Therapeutics

Current clinical practice is based upon 'our stubborn quest for diagnostic certainty' which in turn is considered as one of the major reasons for ever-increasing health costs. We linked a treatment-threshold concept with classic information theory to show that measurable clinical variables, such as benefit and risk of available treatments, can be used to calculate the acceptable levels of diagnostic uncertainties associated with a particular clinical situation. Our analysis shows that practising physicians should aim for diagnostic certainty only when the benefit of treatment is equal to its associated risk. In all other cases, decisions about treatment do not have to rely on maximum diagnostic certainty. Determination of acceptable levels of diagnostic uncertainty according to the concepts outlined here should lead to improvement of clinical practice and decrease healthcare costs.

D-002 is a mixture of higher aliphatic alcohols isolated from beeswax that inhibits rat microsomal lipid peroxidation in vitro and in vivo. This study was undertaken to investigate whether D-002 also inhibits lipid peroxidation in older subjects. The free radical theory of aging suggests that progressive defects in the protection against free radical reactions leads to progressive deleterious effects of free radicals on cells and tissues. This free radical damage has been implicated in several pathophysiological processes associated with the chronic degenerative diseases that occur with aging. Forty-eight older subjects were randomly assigned, in a double-blind fashion, to receive placebo or D-002 tablets (50 mg/day) once daily. At baseline, D-002 and placebo groups were well matched regarding several variables. D-002 significantly reduced the susceptibility of nonfractionated plasma samples to copper-mediated lipid peroxidation. It also significantly increased the length of the lag phase (P , .001) and the total antiioxidant status (P , .05) compared with baseline and placebo. In addition, D-002 significantly decreased malondialdehyde levels (expressed in terms of thiobarbituric acid reactive substances (TBARS, P , .001) compared with baseline, but not with placebo. No significant changes on lipid peroxidation parameters were observed in the placebo group. We conclude that D-002 treatment may be useful to prevent or manage certain pathophysiological conditions in the elderly.

The pursuit of nutraceuticals to improve the quality of life for patients with neurodegenerative conditions is a dynamic field within neuropharmacology. Unfortunately, many nutraceuticals that show promise in preclinical studies fail to demonstrate significant clinical benefits in human trials, leading to their exclusion as therapeutic options. This discrepancy may stem from the categorical interpretation of preclinical and clinical results. Basic researchers often assume that non-human experimental animals exhibit less phenotypic variability than humans. This belief overlooks interindividual phenotype variation, thereby leading to categorical conclusions being drawn from experiments. Consequently, when human clinical trials are conducted, the researchers expect similarly conclusive results. If these results are not achieved, the nutraceutical is deemed ineffective for clinical use, even if numerous individuals might benefit. In our study, we evaluated whether analyzing
phenotype variability and similarity through non-categorical methods could help identify rotenone (ROT)-treated rats that might benefit from consuming nano-emulsified punicic acid (Nano-PSO), even if the prevention of “parkinsonism” or the restoration of neurometabolic function is inconsistent across individuals. Our findings supported this hypothesis. The benefits of Nano-PSO were not categorical; however, analyzing phenotype variance allowed us to identify ROT rats with varying
degrees of benefit from Nano-PSO consumption. Hence, the translational potential of results from basic science studies testing nutraceuticals as pharmaceutical products against neurodegeneration may improve if researchers also interpret their results using non-categorical methods of data analysis for population screening, even if the overall therapeutic outcomes for the entire population show internal inconsistencies.

Gold nanoparticles are widely employed in drug delivery, diagnosis and therapy of illnesses. Carbon nanotubes, peptide nanostructures, liposomes and polymers are a few of the functionalized nanomaterials available. Recent improvements in synthetic techniques have enabled accurate control of the size, shape and surface chemistry of GNPs, rendering them a viable and safer option in cancer treatment and drug delivery. In light of the rapid progress in nanotechnology, numerous studies have been conducted on GNPs, and more are to follow. Hence, the intention of this review is to analyze the potential of the novel nanomaterials based on GNPs in biomedical applications like drug delivery and cancer therapy, in addition to their viability, characteristics and cytotoxicity.

Context: Therapeutic drug monitoring (TDM) allows personalizing the dose of valproic acid in patients with epilepsy to optimize drug therapy, minimize adverse effects and detect interactions. Aims: To determine valproic acid concentrations in serum samples from people with epilepsy and to analyze its clinical implications. Methods: Cloned donor enzyme immunoassay; descriptive, cross-sectional, non-randomized, convenience recruitment study of 57 voluntary patients with epilepsy (n = 39 male, 68.42%; n = 18 female, 31.58%) aged between 19 and 62 years. After three months of treatment with valproic acid, a single blood sample was collected from each volunteer at a minimal concentration. Results: Serum drug concentrations 51.30-100.10 mg/L (SD 5.94) and level/dose 2.17-5.31 (SD 1.14) were observed. Association was shown between the dose ratio/dose of valproic acid (R2 = 0.8693; p<0.05) and the Mann-Whitney U test (p<0.05). Valproic acid monotherapy and association with carbamazepi...

La terapia contra el cáncer ha experimentado importantes avances que se han producido con una celeridad inusitada. En los inicios del siglo XXI, el arsenal terapéutico disponible para el paciente enfermo de cáncer ha crecido considerablemente comparado con el de hace tan solo veinte años. De hecho, ha pasado poco más de un siglo desde que, en 1901, el premio Nobel alemán Paul Ehrlich enunciase la conocida teoría de la «bala mágica», en la que se refería a las cualidades que debería poseer un buen fármaco antibiótico. Según esta teoría, un tratamiento de quimioterapia sería tanto más efi caz cuanto más se pareciese a una bala mágica capaz de identifi car y atacar únicamente el objetivo para el cual se administraba, dejando indemne el resto de tejidos sanos del organismo, lo que reduciría su toxicidad sin comprometer su efi cacia.

The aim of this study was to demonstrate the role of nutrition factors on a 28-d mortality outcome and sepsis occurrence in surgical intensive care unit. Methods: The data was extracted from a THAI-SICU study that prospectively recruited participants (18 y of age) from three Thai surgical intensive care units (SICUs) of university-based hospitals. The demographic data and nutrition factors at SICU admission included energy delivery deficit, weight loss severity, route of energy delivery, and albumin and nutrition risk screening (NRS-2002). The outcomes were 28-d hospital mortality and sepsis occurrence. The statistical analysis was performed using Cox regression. Results: The study included 1503 eligible patients with a predominantly male population. The 28-d mortality and sepsis occurrences were 211 (14%) and 452 (30%), respectively. Regarding multivariable analysis, for mortality outcome, the protective effects of nutrition variables were higher body mass index (BMI; hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.68À0.99; P = 0.039), tube feeding (HR, 0.46; 95% CI, 0.26À0.83; P = 0.010), and a combination of enteral and parenteral nutrition (HR, 0.24; 95% CI, 0.07À0.77; P = 0.016). The harmful effects were severe weight loss (HR, 1.61; 95% CI, 1.16À2.22; P = 0.004), albumin 2.5 (HR, 2.15; 95% CI, 1.20À3.84; P = 0.010), and at risk according to NRS-2002 (HR, 1.34; 95% CI, 0.98À1.85; P = 0.071). For the sepsis occurrence, only tube feeding had a protective effect (HR, 0.58; 95% CI, 0.39À0.88; P = 0.009), and only albumin 2.5 had a harmful effect (HR, 1.71; 95% CI, 1.20À2.45; P = 0.003). Conclusion: Nutrition factors affecting the mortality or sepsis occurrence in this study were BMI, enteral feeding or combination with parenteral nutrition, severe weight loss, preadmission albumin 2.5, and at risk according to NRS-2002.

Viral infections are the cause of serious infirmities in humans and kill millions of people every year. Management of viral diseases is one of the challenges faced by the whole world which needs improvement in prevention and treatment options. Complete understanding of the consequences of viral proteins interaction network on host physiology is essential. Towards this goal, deciphering viral protein-protein interactions is one of the perspective which can help in our understanding about the basis of viral pathogenesis and the development of new antivirals. Indeed, viral infection network based on viral-viral proteins will provide an elusive and investigative framework to articulate rationalize drug discovery based on proteomics scale of viruses. In this study, proteomics a collection of viral-viral protein interactions reporting different studies of Hepatitis C virus, Influenza A virus, Dengue virus and SARS Coronavirus. Our effort of protein-interactions was focused on different st...

Recently, modified directly observed therapy (MDOT) has emerged as a promising intervention to address nonadherence for hard-to-reach populations infected with HIV. To date, there are no existing data on MDOT focusing exclusively on African Americans. The present study sought to determine the feasibility of MDOT among 31 HIV-seropositive African American substance users in the South. An outreach worker observed the participants' medication intake 5 days per week (once per day) for a period of 3 months (intensive phase). This phase was followed by a transition phase of 3 months during which the frequency of MDOT was gradually tapered from 5 days to once weekly. Assessments to gather demographic information, HIV risk behaviors, substance use, depression, and medication adherence were conducted at baseline, 3 months, and 6 months. Results indicated that more participants adhered to their medication regimen and had viral loads of less than 400 copies per milliliter at 3 and 6 months compared to baseline. Participants reported significantly less depressive symptoms at the 6-month assessment compared to baseline and 3 months. With regard to acceptability, 95% of participants indicated they liked having the outreach visits, 100% reported MDOT helped them take their medications, and only 5% felt MDOT was a violation of privacy. These results suggest MDOT is feasible among African American substance users in the South and a larger controlled study of MDOT with this population is warranted.

Purpose: When patients show progression after conventional fractionated radiation for spine metastasis, further radiation and surgery may not be options. Stereotactic body radiotherapy (SBRT) has been successfully used in treatment of the spine and may be applicable in these cases. We report the use of SBRT for 60 consecutive patients (81 lesions) who had radiological progressive spine metastasis with epidural involvement after previous radiation for spine metastasis. Methods and Materials: SBRT was used with fiducial and vertebral anatomy-based targeting. The radiation dose was prescribed based on the extent of spinal canal involvement; the dose was 8 Gy  3 = 24 Gy when the tumor did not touch the spinal cord and 5 to 6 Gy x 5 = 25 to 30 Gy when the tumor abutted the cord. The cord surface received up to the prescription dose with no hot spots in the cord. Results: The median overall survival was 11 months, and the median progression-free survival was 9 months. Overall, 93% of patients had stable or improved disease while 7% of patients showed disease progression; 65% of patients had pain relief. There was no significant toxicity other than fatigue. Conclusions: SBRT is feasible and appears to be an effective treatment modality for reirradiation after conventional palliative radiation fails for spine metastasis patients.

Introduction: It has been verified a growing insatisfaction regarding conventional medicine (CM), this determines a greater use of some kind of alternative and / or complementary (ACM) methods of by some patients. The objective of this work has been to evaluate the impact and integration between ACM and CM studying medical Tabla 3: Publicaciones periódicas MAC indexadas por MEDLINE

Recent emergence of antimicrobial resistance of Neisseria gonorrhoeae worldwide has resulted in limited therapeutic choices for treatment of infections caused by this organism. We performed global transcriptomic analysis of N. gonorrhoeae in subjects with gonorrhea who attended a Nanjing, China, sexually transmitted infection (STI) clinic, where antimicrobial resistance of N. gonorrhoeae is high and increasing. We found that N. gonorrhoeae transcriptional responses to infection differed in genital specimens taken from men and women, particularly antibiotic resistance gene expression, which was increased in men. These sex-specific findings may provide a new approach to guide therapeutic interventions and preventive measures that are also sex specific while providing additional insight to address antimicrobial resistance of N. gonorrhoeae .

Like humans, animals use plants and other materials as medication against parasites.
Recent decades have shown that the study of insects can greatly advance
our understanding of medication behaviors. The ease of rearing insects under laboratory
conditions has enabled controlled experiments to test critical hypotheses,
while their spectrum of reproductive strategies and living arrangements – ranging
from solitary to eusocial communities – has revealed that medication behaviors
can evolve to maximize inclusive fitness through both direct and indirect fitness
benefits. Studying insects has also demonstrated in some cases that medication
can act through modulation of the host’s innate immune system and microbiome.
We highlight outstanding questions, focusing on costs and benefits in the context
of inclusive host fitness.

This investigation delineates a thorough methodology for the formulation of a parametric model about a palm fruit digester apparatus, employing the tenets of dimensional analysis. The palm fruit digester, an essential component within the palm oil manufacturing processes, encompasses intricate interactions among various parameters that influence its operational efficiency and throughput. A palm fruit digester was conceptualised and fabricated locally to attain a more profound comprehension of these interrelationships. The performance parameter was scrutinized as data were amassed during the apparatus's testing, and the Buckingham Pi theorem was utilized to derive dimensionless Pi terms from pertinent parameters. The results of our analysis indicated that R 2 values of 0.9956 for both throughput and machine efficiency were achieved. Consequently, the model can forecast the efficiency and throughput of the palm fruit digester. This helps researchers understand that the palm fruit digester's operational efficien

Mitochondrial dysfunction is implicated in nine of the ten leading causes of death in the US, yet there are no FDA-approved therapeutics to treat it. Synthetic mitochondria-targeted peptides (MTPs), including the lead compound SS-31, offer promise, as they have been shown to restore healthy mitochondrial function and treat a variety of common diseases. At the cellular level, research has shown that MTPs accumulate strongly at the inner mitochondrial membrane (IMM), slow energy sinks (e.g., proton leaks), and improve ATP production. Modulation of electrostatic fields around the IMM has been implicated as a key aspect in the mechanism of action (MoA) of these peptides; however, molecular and mechanistic details have remained elusive. In this study, we employed all-atom molecular dynamics simulations (MD) to investigate the interactions of four MTPs with lipid bilayers and calculate their effect on structural and electrostatic properties. In agreement with previous experimental findings, we observed the modulation of the membrane surface and dipole potentials by MTPs. The simulations reveal that the MTPs achieve a reduction in the dipole potential by acting to disorder both lipid head groups and water layers proximal to the bilayer surface. We also find that MTPs decrease the bilayer thickness and increase the membrane's capacitance. These changes suggest that MTPs may enhance how much potential energy can be stored across the IMM at a given transmembrane potential difference. The MTPs also displace cations away from the bilayer surface, modulating the surface potential and offering an alternative mechanism for how these MTPs reduce mitochondrial energy sinks like proton leaks and mitigate Ca2+ accumulation stress. In conclusion, this study highlights the therapeutic potential of MTPs and underlines how interactions of MTPs with lipid bilayers serve as a fundamental component of their MoA.

Resumen Context: Peripheral neuropathy is a common neurologic disease that accounts for a lot of physician visits. Aims: To evaluate the efficacy of a Ghanaian herbal product prepared from the stem bark of Antiaris toxicaria subsp. africana (known as Mist Antiaris) in the management of neurological disorders in patients clinically diagnosed with peripheral neuropathy. Methods: A prospective open label non-comparative study was undertaken involving 24 patients seen at the clinic of the Centre for Plant Medicine Research, Mampong-Akuapem. A modified Neuropathic Symptoms Score (NSS) and a visual analogue scale (VAS) using the standardized Wong-Baker faces rating scale (WBFRS) were used to grade each participant on the first day of visit. The VAS was subsequently used to grade and monitor improvements in the symptom characteristics of peripheral neuropathy at the fourth week and on the eighth week. Results: Mean age of participants involved in the study was 46.08 ± 2.77 years with the m...

The relationship between nutrition, antioxidants, and disease prevention has been extensively studied. Lycopene, a
carotenoid with potent antioxidant properties, and melatonin, a key regulator of circadian rhythms and oxidative stress,
have shown promise in managing lipid metabolism and oxidative stress-related diseases. This study evaluates the efficacy of
melatonin and lycopene rectal suppositories in improving lipid profiles and reducing oxidative stress in statin-resistant patients
with ischemic heart disease, cancer, and neurodegenerative disorders. The study involved 98 participants, divided into
a placebo group (n=43), a melatonin group (n=27), and a lycopene group (n=28), receiving 400 mg melatonin and 400 mg
lycopene suppositories daily for 12 weeks. Significant reductions in oxidative stress markers, such as malondialdehyde (MDA),
and increases in total antioxidant capacity (TAC) were observed in both the melatonin and lycopene groups. Furthermore,
inflammatory biomarkers, including C-reactive protein (CRP) and interleukin-6 (IL-6), were markedly reduced in these
groups. These findings suggest that both melatonin and lycopene effectively improve lipid profiles and reduce oxidative
stress and inflammation, offering promising therapeutic approaches for statin-resistant patients with chronic oxidative
stress-related conditions.

MicroRNA(miRNA)s have been identified as an emerging class for therapeutic interventions mainly due to their extracellularly stable
presence in humans and animals and their potential for horizontal transmission and action. However, treating Type 2 diabetes mellitus using
this technology has yet been in a nascent state. MiRNAs play a significant role in the pathogenesis of Type 2 diabetes mellitus establishing the
potential for utilizing miRNA-based therapeutic interventions to treat the disease. Recently, the administration of miRNA mimics or antimiRs invivo
has resulted in positive modulation of glucose and lipid metabolism. Further, several cell culture-based interventions have suggested beta
cell regeneration potential in miRNAs. Nevertheless, few such miRNA-based therapeutic approaches have reached the clinical phase. Therefore,
future research contributions would identify the possibility of miRNA therapeutics for tackling T2DM. This article briefly reported recent developments
on miRNA-based therapeutics for treating Type 2 Diabetes mellitus, associated implications, gaps, and recommendations for future studies.

This thesis seeks to explore what a non-representational idea in colour (as apprehended via the contemporary visual arts) might look like. Taking the thought of Gilles Deleuze as its starting point, who in Francis Bacon: The Logic of Sensation puts forward a conception of colour that sees it less according to its pre-assigned meaning or intention and more according to the intensive materiality of its sensation, which is both subject and object, the thesis advances a non-representational geographical perspective. Despite witnessing, within recent years, a proliferation of conceptual and methodological approaches (many of which are post-phenomenological) through which geographers have attempted to creatively rethink their relationship with the visual arts, my contention is that these approaches fall short. Specifically, as per post-phenomenological ones, this is because when focusing on the visual art object, they merely reinstate those very same subject-led, phenomenological coordinates that they wish to escape from. Instead, by attending to those pre-individual and impersonal, forces and processes that implicate us in the world, a Deleuzian-inspired, non-representational alternative asserts the primacy of the visceral, artistic experience that sensation-in-itself engenders, beyond any prior subjectivising and representational prescriptions. Thus, in pushing for such alternative, the thesis enacts a non-representational experiment. On the one hand, anchoring its argument conceptually within Deleuze’s writings on art, and on the other, situating itself methodologically within experimental forms of thinking method, the thesis examines three different problematics of colour’s sensation, including: 1) colour’s relationship to the production of thought, 2) the unconscious dimensions of our experience of colour, 3) the processual model of the self that it speaks to. In doing so, the thesis stages a conversation between Deleuze and three other thinkers relevant to the problematic in question, namely: Michel Foucault, Jacques Lacan and Jacques Rancière, which it compliments with an analysis of my empirical engagement with contemporary visual artists Katharina Grosse, Jan Albers and Zinnia Clavo. It is by attending to these problematics of sensation that I argue colour can bring forth radical transformations in our ways of thinking, feeling and becoming-with, whose implications though yet- unknown, are far-reaching for geography and beyond.

Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed ge...

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau‐related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first‐ever Tau2020 Global Conference in Washington, DC, co‐organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research‐advancing tools and insight...

A key predictor for the success of gene-modified T cell therapies for cancer is the persistence of transferred cells in the patient. The propensity of less differentiated memory T cells to expand and survive efficiently has therefore made them attractive candidates for clinical application. We hypothesized that re-directing T cells to specialized niches in the bone marrow (BM) that support memory differentiation would confer increased therapeutic efficacy. We show that overexpression of chemokine receptor CXCR4 in CD8+ T cells (TCXCR4) enhanced their migration towards vascular-associated CXCL12+ cells in the BM and increased their local engraftment. Increased access of TCXCR4 to the BM microenvironment induced IL-15-dependent homeostatic expansion and promoted the differentiation of memory precursor-like cells with low expression of programmed death-1, resistance to apoptosis and a heightened capacity to generate poly-functional cytokine-producing effector cells. Following transfer ...

Oral squamous cell carcinoma (OSCC) is a disease of significant concern with higher mortality rates. Conventional treatment approaches have several drawbacks, leading to the opening of new research avenues in the field of nanoparticle-based cancer therapeutics. The study aimed at the synthesis of gold nanoparticles (Pm-AuNPs) from the aqueous bark extract of Pterocarpus marsupium, followed by its characterization and in vitro anticancer evaluation against OSCC. The synthesized Pm-AuNPs were characterized using UV–visible spectroscopy, particle size analyser, zeta potential, FTIR and SEM techniques. The anticancer potential of the Pm-AuNPs was evaluated against OSCC cell lines (SCC29b, SSC154 and OECM-1) through in vitro assays. The IC50 value was found to be 25 ± 1.2, 45 ± 1.5 and 75 ± 2.1 μg/mL for the three OSCC cell lines, elucidating Pm-AuNPs cytotoxic effects and mechanism of action. Intracellular ROS and SOX detection, mitochondrial transmembrane potential analysis and
apoptosis detection were used to confirm the activity of Pm-AuNPs against OSCC. Acute toxicity studies on Wistar rats confirmed the non-toxic nature of the Pm-AuNPs at a higher dose concentration up to
2000 mg/kg body weight. The findings underscore Pm-AuNPs as promising candidates for future anticancer therapeutics, providing insights into their mechanism of action and therapeutic efficacy against OSCC.

This purpose of this paper is to review and evaluate published literature on the biology and chemistry of lichens and their ecological, ethnopharmacological, pharmaceutical and therapeutic potential. A systematic method was used to gather literature on “the biology and chemistry of lichens and their ecological, ethnopharmacological, pharmaceutical and therapeutic potential.” A total of fifty-five research papers published between the years 1963 to 2022 were selected and utilized for this review. Tables were used to present the results. The subtopics were then chosen using a subjective method: lichens and their benefits/ importance. In this paper, eight (8) ecological functions and fourteen (14) pharmaceutical properties and therapeutic potentials were evaluated and presented. Lichen biology and chemistry and their roles in ethnopharmacological are also discussed. Additionally, lichens as pioneer and keystone species and their role as bioindicators to assess ecosystem health, sustain...

Severe epilepsy with multiple independent spike foci is an electroclinical entity with the following characteristics: (1) EEG showing multiple independent spike foci (three or more foci in both hemisphere, i.e., at least one in each hemisphere) and diffuse slowing of the background activity, (2) very frequent multiple types of seizures but mainly generalized minor seizures, (3) frequent association with mental retardation and neurologic abnormalities, (4) underlying causes of various nonspecific prenatal, perinatal, and postnatal cerebral conditions, and (5) poor prognoses for seizures and psychomotor development. It represents a diffuse encephalopathy with mutual transition between other age-dependent epileptic encephalopathies. This electroclinical condition may be appropriately named Markand-Blume-Ohtahara syndrome, after Markand and Blume, who initially described in detail the EEG pattern of multifocal spike discharges with its major clinical correlates, and Ohtahara, who extensively studied the group of patients with both clinical and EEG characteristics and proposed the concept of severe epilepsy with multiple independent spike foci, classifying it as one type of generalized epilepsy.

Prime editors (PEs) mediate genome modification without utilizing double-stranded DNA breaks or exogenous donor DNA as a template. PEs facilitate nucleotide substitutions or local insertions or deletions within the genome based on the template sequence encoded within the prime editing guide RNA (pegRNA). However, the efficacy of prime editing in adult mice has not been established. Here we report an NLS-optimized SpCas9-based prime editor that improves genome editing efficiency in both fluorescent reporter cells and at endogenous loci in cultured cell lines. Using this genome modification system, we could also seed tumor formation through somatic cell editing in the adult mouse. Finally, we successfully utilize dual adeno-associated virus (AAVs) for the delivery of a split-intein prime editor and demonstrate that this system enables the correction of a pathogenic mutation in the mouse liver. Our findings further establish the broad potential of this genome editing technology for the...

Adeno-associated virus (AAV) vectors are important delivery platforms for therapeutic genome editing but are severely constrained by cargo limits, especially for large effectors like Cas9s. Simultaneous delivery of multiple vectors can limit dose and efficacy and increase safety risks. The use of compact effectors has enabled single-AAV delivery of Cas9s with 1-3 guides for edits that use end-joining repair pathways, but many precise edits that correct disease-causing mutations in vivo require homology-directed repair (HDR) templates. Here, we describe single-vector, ∼4.8-kb AAV platforms that express Nme2Cas9 and either two sgRNAs to produce segmental deletions, or a single sgRNA with an HDR template. We also examine the utility of Nme2Cas9 target sites in the vector for self-inactivation. We demonstrate that these platforms can effectively treat two disease models [type I hereditary tyrosinemia (HT-I) and mucopolysaccharidosis type I (MPS-I)] in mice. These results will enable sin...

RNA-based drugs depend on chemical modifications to increase potency and to decrease immunogenicity in vivo. Chemical modification will likely improve the guide RNAs involved in CRISPR-Cas9-based therapeutics as well. Cas9 orthologs are RNA-guided microbial effectors that cleave DNA. Here, we explore chemical modifications at all positions of the crRNA guide and tracrRNA cofactor. We identify several heavily modified versions of crRNA and tracrRNA that are more potent than their unmodified counterparts. In addition, we describe fully chemically modified crRNAs and tracrRNAs (containing no 2′-OH groups) that are functional in human cells. These designs will contribute to Cas9-based therapeutics since heavily modified RNAs tend to be more stable in vivo (thus increasing potency). We anticipate that our designs will improve the use of Cas9 via RNP and mRNA delivery for in vivo and ex vivo purposes.

Background: Medicinal plants have been employed to prevent and ameliorate many disorders and health conditions including toxicities and failing health conditions. This study aims to investigate the Modulatory Effects of Aqueous Leaf Extract of Ocimum basilicum on the Lipid Profiles and Body Weight of Male Wistar Rats, Exposed to Sodium Arsenite. Methods: The study was carried out using 48 male Wistar rats weighing 160-250g, divided into eight (8) groups, each containing 6 rats. Group 1 served as negative control and received only distilled water. Group 2 was the positive control and received 6mg/kg of body weight of Sodium arsenide only. Groups 3, 4 and 5 received the aqueous leaf extract of Ocimum basilicum (ALEOB) in concentrations of 400mg/kg, 600mg/kg and 800mg/kg of body weight respectively while groups 6, 7 and 8 received 6mg/kg of body weight of Sodium arsenide and ALEOB in concentrations of 400mg/kg, 600mg/kg and 800mg/kg of body weight respectively for 6 weeks. Results: At the end of the experimentation, the animals were weighed and sacrificed and blood samples were collected to determine the biochemical parameters. The ALEOB was found to cause a significant decrease in the concentration of Total cholesterol (TC), Triglycerides (TG) and very low-density lipoprotein (VLDL), while causing a significant increase in High density lipoprotein cholesterol. It was also found to ameliorate the adverse toxicity caused by Sodium Arsenite on TC, TG, HDL-C and VLDL. It also caused an insignificant increase in body weight. Conclusion: The ALEOB was found to have an ameliorative effect on Sodium Arsenide induced toxicity on the lipid profile and body weight of the experimental rats.

Objective.We examined the longterm effectiveness of corticosteroid or hyaluronic acid injections in relieving symptoms among persons with knee osteoarthritis (OA).Methods.Using Osteoarthritis Initiative data, a new-user design was applied to identify participants initiating corticosteroid or hyaluronic acid injections (n = 412). Knee symptoms (pain, stiffness, function) were measured using The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). We used marginal structural models adjusting for time-varying confounders to estimate the effect on symptoms of newly initiated injection use compared to nonusers over 2 years of followup.Results.Among 412 participants initiating injections, 77.2% used corticosteroid injections and 22.8% used hyaluronic acid injections. About 18.9% had additional injection use after initiation, but switching between injection types was common. Compared to nonusers, on average, participants initiating a corticosteroid injection experienced ...

Cancer presents a formidable globalized public health challenge with extensive socioeconomic ramifications. This paper investigates the socioeconomic optimality of mRNA-based oncological platforms concerning cancer amelioration. Quantitative analysis discerned the socioeconomic effectiveness of mRNA candidates. Clinical immunogenicity data demonstrated efficacy variability amongst platforms. Cost-benefit assessment discerned CV9202's superior cost-effectiveness, representing socioeconomic optimality. These methodological developments provide a comparative basis to contextualize implementation gaps and accessibility disparities. Socioeconomic cognizance permits tailored therapeutic accommodation for economic constraints, improving patient outcomes through optimized distribution. Further generalization necessitates extensive efficacy data over prolonged timeframes encompassing long-term immunological durability. Societal stigmatization presents additional complications. This research delineates an analytical paradigm to discern optimal therapeutic allocation given socioeconomic circumstances. Improved patient-provider relations may arise from responsive distribution models sensitive to socioeconomic factors. Optimal distribution has advantageous implications for stakeholders. Future research could assess preventative applications, combination therapies, infrastructural variables, and extensive candidates. In conclusion, this methodology demonstrates means of optimizing distribution congruent with socioeconomic factors to improve accessibility and cancer outcomes through cost-effective therapeutic platforms like mRNA vaccination.

Objective: To determine the complexity of the therapeutic regimen for polypathological patients hospitalised in internal medicine departments. Methods: A multicentre observational study included polypathological patients hospitalised in internal medicine departments. Patients who were readmitted or died were excluded. Data were collected on age, sex, residence, disease, Charlson, Barthel and Lawton-Brody indices, Pfeiffer questionnaire, Gijón scale, number of hospitalisations in the previous year, delirium, need for and availability of caregivers and the PROFUND index score. We calculated the therapeutic complexity with the Medication Regimen Complexity Index (MRCI). We considered a therapeutic regimen complex when the MRCI score was in the fourth quartile. To determine the factors associated with complexity, we constructed a logistic regression model. Results: We included 233 polypathological patients, 52.9% of whom were women, with a mean age of 79.8 (SD: 8.6) years. The mean number of drugs consumed was 8.4 (SD: 3.3). The mean MRCI score was 30 (SD: 15.2). The MRCI score by quartiles was 0-20, 20.5-30, 30.5-42, 42.5-80. The respiratory diseases (OR: 4.185; 95% CI: 2.015-8.693; p < .001) were independently associated with increased therapeutic complexity, and the neurological diseases with permanent mental deficiency (OR: 0.265; 95% CI: 0.085-0.828; p = .022) were associated with less complexity. Conclusions: Patients with comorbidities are polymedicated and have complex therapeutic drug regimens. Respiratory diseases determine greater therapeutic complexity, while cognitive impairment determines a lower therapeutic complexity.

Internet-based interventions for depression may be a valuable resource to reduce the treatment gap for those living in developing countries. However, evidence comes mainly from developed countries. This systematic review summarized the evidence on preventive or therapeutic Internet-based interventions for depression for people who reside in developing countries. CINAHL, EMBASE, PubMed, SciELO Citation Indexes, the Journal of Medical Internet Research, and the Telemedicine and e-Health journal, were searched up to June 2017, to identify feasibility or effectiveness studies of preventive or therapeutic Internet-based interventions for depression, with or without human support. Studies included subjects residing in developing countries, and were published in English or Spanish. Study protocols were included. Risk of bias and/or quality of the reporting of the studies included was assessed. Five feasibility studies, aimed at the prevention of depression, and a study protocol were includ...

Terapia tópica para heridas crónicas: contribuciones de un módulo de enseñanza a distancia para el conocimiento de estudiantes de enfermería Terapia tópica para feridas crônicas: contribuições de um módulo de ensino à distância para o conhecimento de estudantes de enfermagem Topical therapy for chronic wounds: contributions of a distance learning unit to the knowledge of nursing students

Context: Diabetes mellitus is considered one of the scourges of the third millennium in the world for several years. Aims: To evaluate, identify and preserve the experiences gained over the centuries. It is about therapeutic use of medicinal plants exploited for the treatment of diabetes, and to clarify its toxicities, in order to sensitize the population of the High Atlas Central (HAC) of Morocco not only on the risk but also the benefit of the use of phytotherapy. Methods: The surveys ethnopharmacological were conducted 834 the interviewees, using semi-structured survey, by application of quantitative indices such as Consensus index (CI %), Use value (UVi), family UV (FUV), relative frequency of citation (RFC), plant part value (PPV), and informant consensus factor (ICF) to assess the exact value of medicinal plants (MP). Results: We found that 144 medicinal plants in 121 genera and 52 plant families were traditionally used to treat diabetes, of which seven species were endemic to...

Backgrounds Treatment of di cult-to-treat rheumatoid arthritis (D2T-RA) is one of the greatest unmet needs in rheumatology. This study aims to nd out preferable treatment option for a group of D2T-RA patient who are refractory to multiple biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Methods: Data were obtained from patients enrolled in the FIRST registry who started either TNF-inhibitor (TNFi), interleukin-6 receptor inhibitor, cytotoxic T-lymphocyte-associated antigen-4 immunoglobulin, or Janus-kinase inhibitor (JAKi) in the period of August 2013-December 2020. Those who failed to ≥2 and ≥3 b/tsDMARDs were categorised as D2T-RA and very D2T-RA (vD2T-RA), respectively. Change in clinical disease activity index (CDAI) and health assessment questionnaire disability index were compered among groups using propensity-based inverse-probability treatment weighted (IPTW) method. Results: Of 2,128cases included, 353 were categorised as D2T-RA. Among the D2T-RA, 106 were identi ed as vD2T-RA. JAKi showed signi cant improvement in CDAI in the patients with D2T-RA and vD2T-RA, compared to IPTW-adjusted patients treated with the other 3 regimens. Latent class analysis of the trajectories of treatment response revealed that the proportion of a group of patients who showed poor response was lower among JAKi subgroup than those with other subgroups. This superiority of JAKi was more apparent among in methotrexate-and glucocorticoid-free individuals. Hazard ratio of severe adverse events were comparable among the four treatment subgroups in both the D2T-RA and b/tsDMARD-naïve groups. Conclusions: This study compared responsiveness to different classes of b/tsDMARDs among D2T-RA and vD2T-RA patients who were refractory to multiple b/tsDMARDs. The results suggest JAKi is a preferable treatment choice for this type of D2T-RA.

Honey, a natural food product available abundantly all over the world, has a wide range of pharmacological activities. The search for anti-proliferative agents that reduce cervical cancer is a task of great importance. The objective of this study was to observe the cytotoxic activity of honey from Litchi chinensis and purified honey protein (PHP) on HeLa cells. Initially, protein was isolated from honey using ethanol (60%, v/v) followed by purification using single-step Q-sepharose anion exchange chromatography. Honey (1-10%, v/v) and PHP (0-60 mg/mL) exposure significantly reduced the cancer cell viability, indicating apoptosis in a dose dependent manner. The MTT assay showed the IC 50 of honey and PHP to be 3.5 mg/mL and 4.13 ng/mL, respectively. The MMP (Δψm) and TUNEL assay showed more apoptosis under PHP intervention than in honey-treated cells. This in vitro evaluation of the cytotoxicity of honey and PHP against cancer cells provides scientific rationale for an effective anti-proliferative agent and endorses lychee honey and PHP as herbal medicines.

Honey, often referred to as 'liquid gold,' a time-honoured natural food with a rich history, has now ascended to the status of a superfood in today's global market, thanks to its myriad nutraceutical properties. Despite its esteemed position, the global honey industry confronts a formidable challenge posed by the surge in adulteration driven by economic motives. This predicament complicates the authentication process, as sophisticated fraudulent methods come into play. The repercussions of such deceptive practices extend across the honey market, affecting its pricing, quality, and nutritional value, leading to an erosion of consumer trust and potential health risks. Notably, the analytical techniques employed for verifying honey authenticity often yield intricate, datarich certificates of analysis that may be opaque to stakeholders lacking specialized knowledge. Recent initiatives have emerged to counteract this issue, incorporating modern rapid and sensitive techniques, establishing auditing, implementing certification processes, and garnering the involvement of global regulatory bodies. Collaborative actions are essential to preserve the integrity of honey, protect consumer interests, and foster a resilient and transparent honey industry worldwide. Consequently, this article underscores the comprehensive measures and technological advancements in detection of adulteration, and the layers of authentication processes to ensure ethical practices within the honey industry.

Background: Efavirenz is a widely used antiretroviral medication for managing HIV infection, known for its role as a Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI). By targeting and inhibiting the reverse transcriptase enzyme, it effectively hinders the replication of HIV, making it a crucial component of combination therapy for the virus. Materials and Methods: The purpose of this research is to develop an accurate, selective and sensitive HPLC method for the regular quantification of efavirenz in laboratory settings. In this research, tert butyl methyl ether is used as a diluent and methanol is used as a mobile phase while the assay test involved analyzing the Active Pharmaceutical Ingredient (API) and market formulations of efavirenz. EFZ was extracted from market formulations, diluted in tert-butyl methyl ether and analyzed using the developed HPLC method. The results indicated that the method accurately quantified EFZ in both the API and market formulations. Results: The Separation process utilized using a (X-Bridge® C8 5 µm 4.6×250 mm), with mobile phase consisting of Methanol. The Flow rate was maintained at 0.8 mL/min and EFZ detection occurred at a wavelength of 252 nm, using a manual injection volume of 10 µL and retention time was found to be 3.7 min. Linearity was examined and proven at different concentrations in the range of EFZ (2-64 µg/mL), respectively and correlation coefficient R 2 was found to be 0.9998. The method achieved very good validation parameters LOQ about 0.03 mg/mL and LOD about 0.01 mg/mL for EFZ. The high value of recoveries obtained for EFZ indicates that the proposed method was found to be accurate. Conclusion: The developed HPLC method for quantifying efavirenz in pharmaceutical formulations is straightforward, accurate and reproducible. It satisfies all validation criteria, making it suitable for routine quality control and ensuring the consistency and safety of efavirenz products.

Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of noninvasive tests. Here, we propose monoamine-derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine-derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF-D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L-histidine analog, or a low L-histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.

Background: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. Methods: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor β1 (TGF−β). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and α-smooth muscle actin [α-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF−β-containing media was performed. Results: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF−β. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. Conclusions: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach.