CRISPR-Based Therapies: Revolutionizing Drug Development and Precision Medicine.

With the discovery of CRISPR-Cas9, drug development and precision medicine have undergone a major change. This review article looks at the new ways that CRISPR-based therapies are being used and how they are changing the way medicine is done. CRISPR technology's ability to precisely and flexibly edit genes has opened up new ways to find, validate, and develop drug targets. Also, it has made way for personalized gene therapies, precise gene editing, and advanced screening techniques, all of which hold great promise for treating a wide range of diseases. In this article, we look at the latest research and clinical trials that show how CRISPR could be used to treat genetic diseases, cancer, infectious diseases, and other hard-to-treat conditions. However, ethical issues and problems with regulations are also discussed in relation to CRISPR-based therapies, which shows how important it is to use them safely and responsibly. As CRISPR continues to change how drugs are made and used, this review shines a light on the amazing things that have been done and what the future might hold in this rapidly changing field.

Global Considerations in Asthma Treatment: Management in Low Resource Settings.

Low-resource settings have a disproportionately higher burden of asthma due to factors that include environmental triggers, access to healthcare, availability of medications, and uncoordinated health systems. The application of guideline-based management can vary, which further impacts the treatment delivered. This chapter aims to outline the global landscape of asthma management, including cultural and social factors, with suggestions for interventions.

Diet in Early Life Is Related to Child Mental Health and Personality at 8 Years: Findings from the Norwegian Mother, Father and Child Cohort Study (MoBa).

There is rising concern about population mental health. Personality and mental health traits manifest early. Sufficient nutrition is fundamental to early development. However, little is known about early life dietary impact on later mental health. The aim of this study was to investigate associations of exposure to a healthy and sustainable antenatal and early childhood diet with personality traits and symptoms of depression and anxiety measured at 8 years of age. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN) including 40,566 participants. Mental health measures and personality traits were assessed at 8 years. Dietary data from pregnancy, child age 6 and 18 months and 3 and 7 years were used. With few exceptions, inverse associations were observed between healthier diet at all time points and depression and anxiety symptom scores at age 8. We found positive associations between diet scores at almost all time points and extraversion, benevolence, conscientiousness and imagination. Inverse associations were observed between diet scores and neuroticism. Combined, these findings underpin a probable impact of both maternal pregnancy diet and early childhood diet on several aspects of child mental health.

Adherence to a healthy and potentially sustainable Nordic diet is associated with child development in The Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: The rapid neurodevelopment that occurs during the first years of life hinges on adequate nutrition throughout fetal life and early childhood. Therefore, adhering to a dietary pattern based on healthy foods during pregnancy and the first years of life may be beneficial for future development. The aim of this paper was to investigate the relationship between adherence to a healthy and potentially sustainable Nordic diet during pregnancy and in early childhood and child development. METHODS: This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). In 83,800 mother-child pairs, maternal pregnancy diet and child diet at 6 months, 18 months and 3 years were scored according to adherence to the New Nordic Diet (NND). NND scores were calculated both as a total score and categorized into low, medium, or high adherence. Child communication and motor development skills were reported by parents at 6 months, 18 months, 3 and 5 years, using short forms of the Ages and Stages Questionnaire and the Child Development Inventory. Associations of NND adherence with child development were estimated with linear and logistic regression in crude and adjusted models. RESULTS: When examining the NND and child developmental scores as percentages of the total scores, we found positive associations between the NND scores (both maternal pregnancy diet and child diet) and higher scoring on child development (adjusted [Formula: see text] s [95% confidence intervals] ranging from 0.007 [0.004, 0.009] to 0.045 [0.040, 0.050]). We further found that low and medium adherence to NND were associated with higher odds of later emerging developmental skills compared to high NND adherence at nearly all measured timepoints (odds ratios [95% CI] ranging from significant values 1.15 [1.03-1.29] to 1.79 [1.55, 2.06] in adjusted analyses). CONCLUSIONS: Our findings support that adherence to a healthy and potentially sustainable diet early in life is important for child development every step of the way from pregnancy until age 5 years.

Hypogammaglobulinaemia and B cell lymphopaenia in Barth syndrome.

Barth syndrome (BTHS) is an X linked recessive disorder caused by a mutation in the tafazzin (TAZ) gene classically associated with the triad of neutropaenia and cardiac and skeletal myopathies. Here we present a case of BTHS in a 2-month-old male patient found to have a novel variant of the TAZ gene (hemizygous c.639G>A) leading to early termination of the tafazzin protein (p.Trp213Ter) with presumed loss of function. Our patient was found to have dilated cardiomyopathy, cyclic neutropaenia and growth delays, which in combination with genetic work-up confirmed the diagnosis of BTHS. He also experienced repeated bacterial and viral infections, prompting an immunological work-up which revealed persistent B cell lymphopaenia and hypogammaglobulinaemia. He ultimately required subcutaneous immunoglobulin replacement and GM-CSF for ongoing hypogammaglobulinaemia and neutropaenia. To our knowledge, this case is the first report of BTHS associated with B cell lymphopaenia and hypogammaglobulinaemia.

Development and description of New Nordic Diet scores across infancy and childhood in the Norwegian Mother, Father and Child Cohort Study (MoBa).

In recent years, examining dietary patterns has become a more common way of investigating potential associations between diet and adverse health outcomes. The New Nordic Diet (NND) is a potentially healthy and sustainable dietary pattern characterized by foods that are locally available and traditionally consumed in the Nordic countries. The diet has been typically examined in adult populations, and less is known about compliance to the NND from infancy throughout childhood. In the current study, we therefore aimed to develop and describe child age-specific NND scores. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). We have previously developed a NND score for the maternal diet during pregnancy, and the development of the child diet scores was based on the rationale of this score. Food frequency data from n = 89 715 at child age 6 months, n = 76 432 at 18 months, n = 58 884 at 3 years, and n = 35 978 at 7 years were used to construct subscales in accordance with the maternal diet score. Subscales were composed of responses to a selection of food and drink items or other questions and were dichotomized by the median, yielding four age-specific diet scores where the possible scoring ranged from 0 to 6 at 6 months and 3 years and from 0 to 9 at 18 months and 7 years. The developed scores will be used to examine associations with childhood overweight and cognitive and mental development in future studies.

Childhood adherence to a potentially healthy and sustainable Nordic diet and later overweight: The Norwegian Mother, Father and Child Cohort Study (MoBa).

The New Nordic Diet (NND) is a potentially healthy and sustainable dietary pattern represented by locally available and traditionally consumed foods in the Northern countries. The diet has been commonly examined in adult populations, but less is known regarding its potential associations with overweight/obesity in children. We have previously developed child diet scores measuring compliance to the NND at child age 6 and 18 months and 3 and 7 years. In this study, we aimed to describe child and maternal characteristics and assess potential associations between the age-specific diet scores and child overweight at 8 years. This study is based on the Norwegian Mother, Father and Child Cohort Study (MoBa), including 14,989 mother-child pairs and uses data from the Medical Birth Registry of Norway (MBRN). The scores measured NND compliance as a total score and categorized into low, medium and high NND compliance at each age point. Using logistic regression models, we investigated the association between each age-specific score and the odds of overweight at 8 years. In crude analyses, adherence to the NND at 6 months was inversely associated with odds of overweight at 8 years in the continuous score (odds ratio = 0.95, 95% CI [0.91, 0.98]) and when comparing high versus low NND adherence (odds ratio = 0.81, 95% CI [0.70, 0.94]). The association was almost entirely attenuated in the adjusted models. In conclusion, child NND adherence up to 7 years of age was not associated with odds of overweight at 8 years in adjusted analyses.

Asthma specialist care preferences among parents of children receiving emergency department care for asthma.

Objective: To learn factors associated with desire for asthma specialist care among parents of children seeking emergency department (ED) care for asthma, and if referral was indicated based on national asthma guidelines. Methods: We surveyed parents of children ages 0-18 years seeking pediatric ED asthma care, then comparisons were made according to parental level of interest in asthma specialist care, with regard to socio-demographics, asthma morbidity and care, by chi-squared and logistic regression. Results: Of 149 children, 20% reported specialist care, but 75% met guideline criteria for referral. About 80% of parents not seeing an asthma specialist expressed a desire to see one. Higher rates of prior urgent care visits (48% vs. 22%, p = 0.03), ED visits (82% vs. 35%, p < 0.001) and oral steroid use (53% vs. 22%, p = 0.009) were reported by parents who desired an asthma specialist compared with parents who did not. 87% of parents not seeing a specialist attributed this to a perceived lack of necessity by their primary care provider. An ED visit within the prior 12 months was the most significant predictor in parental desire for specialist care (odds ratio 9.75; 95% CI 3.42-27.76) in adjusted logistic regression models. Conclusion: High rates of parental preference for asthma specialist care suggest that directly querying parents may be an efficient method to identify children appropriate for specialist care in the ED.

Allergic and nonallergic rhinitis.

Rhinitis is characterized by nasal congestion, rhinorrhea, sneezing, and/or posterior nasal drainage. It affects a significant portion of the population and presents a large burden economically and on quality of life. Rhinitis is broadly characterized as allergic and nonallergic, of which nonallergic rhinitis may be divided into inflammatory and noninflammatory etiologies. The inflammatory causes include nonallergic rhinitis with eosinophilia, postinfectious, and rhinitis associated with nasal polyps. The noninflammatory causes include idiopathic nonallergic (vasomotor) rhinitis, medication-induced rhinitis, hormone related (e.g., pregnancy), and systemic disease related. Allergic rhinitis is classified as intermittent or persistent and mild versus moderate-severe. The nasal mucosa is extremely vascular; parasympathetic stimulation promotes an increase in nasal cavity resistance and nasal gland secretion, whereas sympathetic stimulation leads to vasoconstriction. The diagnosis of rhinitis begins with a directed history, particularly noting pattern, chronicity, and triggers of symptoms. Examination of the nasal cavity with attention to appearance of the septum and inferior turbinates is recommended. Skin testing for aeroallergens is helpful in demonstrating the presence or absence of immunoglobulin E antibodies and to differentiate nonallergic from allergic rhinitis. Treatment includes patient education, irritant or allergen avoidance, and pharmacotherapy. Medications used for the treatment of rhinitis include intranasal corticosteroids, oral and intranasal antihistamines, intranasal anticholinergic agents, oral decongestants, and leukotriene receptor antagonists. When used in combination, an intranasal antihistamine spray and nasal steroid provide greater symptomatic relief than monotherapy. Allergen immunotherapy is the only disease-modifying intervention available for allergic rhinitis.

Acute severe asthma (status asthmaticus).

Acute severe asthma, formerly known as status asthmaticus, is defined as severe asthma unresponsive to repeated courses of beta-agonist therapy. It is a medical emergency that requires immediate recognition and treatment. Albuterol in combination with ipratropium bromide in the emergency department (ED) has been shown to decrease the time spent in the ED and the hospitalization rates. The benefits of ipratropium are not sustained after admission to the hospital. Oral or parenteral corticosteroids should be administered to all patients with acute severe asthma as early as possible because clinical benefits may not occur for a minimum of 6 to 12 hours. Viral respiratory infections are a common trigger for acute asthma; other causes include medical nonadherence, allergen exposure (especially pets and mold [e.g., Alternaria species]) in individuals who are severely atopic, nonsteroidal anti-inflammatory exposure in patients with aspirin allergy, irritant inhalation (e.g., smoke, paint), exercise, and insufficient use of inhaled or oral corticosteroids. The patient's history should focus on the acute assessment of asthma control and morbidity, including current use of oral or inhaled corticosteroids; the number of hospitalizations, ED visits, intensive care unit admissions, and intubations; the frequency of albuterol use; the presence of nighttime symptoms; activity intolerance; current medications; exposure to allergens; and other significant medical conditions. Severe airflow obstruction may be predicted by accessory muscle use, difficulty speaking, refusal to recline < 30°, a pulse of >120 beats/min, and decreased breath sounds. More objective measures of airway obstruction via peak flow or forced expiratory volume in 1 second and pulse oximetry before oxygen administration usually are helpful. Pulse oximetry values of >90% are reassuring, although CO2 retention and a low partial pressure of oxygen may be missed.

Unproved and controversial methods and theories in allergy/immunology.

Unproved methods and controversial theories in the diagnosis and management of allergy/immunology are those that lack scientific credibility. Some definitions are provided for perspective, as in chronic medical conditions, frequently nonscientifically based treatments are developed that can have a profound psychological effect on the patients in the absence of objective physical benefit. Standard practice uses methods of diagnosis and treatment used by reputable physicians in a particular subspecialty or primary care practice, with the understanding that diagnosis and treatment options are consistent with established mechanisms of conditions or diseases. Conventional medicine (Western or allopathic medicine) is that which is practiced by the majority of physicians, osteopaths, psychologists, registered nurses, and physical therapists. Complementary medicine involves diverse practices or products that are used with the practice of conventional medicine, such as using acupuncture in addition to opioids for pain relief. Alternative medicine implies use of complementary practices in place of conventional medicine. Unproved and controversial methods and theories do not have supporting data, validation, or sufficient scientific scrutiny, and they should not be used in the practice of allergy/immunology. Some examples of unproven theories about allergic/immunologic conditions include allergic toxemia, idiopathic environmental intolerance, and toxic disease from indoor molds. Unconventional diagnostic methods for allergic conditions include cytotoxic tests, provocation-neutralization, electrodermal diagnosis, applied kinesiology assessments, chemical analysis of body fluids, and serum immunoglobulin G (IgG) or IgG4 testing. Unproven treatments and intervention methods for allergic/immunologic conditions include acupuncture, homeopathy, halotherapy, and autogenous urine injections.

Nanonetwork of Coordination Polymer AHMT-Ag for the Effective and Broad Spectrum Detection of 6-Mercaptopurine in Urine and Blood Serum.

Nanocrystalline coordination polymers (NCCPs) have been considered as an incredible electrochemical sensor for the effective detection of biologically dynamic drug 6-mercaptopurine (6-MP). In the present report, a significantly stable infinite arrayed coordination polymeric network was self-assembled via metal with efficient organic tecton 4-amino-3-hydrazino-5-mercapto-1,2,4,-triazole (AHMT) in which silver(I) ions are coordinated by AHMT via hydrazino and exocyclic thiol linkage to form AHMT-Ag NCCP. An efficient and highly sensitive detection of 6-MP is attained owing to eminent electron channeling via polymeric nanocrystallite pores. An effective charge transfer leads to an interface of the AHMT-Ag nano-pores and electrolyte anchored electrode via π-π electron coupling and hydrophobic interaction. The voltammogram exposes acute redox behavior of 6-MP and discloses an impeccable illustration for the AHMT-Ag facilitated oxidation of 6-MP. This unique signature was applied in voltammetric detection of 6-MP in blood serum, human urine, and pharmaceutical formulation (tablet) by a considerable high sensitivity of 0.074, 0.058, and 0.036 µA/µM and a detection limit of 87, 97, and 37 nM, respectively. Thus, the prepared AHMT-Ag NCCP can provide a valuable platform for fabrication of highly sensitive electrochemical devices to assay biologically essential drug molecules.

Managing Younger Siblings of Food Allergic Children.

Current guidelines state that there is insufficient evidence to recommend testing siblings of food allergic children before introduction of potential allergic foods, but the topic continues to remain controversial. Although the proportion of siblings who are sensitized to a food without clinical reactivity is high in comparison to those with a true food allergy, there is still a known increased risk amongst siblings of children with food allergies that has led to much apprehension about management. The appropriateness of testing and further steps for management of sensitization in the absence of history of clinical reactivity should be discussed with parents.

Predictors of prior asthma specialist care among pediatric patients seen in the emergency department for asthma.

Background: Asthma guidelines recommend specialist care for patients experiencing poor asthma outcomes during emergency department (ED) visits. The prevalence and predictors of asthma specialist care among an ED population seeking pediatric asthma care are unknown. Objective: To examine, in an ED population, factors associated with prior asthma specialist use based on parental reports of prior asthma morbidity and asthma care. Methods: Parents of children ages 0 to 17 years seeking ED asthma care were surveyed regarding socio-demographics, asthma morbidity, asthma management and current asthma specialist care status. We compared prior asthma care and morbidity between those currently cared for by an asthma specialist versus not. Multivariable logistic regression models to predict factors associated with asthma specialist use were adjusted for parent education and insurance type. Results: Of 150 children (62% boys, mean age 4.7 years, 69% Hispanic), 22% reported asthma specialist care, 75% did not see a specialist and for 3% specialist status was unknown. Care was worse for those not seeing a specialist, including under-use of controller medications (24% vs. 64%, p < 0.001) and asthma action plans (20% vs. 62%, p < 0.001). Multivariable logistic regression revealed that lack of recommendation by the primary care physician reduced the odds of specialist care (OR 0.01, 95% CI <0.01, 0.05, p < 0.001). Conclusions: Asthma specialist care was infrequent among this pediatric ED population, consistent with the sub-optimal chronic asthma care we observed. Prospective trials should further investigate if systematic referral to asthma specialists during/after an ED encounter would improve asthma outcomes.

The role of novel prognostic markers PROX1 and FOXC2 in carcinogenesis of oral squamous cell carcinoma.

OBJECTIVE: Oral squamous cell carcinoma is the most common malignant tumor of the head and neck regions and accounts for more than 90% of cancers in the oral cavity. The angiogenesis, lymphangiogenesis and epithelial mesenchymal transition are known to be pivotal for tumor progression and metastasis. In the last decade, much data has been generated concerning the molecular mechanisms of angiogenesis, lymphangiogenesis and its significance in pathological conditions. The main angiogenic and lymphangiogenic factors have been identified as vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor 2 (VEGFR-2), forkhead box (FOX) C2 while vascular endothelial growth factor C/D (VEGF-C/D), vascular endothelial growth factor receptor 3 (VEGFR-3), Prospero homeobox 1 (PROX1), LYVE-1, podoplanin, Tie/Angioprotein (Ang) 2 and EphrinB2 respectively. PROX1 is a mammalian homologue of Drosophilia homeobox protein, prospero and important for the embryonic development of many mammalian tissues. It has been suggested that it plays various tissue dependent functional roles, which reflects both oncogenic potential and a tumor suppressive role. The exact role in OSCC remains controversial. FOXC2 is a transcription factor belongs to large family of protein, forkhead box. It has been shown to be involved in cancer angiogenesis, proliferation and metastasis through its induction of epithelial-to-mesenchymal transition while its significance in OSCC remains unknown. Based on these data, this article reviews the role of novel prognostic factors PROX1 and FOXC2 in carcinogenesis of OSCC so that they might be considered as an attractive therapeutic target for both tumor associated blood vessels, lymphatic vessels and tumor cells.

Time dependent DFT investigation of the optical properties of artificial light harvesting special pairs.

Computational modeling of selected artificial special pairs has been carried out. The structures chosen are bio-inspired molecular models of the light harvesting system II that have been previously investigated experimentally. Time-dependent density functional theory calculations have been employed to characterize the inter-macrocycle interactions resulting from two zinc porphyrins that are covalently linked with rigid linkers that vary the inter-porphyrin distance and the inter-planar angle in a C2v framework. The effects of varying the linker structure have been explored for electronic states with energies up to and including the Soret-correlated states in the dimer. An expansion of the Gouterman four orbital model for the monomers to an eight orbital model in the dimers provides a reasonable explanation of the inter-macrocycle interactions and provides insight into their experimental properties.

Scavenging mechanism of curcumin toward the hydroxyl radical: a theoretical study of reactions producing ferulic acid and vanillin.

Curcumin is known to be an antioxidant, as it can scavenge free radicals from biological media. A sequence of H-abstraction and addition reactions involving up to eight OH radicals and curcumin or its degradation products leading to the formation of two other antioxidants, namely, ferulic acid and vanillin, was studied. Single electron transfer from curcumin to an OH radical was also studied. All relevant extrema on the potential energy surfaces were located by optimizing geometries of the reactant and product complexes, as well as those of the transition states, at the BHandHLYP/6-31G(d,p) level of density functional theory in the gas phase. Single-point energy calculations were also performed in the gas phase at the BHandHLYP/aug-cc-pVDZ and B3LYP/aug-cc-pVDZ levels of theory. Solvent effects in aqueous media were treated by performing single-point energy calculations at all of the above-mentioned levels of theory employing the polarizable continuum model and the geometries optimized at the BHandHLYP/6-31G(d,p) level in the gas phase. A few reaction steps were also studied by geometry optimization in aqueous media, and the thus-obtained Gibbs free energy barriers were similar to those obtained by corresponding single-point energy calculations. Our calculations show that the hydrogen atom of the OH group attached to the phenol moiety of curcumin would be most efficiently abstracted by an OH radical, in agreement with experimental observations. Further, our study shows that OH addition would be most favored at the C10 site of the heptadiene chain. It was found that curcumin can serve as an effective antioxidant.

Quantum theoretical study of cleavage of the glycosidic bond of 2'-deoxyadenosine: base excision-repair mechanism of DNA by MutY.

The enzyme adenine DNA glycosylase, also called MutY, is known to catalyze base excision repair by removal of adenine from the abnormal 2'-deoxyadenosine:8-oxo-2'-deoxyguanosine pair in DNA. The active site of the enzyme was considered to consist of a glutamic acid residue along with two water molecules. The relevant reaction mechanism involving different barrier energies was studied theoretically. Molecular geometries of the various molecules and complexes involved in the reaction, e.g., the reactant, intermediate, and product complexes as well as transition states, were optimized employing density functional theory at the B3LYP/6-31G(d,p) level in the gas phase. It was followed by single-point energy calculations at the B3LYP/AUG-cc-pVDZ, BHandHLYP/AUG-cc-pVDZ, and MP2/AUG-cc-pVDZ levels in the gas phase. Single-point energy calculations were also carried out at the B3LYP/AUG-cc-pVDZ and BHandHLYP/AUG-cc-pVDZ levels in aqueous media as well as in the solvents chlorobenzene and dichloroethane. For the solvation calculations, the integral equation formalism of the polarizable continuum model (IEF-PCM) was employed. It is found that glutamic acid along with two water molecules would effectively cleave the glycosidic bond of adenosine by a new two-step reaction mechanism proposed here which is different from the three-step mechanism proposed by other authors earlier regarding the working mechanism of MutY.