Nursing interventions to promote dyspnea self-management of complex chronic patients: An integrated review.

Objectives: Chronic dyspnea, a distressing symptom in patients with complex chronic conditions, is linked to higher risks of mortality. This study aimed to identify nursing interventions that could improve self-management for complex chronic patients, thereby enhancing control over chronic dyspnea. The findings intend to guide nursing care strategies that promote self-management among this population. Methods: We searched the databases Medline, Scopus, Web of Science, CINAHL, Cochrane Database of Systematic Reviews (CDSR), and Joanna Briggs Institute (JBI) databases were searched in December 2023. We included adult patients with complex chronic conditions with chronic dyspnoea. The team screened articles collaboratively, using Rayyan software. A qualitative appraisal was performed according to JBI Critical Appraisal Checklist tools. The review protocol is registered under the number CRD42023456021. Results: Our review included 18 studies that explored a variety of interventions for chronic dyspnea. We identified pharmacological interventions (such as oxygen therapy and inhalation treatments) and non-pharmacological approaches (including educational programs, breathing exercises, fluid intake management, body awareness techniques, peer support, emotional intelligence training, and the use of web applications). Those interventions empower patients, improve their ability to fulfill life roles, mitigate emotional distress, and improve overall quality of life. Nursing care can be crucial in enabling individuals to achieve independence and autonomy in self-care. Conclusions: Promoting self-management for chronic dyspnea in complex chronic patients requires a holistic approach, encompassing multidisciplinary interventions, individualized self-care education, peer engagement, and technological support. Current research on self-management inadequately addresses interventions targeting patient behaviour change. It highlights the need to delve deeper into the self-management process. Further research is needed to expand the evidence base and refine these interventions.

Pancreaticopleural fistula as the inaugural presentation of chronic pancreatitis: A case report.

INTRODUCTION: Pancreaticopleural fistula is a rare complication most associated with alcohol-induced chronic pancreatitis. This usually presents with chest symptoms instead of abdominal ones. Diagnosis requires a high index of suspicion in patients with pancreatitis and persistent pleural effusions. PRESENTATION OF CASE: We present a case of an 81-years-old man admitted in the emergency department with a one week complaints of productive cough, fever, dyspnea and left-side chest pain. The chest X-ray revealed a moderated-volume left-side pleural effusion. The pleural fluid analysis was consistent with an exsudative pleural effusion with high levels of amylase. The thoracoabdominal CT raised the suspicion of a pancreaticopleural fistula, confirmed by ERCP. A pancreatic main duct stenting was performed with good results. The patient was discharged asymptomatic after 18 days of hospitalization. DISCUSSION: Because of PPF insidious presentation it poses a great number of differential diagnosis, so pleural fluid analysis is of paramount importance with high levels of amylase confirming the diagnosis. MRCP and ERCP may establish the fistulous tract between the pancreatic duct and the pleural cavity, with the latter being also therapeutic. CONCLUSION: The rarity of this complication related to pancreatitis and the seldomly presence of abdominal pain in contrast with chest symptoms poses a diagnostic challenge.

Host E3 ubiquitin ligase ITCH mediates Toxoplasma gondii effector GRA35-triggered NLRP1 inflammasome activation and cell-autonomous immunity.

Toxoplasma gondii is an intracellular parasite that can activate the NLRP1 inflammasome leading to macrophage pyroptosis in Lewis rats, but the underlying mechanism is not well understood. In this study, we performed a genome-wide CRISPR screen and identified the dense granule proteins GRA35, GRA42, and GRA43 as the Toxoplasma effectors mediating cell death in Lewis rat macrophages. GRA35 localizes on the parasitophorous vacuole membrane, where it interacts with the host E3 ubiquitin ligase ITCH. Inhibition of proteasome activity or ITCH knockout prevented pyroptosis in Toxoplasma-infected Lewis rat macrophages, consistent with the "NLRP1 functional degradation model." However, there was no evidence that ITCH directly ubiquitinates or interacts with rat NLRP1. We also found that GRA35-ITCH interaction affected Toxoplasma fitness in IFNγ-activated human fibroblasts, likely due to ITCH's role in recruiting ubiquitin and the parasite-restriction factor RNF213 to the parasitophorous vacuole membrane. These findings identify a new role of host E3 ubiquitin ligase ITCH in mediating effector-triggered immunity, a critical concept that involves recognizing intracellular pathogens and initiating host innate immune responses.IMPORTANCEEffector-triggered immunity represents an innate immune defense mechanism that plays a crucial role in sensing and controlling intracellular pathogen infection. The NLRP1 inflammasome in the Lewis rats can detect Toxoplasma infection, which triggers proptosis in infected macrophages and eliminates the parasite's replication niche. The work reported here revealed that host E3 ubiquitin ligase ITCH is able to recognize and interact with Toxoplasma effector protein GRA35 localized on the parasite-host interface, leading to NLRP1 inflammasome activation in Lewis rat macrophages. Furthermore, ITCH-GRA35 interaction contributes to the restriction of Toxoplasma in human fibroblasts stimulated by IFNγ. Thus, this research provides valuable insights into understanding pathogen recognition and restriction mediated by host E3 ubiquitin ligase.

Growth of long bones in European and Japanese quail from the 13th day of incubation to day 35 post-hatch.

This study described the growth, morphometric, biomechanical, and chemical properties of the femur, tibiotarsus, and tarsometatarsus of European and Japanese quail. Analyses were performed at 13 and 15 days of incubation, at hatch, and at 4, 7, 10, 14, 21, 28, and 35 days post-hatch (n=6/subspecies/period). Bone specimens were analyzed by cone-beam computed tomography, biomechanical assays, chemical analyses, and histomorphometry. Variables were fitted by the Gompertz function and its derivative or assessed using the analysis of variance. Analysis of the derivative of Gompertz curves showed that the growth behavior of the tarsometatarsal bone was similar between quail subspecies, and the femur and tibiotarsus of European quail increased first in width and then in length, whereas the opposite occurred in Japanese quail. There was an interaction between quail subspecies and days of growth on femoral, tarsometatarsal, and tibiotarsal bone densities. Femoral and tibiotarsal cross-sectional areas were influenced by the interaction of quail subspecies and day of growth. Interaction effects were significant for breaking strength and phosphorus percentage. European and Japanese quail have different femoral and tibiotarsal growth patterns, especially in the first few days after hatching, whereas tarsometatarsal growth is similar between subspecies.

Growth of breast muscles in European and Japanese quail raised in meat production system: a morphological analysis.

Growth curves have been described in the quail but with no attention to the muscle composing of the breast. The description of the characteristics of growth curves to body weight and to breast muscle was the aim of this study. Morphological development of Musculus supracoracoideus and Musculus pectoralis in European and Japanese quail was assessed from the final incubation of to 35 days. Gompertz models were adjusted with maximum growth rates to body weight, breast weight, and Musculus pectoralis and supracoracoideus weight at 17.6; 22.2; 23.5, and 21.4 days. The European quail had a higher body and breast weight at maturity. Musculus supracoracoideus developed faster in both subspecies but with larger Musculus pectoralis. Both musculus had a greater number of fibers type IIA and largest fibers IIB, with quadratically increasing in fiber diameter with age in both subspecies and muscles. At 35 days, results of meat quality indicated similarity between genders and subspecies, with darker and redness breast meat in Japanese quail. In conclusion, breast weight gain was a result of type IIA and IIB fiber hypertrophy in both muscles and, despite the difference in size and aptitude, Japanese and European quail showed similar body and muscle growth patterns.

Affective theory of mind in people with mild and moderate Alzheimer's disease.

OBJECTIVE: This study compared the affective theory of mind (ToM) of people with mild and moderate Alzheimer's disease (AD) and healthy older adults and also investigated the relationship between affective ToM and cognitive and clinical functioning in AD people. METHODS: This cross-sectional study included 156 older adults with AD and 40 healthy older adults. We used an experimental task involving reasoning processes in different contextual situations. RESULTS: The affective ToM was impaired in AD groups compared with healthy group, with moderate AD group showing lower performance than mild AD group. The affective ToM task of mild AD group was significantly correlated with the Mini-Mental State Examination (MMSE) and education years. Linear regression showed only education years as a predictor of ToM task performance. The neuropsychiatric symptoms and functionality were not correlated with the affective ToM. CONCLUSIONS: Our findings demonstrated that people with mild and moderate AD presented impairments in affective ToM that can be explained by the difficulties to infer emotion from reasoning processes. In addition, the education years variable proved to be an affective ToM performance's predictor for the mild AD group, but not for the moderate AD group, indicating that ToM abilities are affected differently in different stages of AD. Neuropsychiatric symptoms and functionality seem to have no influence on affective ToM impairments in people with AD.

Productive performance, breast growth and digestive system development in European quail subjected to post-hatch fasting for different periods.

This study assessed the effect of different periods of post-hatch fasting on animal performance and breast and digestive system growth in European quail. Quail chicks were distributed in a completely randomized design, with four fasting periods (0, 24, 36, and 48 hs) and four replications of 40 birds per treatment. In 1 to 14-day-old chicks, weight gain decreased with increasing fasting time. Compensatory gain was observed from 15 days of age onward. Fasted quail had a lower length and relative weight of the digestive system than fed animals for up to 14 days. Histologically, the duodenal villus height was significantly lower in 3-day-old quail fasted for 36 hs than in those fasted for 48 hs, but this effect was not observed at 7 days. Scanning electron microscopy showed no differences in the small intestinal mucosa between fasted and fed birds at 3 days of age. Post-hatch fasting reduced the relative weight of the breast in quail aged 1 to 14 days but did not affect type IIa and IIb fiber diameter at 35 days. On the basis of these results, it is recommended that European quail raised for meat should not be fasted for more than 48 hs post-hatch.

The relationship between burden and caregiver's sleep disturbances in dementia: a systematic review.

Caregivers of people living with dementia (PLwD) have a high burden degree that leads to health issues, including sleep. Objective: This study aimed to analyze the impacts of the caregiving burden on caregiver's sleep disturbances. Methods: This systematic review involved a qualitative analysis of publications on Web of Science and Pubmed/Medline databases published between February 2018 and August 2022. Results: A total of 27 studies were identified and analyzed. Caregiver's sleep presents impairments in sleep latency, sleep fragmentation, sleep duration, subjective sleep quality, daytime dysfunction, and insomnia. Caregiver's distress and depressive symptoms have a dual relationship with sleep problems. Conclusion: Sleep disturbances presented by caregivers are correlated with higher burden levels and lead to more vulnerability to psychiatric symptoms and health issues.

Cuidadores de pessoas com demência possuem alto grau de sobrecarga que impacta de forma objetiva o sono e suas dimensões. Objetivo: Este estudo teve o objetivo de analisar o impacto da sobrecarga nas alterações do sono do cuidador. Métodos: Esta revisão sistemática envolveu a análise de resultados quantitativos e qualitativos de publicações das bases de dados Web of Science e PubMed/ Medical Literature Analysis and Retrieval System Online (Medline) publicadas entre fevereiro de 2018 e agosto de 2022. Resultados: O total de 27 estudos foi identificado e analisado. Cuidadores apresentam prejuízos na latência, fragmentação, duração e qualidade subjetiva do sono, disfunção diurna e insônia. O estresse e sintomas depressivos apresentados pelo cuidador possuem com o sono uma relação bidirecional. Conclusão: Os distúrbios do sono apresentados pelos cuidadores estão correlacionados com o alto nível de sobrecarga e geram maior vulnerabilidade para sintomas psiquiátricos e problemas de saúde.

A Longitudinal Evaluation of the Pattern of Social Cognition Impairment in Brazilians With Alzheimer's Disease.

BACKGROUND: Social cognition (SC) impairments contribute to the dependence of people with Alzheimer disease (AD), influencing their functional disability and the burden on family members and caregivers. Our objective was to longitudinally investigate the relationship between SC and cognitive and clinical variables in persons with AD and their caregivers. We also evaluated the different SC predictors from 3 perspectives: people with AD, caregivers of people with AD, and discrepancy analysis. METHODS: In all, 137 dyads (people with AD and their caregivers) underwent 2 assessments: at baseline (M1) and after 1 year (M2). During follow-up, 58 dyads were excluded, and the study was thus concluded with 79. RESULTS: Longitudinal analysis of the people with AD showed that while some cognitive functions declined (which is consistent with disease progression), SC impairments showed a more stable pattern. Another interesting result was related to SC predictors. For people with AD, SC was associated with cognition at both time points. For caregivers, besides cognition, other predictors included reduced functional abilities and quality of life in people with AD. These results are consistent with the discrepancy predictors. CONCLUSION: The stable pattern in SC functioning over 12 months in AD suggests that this neurocognitive domain may be influenced more by emotional processing than by cognitive impairment. In addition, the SC predictors showed that the investigation of different points of view enables a more global understanding, contributing to better and more targeted treatment for the patient.

Implantação do Time de Resposta Rápida em um Hospital Público Pediátrico

Este artigo tem por objetivo descrever a experiência na implantação e condução do trabalho do Time Reposta Rápida em um hospital público pediátrico 100% Sistema Único de Saúde, indicando fatores que funcionaram como facilitadores e dificultadores desta implantação. Realizado estudo descritivo, qualitativo, do tipo relato de experiência. Na implantação do Time Reposta Rápida na enfermaria A do Hospital Infantil Nossa Senhora da Glória (Milena Gottardi), foram identificados vários fatores que funcionaram como facilitadores para esta implantação, dentre eles o envolvimento de grande parte da equipe em todas as etapas. Quanto aos dificultadores cita-se a demora na aquisição dos equipamentos, materiais e insumos, face às questões legais e burocráticas no processo de licitação e compras; grande esforço para adaptar as escalas dos profissionais a realidade do serviço; demora no processo de capacitação dos médicos da equipe; resistência de alguns profissionais por não compreenderem a magnitude do Time Reposta Rápida na realidade local. A implantação do Time Reposta Rápida pode oferecer subsídios para reorganização dos processos de trabalho.

Building pathologies caused by failure of Fundão Tailing Dam: A principal component analysis aproach.

This article presents a study of the impacts caused by Fundão dam failure in buildings from Gesteira district, Barra Longa city, Brazil. The analyzed dataset was built using technical reports from surveys carried out in 152 buildings. Principal component analysis was capable of explain the interdependence of data variable and allowed conditions of understand the consequences and evidenced pathologies. Heavy vehicle traffic caused more damage (57% of buildings) to the studied buildings than the contact with the tailing mud (43% of buildings).

Genome-wide CRISPR screen identifies genes synthetically lethal with GRA17, a nutrient channel encoding gene in Toxoplasma.

Toxoplasma gondii is a parasite that replicates within a specialized compartment called the parasitophorous vacuole (PV), which is surrounded by the PV membrane (PVM). To obtain essential nutrients, Toxoplasma must transport molecules across the PVM, a process mediated by the secreted parasite proteins GRA17 and GRA23. These proteins form pores in the PVM through which small molecules can diffuse in and out of the PV. GRA17 and GRA23 are synthetically lethal, suggesting that at least one pore type is essential for parasite survival. In the 'nutrient sensitized' Δgra17 strain it is likely that other Toxoplasma genes become essential, because they mediate nutrient acquisition from the host or are involved in the trafficking of GRA23 to the PVM. To identify these genes, a genome-wide loss-of-function screen was performed in wild-type and Δgra17 parasites, which identified multiple genes that were synthetically sick/lethal with GRA17. Several of these genes were involved in the correct localization of GRAs, including GRA17/GRA23, to the PVM. One of the top hits, GRA72, was predicted to form a pore on the PVM, and its deletion led to the formation of enlarged "bubble vacuoles" with reduced PVM small molecule permeability, similar to what was previously observed for Δgra17 parasites. Furthermore, Δgra72 parasites had reduced in vitro growth and virulence in mice. These findings suggest that in the absence of GRA17, other genes become essential, likely because they play a role in the proper localization of GRA23 (and other GRAs) or because they determine host-derived nutrient acquisition at the PVM.

Alignment-Rheology Relationship of Biosourced Rod-Like Colloids and Polymers under Flow.

Fluids composed of biosourced rod-like colloids (RC) and rod-like polymers (RP) have been extensively studied due to various promising applications relying on their flow-induced orientation (e.g., fiber spinning). However, the relationship between RC and RP alignment and the resulting rheological properties is unclear due to experimental challenges. We investigate the alignment-rheology relationship for a variety of biosourced RC and RP, including cellulose-based particles, filamentous viruses, and xanthan gum, by simultaneous measurements of the shear viscosity and fluid anisotropy under rheometric shear flows. For each system, the RC and RP contribution to the fluid viscosity, captured by the specific viscosity ηsp, follows a universal trend with the extent of the RC and RP alignment independent of concentration. We further exploit this unique rheological-structural link to retrieve a dimensionless parameter (ß) directly proportional to ηsp at zero shear rate (η0,sp), a parameter often difficult to access from experimental rheometry for RC and RP with relatively long contour lengths. Our results highlight the unique link between the flow-induced structural and rheological changes occurring in RC and RP fluids. We envision that our findings will be relevant in building and testing microstructural constitutive models to predict the flow-induced structural and rheological evolution of fluids containing RC and RP.

CAN THE PERCUTANEOUS CHEVRON AND AKIN (PECA) TECHNIQUE CORRECT THE PRONATION OF THE FIRST METATARSAL IN HALLUX VALGUS?

Objective: Pronation of the first metatarsal in hallux valgus has recently been discussed among foot and ankle surgeons. This study aimed to evaluate the potential radiographic correction of moderate and severe hallux valgus using the percutaneous Chevron and Akin (PECA) technique. Methods: We evaluated 45 feet in 38 patients (mean age 65.3 years old [36 - 83]; 4 men; 34 women; 7 bilateral) who underwent surgical correction using the PECA technique. The radiographic images evaluated were anteroposterior radiographs obtained pre- and postoperatively at least 6 months after surgery, including the metatarsophalangeal angle, the intermetatarsal angle, pronation of the first metatarsal, displacement of the distal fragment, medial sesamoid position and bone union. Results: All parameters evaluated showed significant postoperative improvement, including correction of pronation of the first metatarsal (p < .05) and position of the sesamoid (p < .05). There was a union of osteotomies in all feet. No complications were observed, such as screw loosening or necrosis of the first metatarsal head. Conclusion: The PECA technique can correct pronation of the first metatarsal in moderate and severe hallux valgus, and other deformity-associated parameters. Level of Evidence IV; Case Series.

Objetivo: A pronação do primeiro metatarso no hálux valgo tem sido um tema de discussão recente entre os cirurgiões de pé e tornozelo. O objetivo deste estudo foi avaliar o potencial de correção radiográfica do hálux valgo moderado e grave utilizando a técnica percutânea de Chevron e Akin (PECA). Métodos: Avaliamos 45 pés em 38 pacientes (média de idade 65,3 anos [36 - 83]; 4 homens; 34 mulheres; 7 bilaterais) submetidos à correção cirúrgica pela técnica PECA. As imagens radiográficas avaliadas foram radiografias anteroposteriores obtidas no pré e pós-operatório com no mínimo 6 meses após a cirurgia, incluindo ângulo metatarsofalângico, ângulo intermetatarsal, pronação do primeiro metatarso, deslocamento do fragmento distal, posição do sesamoide medial e união óssea. Resultados: Todos os parâmetros avaliados apresentaram melhora significativa no pós-operatório, incluindo correção da pronação do primeiro metatarso (p < 0,05) e posição do sesamoide (p < 0,05). Houve união de osteotomias em todos os pés. Não foram observadas complicações, como soltura do parafuso ou necrose da cabeça do primeiro metatarso. Conclusão: A técnica PECA pode corrigir a pronação do primeiro metatarso no hálux valgo moderado e grave, bem como outros parâmetros associados à deformidade. Nível de Evidência IV; Série De Casos.

Econometric model of iron ore through principal component analysis and multiple linear regression.

Price of iron ore is affected by instabilities of microeconomic balance between supply and demand. Periods of equilibrium adjustment result in huge swings, growth or global recession. They also impact the viability of mineral enterprises and generate consequences to important global economic scenarios. This research aims to evaluate the market variables capable of influencing the price of iron ore through multivariate statistical techniques. Principal component analysis and multiple linear regression, booth multivariate statistical techniques were used. The studied variables were rate export of iron ore and concentrates from Brazil, steel production from China, steel production from Japan, production from Europe, steel production from the United States, steel production from India, steel price, coal price, China's Construction Gross Domestic Production, United States construction index, oil price and global oil production. First three components explained 89.12% of the variability of the data matrix. Multiple linear regression highlighted the significance of five variables. They are export iron ore from Brazil, steel production from China, price of coal, steel production from India and price of steel.

[The ethics of care and pediatric palliative care: a potential dialogue]. / A ética do cuidado e cuidado paliativo pediátrico: um diálogo possível.

This article, in an essay format, seeks to establish a dialogue between the ethics of care and pediatric palliative care, taking into consideration the fact that moral perceptions are based on a network of relationships, while care is built on intersubjectivity. Four pillars that are referred to as movements are discussed: the ethics of care, as a feminist ethic, in a dialogue with pediatric palliative care, and communication and autonomy as tools of care based on their relational aspects. The conclusion drawn is that considering these aspects from a palliative standpoint can be a way to implement a moral commitment of care.

Este artigo, sob a forma de ensaio, tem como objetivo fazer uma interlocução entre a ética do cuidado e o cuidado paliativo pediátrico, considerando que as percepções morais são tecidas a partir de uma rede de relações e que o cuidado se constrói na intersubjetividade. Discute-se com base em quatro pilares, a que chamamos de movimentos: a ética do cuidado, como ética feminista, em diálogo com o cuidado paliativo pediátrico, a comunicação e a autonomia como ferramentas de cuidado a partir de suas características relacionais. Conclui-se que considerar esses aspectos na abordagem paliativa pode ser um caminho para exercer um compromisso moral de cuidado.

A ética do cuidado e cuidado paliativo pediátrico: um diálogo possível / The ethics of care and pediatric palliative care: a potential dialogue

Resumo Este artigo, sob a forma de ensaio, tem como objetivo fazer uma interlocução entre a ética do cuidado e o cuidado paliativo pediátrico, considerando que as percepções morais são tecidas a partir de uma rede de relações e que o cuidado se constrói na intersubjetividade. Discute-se com base em quatro pilares, a que chamamos de movimentos: a ética do cuidado, como ética feminista, em diálogo com o cuidado paliativo pediátrico, a comunicação e a autonomia como ferramentas de cuidado a partir de suas características relacionais. Conclui-se que considerar esses aspectos na abordagem paliativa pode ser um caminho para exercer um compromisso moral de cuidado.

Abstract This article, in an essay format, seeks to establish a dialogue between the ethics of care and pediatric palliative care, taking into consideration the fact that moral perceptions are based on a network of relationships, while care is built on intersubjectivity. Four pillars that are referred to as movements are discussed: the ethics of care, as a feminist ethic, in a dialogue with pediatric palliative care, and communication and autonomy as tools of care based on their relational aspects. The conclusion drawn is that considering these aspects from a palliative standpoint can be a way to implement a moral commitment of care.

CRISPR Screens Identify Toxoplasma Genes That Determine Parasite Fitness in Interferon Gamma-Stimulated Human Cells.

Toxoplasma virulence depends on its ability to evade or survive the toxoplasmacidal mechanisms induced by interferon gamma (IFNγ). While many Toxoplasma genes involved in the evasion of the murine IFNγ response have been identified, genes required to survive the human IFNγ response are largely unknown. In this study, we used a genome-wide loss-of-function screen to identify Toxoplasma genes important for parasite fitness in IFNγ-stimulated primary human fibroblasts. We generated gene knockouts for the top six hits from the screen and confirmed their importance for parasite growth in IFNγ-stimulated human fibroblasts. Of these six genes, three have homology to GRA32, localize to dense granules, and coimmunoprecipitate with each other and GRA32, suggesting they might form a complex. Deletion of individual members of this complex leads to early parasite egress in IFNγ-stimulated cells. Thus, prevention of early egress is an important Toxoplasma fitness determinant in IFNγ-stimulated human cells. IMPORTANCE Toxoplasma infection causes serious complications in immunocompromised individuals and in the developing fetus. During infection, certain immune cells release a protein called interferon gamma that activates cells to destroy the parasite or inhibit its growth. While most Toxoplasma parasites are cleared by this immune response, some can survive by blocking or evading the IFNγ-induced restrictive environment. Many Toxoplasma genes that determine parasite survival in IFNγ-activated murine cells are known but parasite genes conferring fitness in IFNγ-activated human cells are largely unknown. Using a Toxoplasma adapted genome-wide loss-of-function screen, we identified many Toxoplasma genes that determine parasite fitness in IFNγ-activated human cells. The gene products of four top hits play a role in preventing early parasite egress in IFNγ-stimulated human cells. Understanding how IFNγ-stimulated human cells inhibit Toxoplasma growth and how Toxoplasma counteracts this, could lead to the development of novel therapeutics.