Re-thinking the current paradigm for clinical immunogenicity assessment: an update from the discussion in the European Bioanalysis Forum.

Immunogenicity regulatory guidance and industry recommendations have evolved over the last two decades since unexpected immune reactions were first reported with erythropoietin. Since then, the guidelines and practices for immunogenicity have stemmed from a reaction to a high-risk molecule causing significant clinical impact. Similar thinking is often applied to all biotherapeutic drugs, even when a well-defined risk assessment suggests otherwise. In recent years, the current testing paradigm for immunogenicity has been challenged with more informative approaches being proposed. In a Focus Workshop held by the European Bioanalysis Forum in September 2023, the current immunogenicity testing paradigm was challenged based on the experience and learning of 20+ years of immunogenicity strategies. The workshop recommendations proposed a new paradigm, challenging the value of multiple tiers depending on the immunogenicity risk assessment based on context of use and moving toward treating immunogenicity as a pharmacodynamic biomarker for the drug. Such rethinking ultimately results in the appropriate and efficient focusing of resources on immunogenicity testing strategies that benefit patients most, moving to a new paradigm where implementation of appropriate and truly informative immunogenicity testing strategies, depending on the context-of-use, become the norm .

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Structured Routine Use of Styletubation for Oro-Tracheal Intubation in Obese Patients Undergoing Bariatric Surgeries-A Case Series Report.

The aim of this case series report is to provide a new topical view of styletubation (video intubating stylet technique) in obese patients undergoing bariatric surgeries. In contrast to various conventional direct laryngoscopes (DLs), videolaryngoscopes (VLs) have been applied in such obese populations with potentially difficult airway complications. The safety and effectiveness of VLs have been repeatedly studied, and the superiority of VLs has then been observed in and advocated for routine use. In this article, among our vast use experiences with styletubation (more than 54,998 patients since 2016) for first-line routine tracheal intubation, we present the unique experience to apply the styletubation technique in obese patients undergoing bariatric surgery. Consistent with the experiences applied in other patient populations, we found the styletubation technique itself to be swift (the time to intubate from 5 s to 24 s), smooth (first-attempt success rate: 100%), safe (no airway complications), and easy (high subjective satisfaction). The learning curve is steep, but competency can be enhanced if technical pitfalls can be avoided. We, therefore, propose that the styletubation technique can be feasibly and routinely applied as a first-line airway modality in obese patients undergoing bariatric surgery.

ISE/ISHNE expert consensus statement on the ECG diagnosis of left ventricular hypertrophy: The change of the paradigm.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria. The classical paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces, reflected in the augmented QRS amplitude. However, the low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm. The theoretical background for voltage measured at the body surface is defined by the solid angle theorem, which relates the measured voltage to spatial and non-spatial determinants. The spatial determinants are represented by the extent of the activation front and the distance of the recording electrodes. The non-spatial determinants comprise electrical characteristics of the myocardium, which are comparatively neglected in the interpretation of the QRS patterns. Various clinical conditions are associated with LVH. These conditions produce considerable diversity of electrical properties alterations thereby modifying the resultant QRS patterns. The spectrum of QRS patterns observed in LVH patients is quite broad, including also left axis deviation, left anterior fascicular block, incomplete and complete left bundle branch blocks, Q waves, and fragmented QRS. Importantly, the QRS complex can be within normal limits. The new paradigm stresses the electrophysiological background in interpreting QRS changes, i.e., the effect of the non-spatial determinants. This postulates that the role of ECG is not to estimate LV size in LVH, but to understand and decode the underlying electrical processes, which are crucial in relation to cardiovascular risk assessment.

ISE/ISHNE Expert Consensus Statement on ECG Diagnosis of Left Ventricular Hypertrophy: The Change of the Paradigm. The joint paper of the International Society of Electrocardiology and the International Society for Holter Monitoring and Noninvasive Electrocardiology.

The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria, i.e. the increased QRS complex amplitude in defined leads. The classical ECG diagnostic paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces. These increased forces are reflected in the augmented QRS amplitude in the corresponding leads. However, the clinical observations document increased QRS amplitude only in the minority of patients with LVH. The low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm.

Healthcare is not about health.

Initiatives designed to reduce the disease burden and improve the health of the US population that focus on increasing access to health care have been disappointing. Progress requires multifaceted change. We must first acknowledge that the healthcare system is focused on reversing or modifying disease, not enhancing health. Our conceptualization of the development of ill health and disease must also change. Scientific advances are clarifying the complex interactions among the development of ill health and disease and an individual's behaviors, their microbiota, and their physical, social, and emotional environments. A person's genetic makeup predisposes them to a wide array of disease conditions but is rarely deterministic in and of itself. Factors extrinsic to the individual, including the social determinants of health, play a major role in disease development, often decades later. The complexity of health and disease requires a "team" accountable for the health of our populations, and these teams must be expanded beyond the medical professions. Governmental officials, architects, business leaders, civic organizations, social and neighborhood groups are among the key stakeholders on the health side of the equation. If and when disease does become manifest, then the care part of the healthcare system assumes the larger role. This has major implications for the education of our clinically focused health science students, but also of professional disciplines previously deemed peripheral to health. Simply redoubling our efforts and focusing on our current healthcare system is insufficient to make progress in the health of the populace. One example of a multipronged approach in Allentown, PA is explored in depth.

Contribution to the Personalized Management of the Nosocomial Infections: A New Paradigm Regarding the Influence of the Community Microbial Environment on the Incidence of the Healthcare-Associated Infections (HAI) in Emergency Hospital Surgical Departments.

Background: The management of acute surgical pathology implies not only the diagnosis-treatment sequence but also an important preventive component. In the surgical hospital department, wound infection is one of the most frequent complications which must be managed both in a preventive and a personalized manner. To achieve this goal, several factors of negative local evolution, contributing to the slowdown of the healing processes, such as the colonization and contamination of the wounds, need to be emphasized and controlled from the first moment. In this context, knowing the bacteriological status at admission ensures the distinction between the colonization and infection processes and could help to manage in an efficient way the fight against bacterial pathogen infections from the beginning. Methods: A prospective study was performed for 21 months on 973 patients hospitalized as emergencies in the Plastic and Reconstructive Surgery Department within the Emergency University County Hospital of Brasov, Romania. We analyzed the bacteriological profile of the patients from admission to discharge and the bidirectional and cyclic microorganism dynamics both in the hospital and the community microbial environment. Results: Of the 973 samples collected at admission, 702 were positive, with 17 bacterial species and one fungal, with a predominance of Gram-positive cocci at 74,85%. The most frequently isolated strains were Staphylococcus species (86.51% of the Gram-positive/64.7% of the total isolated strains), while Klebsiella at 8.16% and Pseudomonas aeruginosa species at 5.63% were mainly emphasized in the case of Gram-negative bacilli. Two to seven pathogens were introduced after admission, suggesting that the community microbial environment is in a process of evolution and enrichment with hospital pathogens. Conclusions: The high level of positive bacteriological samples and the complex associations of the pathogens found at the admission bacteriological screening sustain the new idea that the pathogenic microorganisms existing in the community microbial environment have started to increasingly influence the hospital microbial environment, in contrast with the previous consideration, which emphasized only the unidirectional relationship between hospital infections and the changing bacteriological characteristics of the community environment. This modified paradigm must become the basis of a new personalized approach to the management of nosocomial infections.

A new validated screening method for endometriosis diagnosis based on patient questionnaires.

BACKGROUND: The time between symptoms onset and endometriosis diagnosis is usually long. The negative impacts of delayed endometriosis diagnosis can affect patients and health outcomes. METHODS: We conducted a case-control study using clinical symptoms and epidemiological data extracted from a prospective pre-operative patient questionnaire compared between patients with histologically proven endometriosis and patients with no endometriosis at surgical exploration from 2005 to 2018, in a French referral center. We used the beta coefficients of the significant variables introduced in a multiple regression model to devise a score (score 1), evaluated by the area under the curve (or C-index), with three levels, defined by a score between 1 and ≥ 25: (i) highly specific, identifying correctly the patients without the disease; (ii) highly sensitive, identifying the patients with the disease; and (iii) a level maximizing sensitivity and specificity for the best classification of the whole population. To minimize patient self-evaluation of pain, we devised a second score (score 2) with the same method and levels and scores definition, excluding visual analog scale pain scores, except for dysmenorrhea. These scores were validated on an internal and external population. FINDINGS: Score 1 had a C-index of 0.81 (95% CI [0.79-0.83]). Results for the three score 1 levels were: ≥ 25: specificity of 91% (95% CI [89-93]); < 11: sensitivity of 91% (95% CI [89-93]); ≥ 18: specificity of 75% (95% CI [72-78]) and sensitivity of 73% (95% CI [70-76]). Score 2 had a C-index of 0.75 (95% CI [73-77]). The three levels of score 2 were: ≥ 24: specificity of 82% (95% CI [80-85]); < 7: sensitivity of 92% (95% CI [90-94]); ≥ 17: specificity of 62% (95% CI [58-65]) and sensitivity of 78% (95% CI [75-81]). The two scores were internally and externally validated. INTERPRETATION: A score based only on a patient questionnaire could allow identification of a population at high risk of endometriosis. This strategy might help referral to specialized radiologists for a non-surgical endometriosis scan. FUNDING: None.

Application and prospect of cutting-edge information technology in biomedical big data.

In recent years, with the development of various high-throughput omics based biological technologies (BT), biomedical research began to enter the era of big data. In the face of high-dimensional, multi-domain and multi-modal biomedical big data, scientific research requires a new paradigm of data intensive scientific research. The vigorous development of cutting-edge information technologies (IT) such as cloud computing, blockchain and artificial intelligence provides technical means for the practice of this new research paradigm. Here,we describe the application of such cutting-edge information technologies in biomedical big data, and propose a forward-looking prospect for the construction of a new paradigm supporting environment for data intensive scientific research. We expect to establish a new research scheme and new scientific research paradigm integrating BT & IT technology, which can finally promote the great leap forward development of biomedical research.

How explanation guides belief change.

Philosophers have argued that people ought to change their graded beliefs via Bayes' rule. Recent work in psychology indicates that people sometimes violate that rule by attending to explanatory factors. Results from computational modeling suggest that such violations may actually be rational.

Diagnosis of haemophilia and other inherited bleeding disorders - Is a new paradigm needed?

The current paradigm for the diagnosis of haemophilia and other inherited bleeding disorders (IBDs) based on clinical assessment followed by screening tests and confirmation by assays of clotting factor levels or platelet functions is complex and cumbersome. These have been difficult to establish and standardize around the world for many reasons. Therefore, more than half of the expected number of people with these disorders in the world remain unidentified. A new approach is therefore needed. Use of validated bleeding assessment tools (BATs) offers an opportunity for standardized evaluation of clinically significant bleeding at the primary care level or even to be self-assessed. Advances in genetic evaluation of these disorders through gene panels covering a wide range of IBDs based on next generation sequencing (NGS) technology enable the identification of the primary defect in the haemostasis system with high degree of accuracy. These methods can be centralized and made highly cost-effective when done in large batches. The combination of high BAT score followed by NGS-based genetic diagnosis could be the new paradigm for the primary diagnosis of IBDs. This will need to be followed by confirmation with functional haemostasis tests, as required. This approach will increase rates of detection of the known common disorders many folds and reduce the burden on these families towards accessing facilities for accurate diagnosis and appropriate treatment based on that.

Alzheimer's Disease Prevention and Treatment: Case for Optimism.

A paradigm shift is under way in the Alzheimer's field. A view of Alzheimer's disease, AD, prevailing until now, the old paradigm, maintains that it is initiated and driven by the overproduction and extracellular accumulation of beta-amyloid, Aß; a peptide assumed to be derived, both in health and disease, solely by proteolysis of its large precursor, ßAPP. In AD, according to this view, Aß overproduction-associated neurodegeneration begins early, accumulates throughout the lifespan, and manifests symptomatically late in life. A number of drugs, designed within the framework of exceptionality of the ßAPP proteolytic/secretory pathway in Aß production in Alzheimer's disease, achieved spectacular successes in treatment, even the reversal, of AD symptoms in animal models. Without exception, they all exhibited equally spectacular failures in human clinical trials. This paradigm provides few causes for optimism with regard to prevention and treatment of AD. In its context, the disease is considered untreatable in the symptomatic phase; even prodromal cases are assumed too advanced for treatment because Aß-triggered damages have been accumulating for preceding decades, presumably starting in the early twenties and, to be effective, this is when therapeutic intervention should commence and continue for life. The new paradigm does not dispute the seminal role of Aß in AD but posits that beta-amyloid produced in the ßAPP proteolytic/secretory pathway causes AD in humans no more than it does in non-human mammals that share this pathway with humans, accumulate Aß as they age, but do not develop the disease. Alzheimer's disease, according to this outlook, is driven by the AD-specific pathway of Aß production, independent of ßAPP and absent in animals. Its activation, late in life, occurs through accumulation, via both cellular uptake of secreted Aß and neuronal retention of a fraction of beta-amyloid produced in the ßAPP proteolytic pathway, of intraneuronal Aß, which triggers mitochondrial dysfunction. Cellular stresses associated with mitochondrial dysfunction, or, probably, the integrated stress response, ISR, elicited by it, activate an AD-specific Aß production pathway. In it, every conventionally produced ßAPP mRNA molecule potentially serves repeatedly as a template for production of severely 5'-truncated mRNA encoding C99 fragment of ßAPP, the immediate precursor of Aß that is processed in a non-secretory pathway, apparently in a neuron-specific manner. The resulting intraneuronally retained Aß augments mitochondrial dysfunction, which, in turn, sustains the activity of the ßAPP mRNA amplification pathway. These self-propagating Aß overproduction/mitochondrial dysfunction mutual feedback cycles constitute the engine that drives AD and ultimately triggers neuronal death. In this paradigm, preventive treatment can be initiated any time prior to commencement of ßAPP mRNA amplification. Moreover, there are good reasons to believe that with a drug blocking the amplification pathway, it would be possible not only to preempt the disease but also stop and reverse it even when early AD symptoms are already manifested. Thus, the new paradigm introduces a novel theory of Alzheimer's disease. It explains the observed discordances, determines defined therapeutic targets, provides blueprints for a new generation of conceptually distinct AD models and specifies design of a reporter for the mRNA amplification pathway. Most importantly, it offers detailed guidance and tangible hope for prevention of the disease and its treatment at the early symptomatic stages.

Novel paradigms in the therapeutic management of heart failure with preserved ejection fraction: clinical perspectives.

Heart failure with preserved ejection fraction (HFpEF) is a pathological complexity that decreases cardiac output and elevates the ventricular filling pressure. HFpEF is usually misdiagnosed and maltreated. HFpEF is usually correlated with excessive morbidity and mortality. The prevalence of HFpEF is growing, and there is a deficiency of evidence-based therapy, creating challenges for the physician with no effective management guidelines. Moreover, HFpEF is not equivalent to diastolic heart failure as previously thought, as diastolic dysfunction is not the only underlying mechanism related to HFpEF and sometimes may be absent. Several other mechanisms may work in concert to produce HFpEF syndrome, either cardiac related (chronotropic incompetence, a longitudinal left ventricular (LV) systolic dysfunction despite a normal ejection fraction) or extracardiac related (pulmonary hypertension, abnormal ventricular-arterial coupling, abnormal exercise-induced vasodilation, extracardiac volume overload). These complex pathophysiologic mechanisms indicate that HFpEF is heterogeneous and that this syndrome might be related to a vascular or an endothelial dysfunction or might be considered a cardiac manifestation of one or more systemic illnesses. The heterogeneity of HFpEF necessitates excluding many differential diagnoses. In addition, the multiple comorbidities that are inherent to this condition need to be controlled in order to achieve effective management. Taken together, these key mechanisms might contribute to the multiple difficulties in the management of HFpEF patients; these mechanisms also explain why medications used in patients with other heart conditions may or may not be successful in these patients. Novel therapies and clinical trials including paradigm shifts in therapeutic management are needed to effectively manage HFpEF. The current review article sheds light on novel paradigms related to pathologies, diagnoses, and strategies, along with some proposed recommendations and clinical options for effective management of HFpEF.

Understanding Conditionals in the East: A Replication Study of With Easterners.

The new probabilistic approaches to the natural language conditional imply that there is a parallel relation between indicative conditionals (ICs) "if s then b" and conditional bets (CBs) "I bet $1 that if s then b" in two aspects. First, the probability of an IC and the probability of winning a CB are both the conditional probability, P(s|b). Second, both an IC and a CB have a third value "void" (neither true nor false, neither wins nor loses) when the antecedent is false (¬s). These aspects of the parallel relation have been found in Western participants. In the present study, we investigated whether this parallel is also present in Eastern participants. We replicated the study of Politzer et al. (2010) with Chinese and Japanese participants and made two predictions. First, Eastern participants will tend to engage in more holistic cognition and take all possible cases, including ¬s, into account when they judge the probability of conditional: Easterners may assess the probability of antecedent s out of all possible cases, P(s), and then may focus on consequent b out of s, P(b|s). Consequently, Easterners may judge the probability of the conditional, and of winning the bet, to be P(s) ∗ P(b|s) = P(s & b), and false/losing the bet as P(s) ∗ P(¬b|s) = P(s & ¬b). Second, Eastern participants will tend to be strongly affected by context, and they may not show parallel relationships between ICs and CBs. The results indicate no cultural differences in judging the false antecedent cases: Eastern participants judged false antecedent cases as not making the IC true nor false and as not being winning or losing outcomes. However, there were cultural differences when asked about the probability of a conditional. Consistent with our hypothesis, Eastern participants had a greater tendency to take all possible cases into account, especially in CBs. We discuss whether these results can be explained by a hypothesized tendency for Eastern people to think in more holistic and context-dependent terms than Western people.

Utilitarian Moral Judgment Exclusively Coheres with Inference from Is to Ought.

Faced with moral choice, people either judge according to pre-existing obligations (deontological judgment), or by taking into account the consequences of their actions (utilitarian judgment). We propose that the latter coheres with a more general cognitive mechanism - deontic introduction, the tendency to infer normative ('deontic') conclusions from descriptive premises (is-ought inference). Participants were presented with vignettes that allowed either deontological or utilitarian choice, and asked to draw a range of deontic conclusions, as well as judge the overall moral rightness of each choice separately. We predicted and found a selective defeasibility pattern, in which manipulations that suppressed deontic introduction also suppressed utilitarian moral judgment, but had little effect on deontological moral judgment. Thus, deontic introduction coheres with utilitarian moral judgment almost exclusively. We suggest a family of norm-generating informal inferences, in which normative conclusions are drawn from descriptive (although value-laden) premises. This family includes deontic introduction and utilitarian moral judgment as well as other informal inferences. We conclude with a call for greater integration of research in moral judgment and research into deontic reasoning and informal inference.

The 4th Report of the Working Group on ECG diagnosis of Left Ventricular Hypertrophy.

The 4th Report provides a brief review of publications focused on the electrocardiographic diagnosis of left ventricular hypertrophy published during the period of 2010 to 2016 by the members of the Working Group on ECG diagnosis of Left Ventricular Hypertrophy. The Working Group recommended that ECG research and clinical attention be redirected from the estimation of LVM to the identification of electrical remodeling, to better understanding the sequence of events connecting electrical remodeling to outcomes. The need for a re-definition of terms and for a new paradigm is also stressed.

Menopause: Genome stability as new paradigm.

Menopause is defined as the age-dependent permanent cessation of menstruation and ovulation due to ovarian failure. Menopause occurs on average around the age of 51 years. Recent genome-wide association studies (GWAS) have identified over 44 genetic variants that are associated with age of onset of natural menopause. Genes linked with menopause can be classified into three major groups: genes implicated in genome stability (DNA repair), immune function and mitochondrial biogenesis. Biological and epidemiological data indicate that reproductive performance, age at menopause and longevity are interlinked through common genetic factors, which play a pivotal role in DNA repair and genome maintenance, which has been linked before with the process of ageing. Consequently, ageing of the soma as a result of inefficient DNA repair appears also to be responsible for failure to reproduce and the subsequent occurrence of menopause. In this way reproductive performance may be strongly linked to the physical condition of the soma and may be a very good predictor of general health in later life.

The relevance effect and conditionals.

More than a decade of research has found strong evidence for P(if A, then C)=P(C|A) ("the Equation"). We argue, however, that this hypothesis provides an overly simplified picture due to its inability to account for relevance. We manipulated relevance in the evaluation of the probability and acceptability of indicative conditionals and found that relevance moderates the effect of P(C|A). This corroborates the Default and Penalty Hypothesis put forward in this paper. Finally, the probability and acceptability of concessive conditionals ("Even if A, then still C") were investigated and it was found that the Equation provides a better account of concessive conditionals than of indicatives across relevance manipulations.

Gregory Bateson e o construtivismo / Gregory Bateson and the constructivism

Esse artigo tem como propósito expor algumas contribuições teóricas de Gregory Bateson (1904-1980), em particular sobre o “Sistema de Codificação-avaliação” e a “Teoria dos Tipos Lógicos”, no sentido de propiciar ao leitor uma reflexão sobre a importância de tais contribuições para a mudança paradigmática que ocorre na ciência. Esta é uma mudança do paradigma característico da chamada era moderna da ciência para um novo paradigma, o da era pós-moderna. O processo de mudança paradigmática foi impulsionado pela contribuição de vários autores que, ao longo do tempo, foram incutindo outro modo de pensar o conhecimento científico. Este artigo aponta para Gregory Bateson.(AU)

This article aims at exposing some theoretical contributions of Gregory Bateson (1904-1980), in particular the “Codification and Evaluation System” and the “Theory of Logical Types”, in order to provide the reader with a reflection on the importance of such contributions to the paradigm shift that occurs in science. This is a shift from the characteristic paradigm of the so-called modern era of science to the new paradigm of the postmodern era. The process of paradigm shift was improved by the contribution of various authors who, over time, were instilling another way of thinking scientific knowledge. This article points at Gregory Bateson.(AU)