Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention.

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based DHODH inhibitors through a scaffold hop from a pyrrole-based series.

A Prospective Longitudinal Study to Demonstrate the Utility of the Palliative Prognostic Index in Forecasting the Short-term Survival of Patients with Advanced Cancer in India.

Objectives: In this study, our primary objectives were to validate the palliative prognostic index (PPI) tool in the context of palliative care for patients with advanced cancer. Specifically, we aimed to assess the accuracy of the PPI in predicting actual survival in these patients through prospective validation.

Materials And Methods: To achieve our objectives, we enrolled a cohort of 227 advanced cancer patients receiving palliative care.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

Exploring the Utility of the Modified Hospitalized-Patient One-Year Mortality Risk Score to Trigger Referrals to Palliative Care for Inpatients With Cancer.

Background: Estimating prognosis can be a barrier to timely palliative care involvement. The modified Hospitalized-patient One-year Mortality Risk (mHOMR) score uses hospital admission data to calculate the risk of death within 12 months and may be a useful tool to trigger a referral to palliative care.

Methods: The mHOMR tool was retrospectively applied to consecutive acute admissions to a quaternary cancer center in Toronto, Canada from March 1 to May 31, 2018.

A Multicentric Field Test to Study the Validity and Feasibility of the SHS-tool to Screen for Serious Health-related Suffering in Adult Patients with Cancer.

Objectives: The 2017 Lancet Commission reports 'Serious Health-related Suffering' (SHS) as an abyss in healthcare services. It lists 20 common health conditions and 15 symptoms as commonly associated with SHS. In 2015, 80% of SHS prevalence, an estimated 61 million, was noted as from low-middle-income countries.

Patient Profile-Based Management with Nintedanib in Patients with Idiopathic Pulmonary Fibrosis.

A severe and progressive interstitial lung disease (ILD) known as idiopathic pulmonary fibrosis (IPF) has an unknown etiology with poorly defined mechanisms of development. Among the currently prescribed pharmacological interventions for IPF, nintedanib demonstrates the ability to decelerate the deterioration of lung function and yield positive clinical outcomes. Multiple randomized placebo-controlled trials have confirmed the efficacy and acceptable safety profile of nintedanib.

An exploratory graphical analysis of the Montgomery-Åsberg Depression Rating Scale pre- and post-treatment using pooled antidepressant trial secondary data.

Background: The 10-item Montgomery-Åsberg Depression Rating Scale (MADRS) is a commonly used measure of depression in antidepressant clinical trials. Numerous studies have adopted classical test theory perspectives to assess the psychometric properties of this scale, finding generally positive results. However, its network configural structure and stability is unexplored across different time-points and treatment groups.

Preferences for Advance Care Planning in Patients with End-Stage Kidney Disease: A Cross-Sectional Survey among Nephrology Healthcare Providers in a Tertiary Care Center in India.

Introduction: Advance care planning (ACP) is essential in managing patients with end-stage kidney disease (ESKD), yet its integration into clinical practice remains limited, particularly in low- and middle-income countries. This study explores the preferences, attitudes and perceived barriers of nephrology healthcare providers toward ACP for patients with ESKD in a tertiary care center in India.

Methods: A cross-sectional survey was conducted among nephrology healthcare providers at a tertiary care center in India.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication.

Electrochemical Charge Transfer Kinetics of Ferrocene in the Light of Different Working Electrodes.

Ferrocene is an accidentally discovered organometallic compound that serves as a crucial redox probe in investigating electrochemical charge transfer dynamics. Besides solution phase studies, ferrocene derivatives are well-explored in molecular thin films, including self-assembled monolayers on various electrodes for understanding on-surface redox behavior, molecular electronics, and charge storage applications. Heterogeneous charge transfer is an imperative parameter for efficient charge transport in spin-dependent electrochemistry, photoelectrochemistry, and molecular electronic devices.

Identification of Dihydropyrazolo[1,5-]pyrazin-4(5)-ones as Cyclic Products of β-Amidomethyl Vinyl Sulfone Alphavirus Cysteine Protease Inhibitors.

Optimized syntheses of ()-5-(2-ethoxyphenyl)--(3-(methylsulfonyl)allyl)-1-pyrazole-3-carboxamide (RA-0002034, ), a promising antiviral covalent cysteine protease inhibitor lead, were developed. The syntheses avoid the contamination of with the inactive cyclic dihydropyrazolo[1,5-]pyrazin-4(5)-one , which is formed by the intramolecular aza-Michael reaction of the vinyl sulfone warhead under basic conditions and slowly at pH 7.4 in phosphate buffer.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication.

Immunoinhibitory effects of anti-tuberculosis therapy induce the host vulnerability to tuberculosis recurrence.

The host immune responses play a pivotal role in the establishment of long-term memory responses, which effectively aids in infection clearance. However, the prevailing anti-tuberculosis therapy, while aiming to combat tuberculosis (TB), also debilitates innate and adaptive immune components of the host. In this study, we explored how the front-line anti-TB drugs impact the host immune cells by modulating multiple signaling pathways and subsequently leading to disease relapse.

Glucose ingestion does not lower testosterone concentrations in men on testosterone therapy.

Oral calorie intake causes an acute and transient decline in serum testosterone concentrations. It is not known whether this decline occurs in men on testosterone therapy. In this study, we evaluated the change in testosterone concentrations following oral glucose ingestion in hypogonadal men before and after treatment with testosterone therapy.

Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Unlabelled: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV non-structural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign.

Initial Experiences With Integration of Palliative Medicine and Specialist Pain Services in a Tertiary Cancer Care Center in India.

Pain management constitutes a pivotal aspect of palliative care. Certain instances of distressing pain are significantly relieved through interventional pain methodologies, demanding the expertise of pain specialists. Our perspective revolves around the integration of these 2 facets, envisaging a symbiotic relationship that could enhance patient outcomes.

The uncharted territory of host-pathogen interaction in tuberculosis.

() effectively manipulates the host processes to establish the deadly respiratory disease, Tuberculosis (TB). has developed key mechanisms to disrupt the host cell health to combat immune responses and replicate efficaciously. antigens such as ESAT-6, 19kDa lipoprotein, Hip1, and Hsp70 destroy the integrity of cell organelles (Mitochondria, Endoplasmic Reticulum, Nucleus, Phagosomes) or delay innate/adaptive cell responses.

TAAR1 agonist ulotaront modulates striatal and hippocampal glutamate function in a state-dependent manner.

Aberrant dopaminergic and glutamatergic function, particularly within the striatum and hippocampus, has repeatedly been associated with the pathophysiology of schizophrenia. Supported by preclinical and recent clinical data, trace amine-associated receptor 1 (TAAR1) agonism has emerged as a potential new treatment approach for schizophrenia. While current evidence implicates TAAR1-mediated regulation of dopaminergic tone as the primary circuit mechanism, little is known about the effects of TAAR1 agonists on the glutamatergic system and excitation-inhibition balance.

A method for consistent cavitation bubble generation at different voltages.

A study of the dynamics of a single cavitation bubble is fundamental for understanding a wide range of applications in science and engineering. Underwater electrical discharge is a widely used method for generating cavitation bubbles to study their inception, subsequent dynamics, and collapse. In this work, an existing underwater low-voltage discharge circuit for generating cavitation bubbles is improved further to get a wider range of maximum bubble radius.