL is Terri's participation in the oversight of an impressive range of CSHL meetings and laboratory courses. For several decades, CSHL meetings and courses have had a major national and international impact through the dissemination of knowledge and experimental skills.I am honored to have the opportunity to express my deepest appreciation for Dr. Terri Grodzicker's monumental role in leading the scientific journal G&D Editorial Board for more than 20 years and as an author of papers published in G&D. Like most historical accounts, my perspective extends beyond facts to personal experiences, but my experiences are undoubtedly consistent with those of many who have had the pleasure of interacting with Terri over the years.As a tribute to Terri's contributions, I offer a brief historical perspective that draws on my own experiences interacting with Terri in various capacities, including my role as a member of the G&D in 1987, followed soon thereafter by the appointment of Terri as the journal's Editor, coincided with the early stages of an explosion in the use of modern molecular biology techniques—including DNA cloning and a number of practical methods for the manipulation of nucleic acids and proteins—to elucidate the mechanisms controlling fundamental molecular processes in viruses and in prokaryotic and eukaryotic cells and organisms. Many of the key molecular biology techniques that drove this explosion were developed in the 1970s, but the expertise required to put them to use was initially limited to a small number of labs, with a dramatic expansion through the 1980s and continuing into the 1990s. The more recent genomics revolution and nascent CRISPR revolution further expanded the capacity to uncover mechanistic principles.The founding of G&D, many of the most significant advances in molecular biology research were published in two general scientific journals that had published important research in diverse disciplines for more than a century, Nature and Science, along with a third journal, Cell, founded in 1974, just before modern molecular biology research began its largest expansion. Molecular biology advances were also published in other highly respected journals, most notably two journals launched in the early 20th century, the Journal of Biological Chemistry and the Proceedings of the National Academy of Sciences, along with Molecular and Cellular Biology, established by the American Society for Microbiology in 1981. These latter journals were and remain highly respected, but they published relatively large numbers of papers each month . In this publication landscape, the launch of G&D provided an opportunity to highlight a limited number of highly meritorious advances in the growing molecular biology field.Prior to the launch of G&D’s standards and reputation. The journal focused on fundamental mechanistic advances relevant to a broad range of molecular processes, including the mechanisms and regulation of gene transcription, pre-mRNA splicing, DNA replication, mRNA stability, polyadenylation, recombination, and transposition, with chromatin structure and nuclear organization covered to an increasing extent beginning in the second half of the 1990s. Published studies covered a broad range of physiological processes and took advantage of diverse genetic model organisms and other experimental systems amenable to molecular and biochemical analyses. When genome sequences became available early in the 21st century, genomic studies were welcomed by the journal when used to address important mechanistic questions.Terri's leadership was instrumental in establishing and solidifying G&D Editorial Board beginning in 2001, and in this capacity I developed a strong appreciation for Terri's talents as an Editor. Terri's talents are due in part to her impressive intellect and unique background for an Editor of a major journal. Most leading journals have traditionally been guided either by professional Editors or by active researchers serving as Editors for a limited time as a professional service activity. Terri is rare; as a dedicated leader of a major journal who had successfully run her own lab for many years. Terri's style includes a strong respect for the insights of expert advisors and reviewers, but with an equally strong appreciation for manuscript authors and for the value to the scientific community of publishing meritorious research as rapidly as possible. Terri relies heavily on the opinions of expert reviewers who evaluate the novelty, impact, and rigor of a study. As an author, I did not always agree with the reviewers’ critiques of my lab's papers or with Terri's decision not to publish a subset of them. However, I found G&D reviews to be consistently fair and insightful, and I had confidence that the reviews reflected the honest opinions of experts in my fields of study.I was honored to serve on the G&D audience, Terri has understood that the long lists of additional experiments sometimes recommended by individual reviewers could be detrimental to the advancement of science due to the long, accompanying delays in disseminating important advances to the research community. Terri has been able to effectively make the key distinctions between requested experiments needed to establish the validity of a study's key conclusions and requests that reflect a reviewer's overreach or natural curiosity to know more. Striking an appropriate balance between disseminating research findings as quickly as possible to advance a field and requiring additional experiments prior to publication is a critical skill required of all journal Editors. From my experiences as both a reviewer and author, Terri's skills in finding a suitable balance are rare.Notably, when a study is deemed to be compelling and suitable for the G&D to two fields that have been the focus of my own lab: eukaryotic transcriptional regulation and molecular immunology. Prior to the launch of G&D, the eukaryotic transcriptional regulation field had witnessed a large number of advances, including but not limited to (1) the identification of the three RNA polymerases present in most eukaryotes, (2) the development of cell-free transcription assays that led to the discovery of the core general transcription factors, and (3) the discovery of transcriptional activators and repressors that bind to specific DNA sequences in the promoters and enhancers of eukaryotic genes and regulate transcription initiation in a gene-specific manner. Although difficult to appreciate in 2023, only a small handful of sequence-specific DNA-binding proteins had been reported when G&D was launched, and genes encoding DNA-binding proteins had been isolated for only a few.I will briefly expand on my perspective of the importance of G&D on reporting the discovery of each new transcription factor unless the study provided a broad mechanistic advance toward elucidating fundamental mechanisms of transcriptional control or revealed an important mechanism by which a specific transcription factor regulates a developmental/physiological process. With respect to fundamental mechanisms of transcription initiation and regulation, early studies focused heavily on the properties and diverse structural organization of promoters and enhancers, the mechanisms by which enhancers communicate with promoters, the diverse mechanisms by which transcriptional regulators communicate with each other and with the general transcription machinery, and the mechanisms by which transcription factor activities are regulated to coordinate developmental and physiological processes. Coactivators and corepressors soon became a major focus of mechanistic research, along with the mechanisms by which nucleosome remodeling and the post-translational modification of histones and other chromatin proteins regulate gene transcription. At a personal level, I paid (and continue to pay) close attention to articles published in G&D because the journal has published an unusually large number of major mechanistic advances closely aligned with my own interests in transcriptional regulatory mechanisms.Thus, there was much to learn through the end of the 1980s and in subsequent decades. Importantly, as more and more transcription factors were being discovered and their genes cloned, Terri wisely chose not to focus G&D has been similarly important for the broad dissemination of advances in the molecular immunology field. A prominent focus of the field has been on the mechanisms by which signaling pathways, transcription factors, and transcriptional control regions regulate both immune cell development and the rapid activation of immune cells during an immune response. Immune cells have features that, beginning in the 1980s, made them highly attractive for fundamental studies of gene regulation during both cell development and cell activation. These features included the availability of cell lines maintained at defined stages of cell development (most notably for B-cell development), the relative ease with which primary cell populations at different stages of development and activation could be isolated and sorted from the blood and tissues of mice and other animals, and the ability to obtain large numbers of primary immune cells in relatively pure form for molecular interrogation. Because of these features, mechanistic studies of signaling and gene regulation during immune cell development and activation often have relevance that extends beyond the immune system. This has made G&D an attractive journal in which to publish mechanistic molecular immunology studies toward the goal of reaching a broader molecular biology audience.G&D became an important repository for articles focused on genetic events that are unique to cells of the adaptive immune system; namely, V(D)J recombination, immunoglobulin class switch recombination, and somatic hypermutation. These genetic events are of broad interest to the molecular biology community, as they represent fascinating mechanisms that evolved in vertebrates specifically for the purpose of responding to infectious agents. Publication of some of the strongest mechanistic research in these important areas in G&D has made it accessible far beyond the immunology field.Finally, G&D through 35 years of the molecular biology field's exceptionally rapid advancement cannot be overstated. The molecular biology community owes a debt of gratitude to Terri for her hard work and her insightful and colossal contributions.To conclude, the importance of Dr. Terri Grodzicker's skillful leadership of


Water quality criteria (WQC) for the protection of aquatic organisms mainly focus on the maximum threshold values of the pollutants that do not have harmful effects on aquatic organisms. The WQC value is the result obtained based on scientific experiments in the laboratory and data fitting extrapolation and is the limit of the threshold value of pollutants or other harmful factors in the water environment. Until now, many studies have been carried out on WQC for the protection of aquatic organisms internationally, and several countries have also issued their own relevant technical guidelines. Thus, the WQC method for the protection of aquatic organisms has been basically formed, with species sensitivity distribution (SSD) as the main method and the assessment factor (AF) as the auxiliary method. In addition, in terms of the case studies on WQC, many scholars have conducted relevant case studies on various pollutants. At the national level, several countries have also released WQC values for typical pollutants. This study systematically discusses the general situation, theoretical methodology and research progress of WQC for the protection of aquatic organisms, and deeply analyzes the key scientific issues that need to be considered in the research of WQC. Furthermore, combined with the specific characteristics of the emerging pollutants, some new ideas and directions for future WQC research for the protection of aquatic organisms are also proposed. Water quality criteria (WQC) refers to the maximum concentration or level at which pollutants or environmental factors in water environments do not have harmful effects on human health or water ecosystems ,2,3. WQCCurrently, the two mainstream WQC research systems internationally are based on those of the United States and the European Union (EU). The United States puts forward the toxicity percentage ranking method, which is a two-value criteria system . It poinVarious relevant factors are comprehensively considered in the derivation process of WQC, and the determination of criteria values is influenced by many water environmental factors, such as water hardness, temperature, pH and dissolved organic matter, and so on ,15,16,17Based on the mentioned above, the main purpose of the present study is to systematically summarize and integrate the current technical methods of WQC, deeply analyze the key issues and technical systems of WQC research methods and summarize the current case studies of WQC. Finally, some new ideas of the derivation method of WQC for emerging pollutants are also explored and prospected.The pioneering study on WQC began in the early 20th century. The United States was the earliest country to conduct WQC research. The development process of water quality standards is presented in the form of a series of WQC papers, reports, and monographs. Additionally, the United States finally issued its national water quality guideline for the protection of aquatic organisms in 1985. In addition, the European Union, the Netherlands, Canada, Australia and New Zealand, Japan, China, and other countries have also formulated their own relevant technical guidelines for WQC and established their own WQC and ecological risk assessment research systems. With the deepening of WQC research, many countries have revised, improved, and updated their guidelines in recent years .For example, the technical guidance of the United States was issued in 1985 [Technical Guidance Document for Risk Assessment” (TGD) in 2003 [The European Union promulgated the Water Framework Directive (WFD) in 2000, which played an important role in developing and promoting the setting of water environmental quality standards. The WFD is a legal framework designed to protect freshwater and marine ecosystems from the adverse effects of pollutants and to protect human health. The European Union (EU) uses environmental risk assessment technology to derive the predicted no-effect concentration (PNEC) of pollutants as water quality protective objectives for environmental management and issued the “ in 2003 . In 2004 in 2003 . This isGuidance Document for Aquatic Effects Assessment in 1995 to evaluate the hazardous effect of pollutants on water environments [A protocol for the derivation of water quality guidelines for the protection of aquatic life” [Australian and New Zealand guidelines for fresh and marine water quality” in 2000 [the Guidance document on deriving environmental risk limits in 2001 [Environmental Quality Standards for Water Pollution in 1971 [In addition to the two mainstream countries of the United States and the European Union, some other countries and organizations have also conducted relevant research on WQC. For example, the Organization for Economic Cooperation and Development (OECD) issued the ronments . In 1999ic life” , which wic life” . The Aus in 2000 , which w in 2000 . The Nat in 2001 , which w in 2001 . The Min in 1971 , which w in 1971 .Technical guideline for deriving WQC for freshwater organisms”, which was first released by the Ministry of Ecology and Environment in 2017 [The research on WQC in China started relatively late, dating back to the 1980s. The initial research was only the collection and collation of relative references and data and integrated the research methods of WQC in different countries and organizations. Subsequently, on the basis of a large number of theoretical explorations and WQC case studies, some monographs and books related to WQC were published one after another ,5,39. Th in 2017 . It is a in 2017 , which iThere are many key steps involved in the extrapolation of WQC for the protection of aquatic organisms. In general, the factors affecting WQC mainly include the reliability of basic data, standardization of toxicity data and the scientificity of statistical analysis methods. All these elements play a very important role in the study of WQC.Firstly, in terms of species selection, the selection of regional native species is crucial for WQC. Many studies have shown that, for the same pollutant, biota differences will lead to the ultimate difference in the WQC value of the pollutant, which further highlights the importance of site-specific or native species ,42,43. T5, which is the concentration at which 5% of species are at risk [Secondly, in terms of WQC derivation methods, the derivation system based on the SSD method and supplemented by the assessment factor (AF) method has been basically formed in the world at present. The main steps of WQC derivation mainly include data collection, data screening and evaluation, and WQC derivation . The bas at risk ,45,46. I at risk  only use at risk , the SSDThe SSD method is an international mainstream method used to establish ecological environment criteria. Model selection is the core and key of this method. When building SSD models, the commonly used derivation methods according to the amount of toxicity data include the normal distribution model, logistic distribution model, etc., and the mainstream trend is to use the best-fit curve to derive the final WQC value ,48,49. SThirdly, in terms of the description and value of the WQC for specific pollutants, the double-value criteria system is mainly used internationally at present. The United States, Canada, China, and other countries adopt double-value criteria. Double-value criteria generally refer to long-term criteria and short-term criteria (or chronic criteria and acute criteria). Long-term criteria (chronic criteria) are designed to protect aquatic life  from the negative effects caused by the indefinite long-term effects of pollutants. In contrast, short-term criteria are designed to protect aquatic organisms from serious negative effects (such as death) caused by short-term effects. Some countries and organizations also use single-value criteria such as the European Union . There aIn recent years, great progress has been made in international research focusing on WQC. Many scholars have carried out a large number of WQC case studies of typical pollutants and published a series of research papers, monographs, etc. These studies not only summarized and explored the theoretical methodology of WQC for the protection of aquatic organisms but also provided case studies on WQC, including conventional pollutants, some physical and chemical parameters of water bodies, and new emerging pollutants ,39,45,52At the same time, the countries and organizations studying WQC were screened, and it was found that China and the United States were significantly ahead of other countries in terms of the number of publications on WQC, with 284 and 134 publications . In China, the Chinese research academy of environmental sciences published the most articles, and its secondary institution, the state key laboratory of environmental criteria and risk assessment, contributed more than 118 articles. The top five countries in terms of the number of articles issued were China, the United States, Canada, the United Kingdom, and Italy. Additionally, the number of WQC articles issued by these five countries accounted for 60% of all the published articles .In terms of the WQC values of toxic substances published at the national level, some countries have also published WQC for the protection of aquatic organisms for some toxic substances at the national level. For example, since the release of the guidelines for WQC in the United States, a number of WQC for toxic substances have been published, and the WQC are updated almost every 2–3 years in combination with the latest research. EPA’s compilation of nationally recommended WQC is presented as a summary table containing recommended WQC for the protection of aquatic life and human health in surface waters. These criteria are published pursuant to the Clean Water Act and provide guidance for states and tribes to use to establish water quality standards and ultimately provide a basis for controlling discharges or releases of pollutants. At present, the latest WQC published by the US EPA contains 186 indicators ,22, inclIn addition to the United States, Australia and New Zealand , Canada The acquisition of toxicity data is the key issue of WQC research. Different types of pollutants have different influencing factors in the study of WQC. For example, the toxic effect of organic matter on organisms is relatively complex, so the endpoint of the toxic effect of organic pollutants on organisms should be clarified in the WQC study, and then the criteria are deduced. The toxic effects of heavy metals are greatly influenced by environmental factors. Another problem encountered in WQC studies is the lack of data on the toxicity of the selected pollutants. The toxicity data could not meet the requirements of fitting the SSD curve, nor could they meet the requirements of the AF method. However, when environmental management is in urgent need, it is necessary to predict the toxicity data of pollutants by means of model prediction. Model prediction includes the following levels. First, how to use laboratory experiments to predict actual toxicity effects in the field? The Biotic Ligand Models (BLM) approach can be used. The BLM is a mechanistic approach that greatly improves our ability to generate site-specific ambient water quality criteria for metals in the natural environment . Water eEmerging pollutants refer to the pollutants produced in production, construction or other activities, which are caused by human activities, that clearly exist but have not been regulated by laws, regulations and standards and harm the living and ecological environment. With the continuous detection of emerging pollutants in the environment, they are gradually receiving widespread attention ,73,74. TCompared with conventional pollutants, emerging pollutants have the following differences. Taking EDC as an example, first, the dose–response relationship of conventional pollutants generally follows the principle of “low dose, low toxicity”, and its toxicity value has a certain threshold. While for EDCs, it is also toxic at low doses, with the characteristics of “low dose, high toxicity”. In addition, EDCs may exhibit certain biological effects, including delayed and multigenerational effects, and may exhibit non-monotonic dose–response relationships ,76. SecoFurthermore, in terms of WQC values, when deriving WQC for conventional pollutants, double criteria values, such as short-term criteria values and long-term criteria values, are generally formulated. Nonetheless, EDCs in a short time exposure generally will not cause serious toxicity on aquatic organisms, while, under trace concentrations, will have irreversible toxicity effects on aquatic organisms. The acute-to-chronic ratio of EDCs is generally large; the largest may reach 10,000 or 100,000 times. Therefore, it is recommended to use single-value criteria when deriving WQC for EDCs, and only the values obtained from chronic toxicity are used to derive the long-term criteria value. In addition, it is also important to establish an effective correlation between toxic effects and endpoints . Many efIn addition, a non-monotonic dose–effect relationship may appear in both in vitro and short-term in vivo studies of the EDCs, but it might not be able to widely predict the toxicity endpoint in long-term in vivo studies. In the absence of the toxicity threshold of EDCs, probabilistic methods should be used to predict the threshold, which is also a new idea for the future study of WQC of emerging pollutants.