Identification and optimization of pyridine carboxamide-based scaffold as a drug lead for Mycobacterium tuberculosis.

New drugs with novel mechanisms of action are urgently needed to tackle the issue of drug-resistant tuberculosis. Here, we have performed phenotypic screening using the Pathogen Box library obtained from the Medicines for Malaria Venture against Mycobacterium tuberculosis in vitro. We have identified a pyridine carboxamide derivative, MMV687254, as a promising hit. This molecule is specifically active against M. tuberculosis and Mycobacterium bovis Bacillus Calmette-Guérin (M. bovis BCG) but inactive against Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Escherichia coli pathogens. We demonstrate that MMV687254 inhibits M. tuberculosis growth in liquid cultures in a bacteriostatic manner. Surprisingly, MMV687254 was as active as isoniazid in macrophages and inhibited M. tuberculosis growth in a bactericidal manner. Mechanistic studies revealed that MMV687254 is a prodrug and that its anti-mycobacterial activity requires AmiC-dependent hydrolysis. We further demonstrate that MMV687254 inhibits M. tuberculosis growth in macrophages by inducing autophagy. In the present study, we have also carried out a detailed structure-activity relationship study and identified a promising novel lead candidate. The identified novel series of compounds also showed activity against drug-resistant M. bovis BCG and M. tuberculosis clinical strains. Finally, we demonstrate that in contrast to MMV687254, the lead molecule was able to inhibit M. tuberculosis growth in a chronic mouse model of infection. Taken together, we have identified a novel lead molecule with a dual mechanism of action that can be further optimized to design more potent anti-tubercular agents.

Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

Two-Fold Oxidative Coupling of Furan with Indole Provides Modular Access to a New Class of Tetra-(hetero)arylated Furans with up to Four Different Substituents.

Highly arylated propeller-shaped heteroarenes constitute an intriguing class of molecular scaffolds for material science applications. Among these, tetraarylated furans demonstrate differentiated properties as compared to other similar heterocyclic cores. The synthetic complexity to access tetraarylated furans increases significantly with increasing number of different peripheral aryl groups. There are only a very limited number of methodologies available to access furans with four different (hetero)aryl substituents. Notably, none of these involve direct oxidative coupling on the furan core as the method of choice. Herein, we report the first methodology based on a sequential two-fold oxidative C-C coupling of furans with indoles to access bis(indolyl)furans (BIFs) - a new class of 'extremely congested' tetra-(hetero)arylated furans with up to four different substituents. The reaction is mediated by inexpensive, earth-abundant FeCl3.6H2O and displays high efficiency, wide substrate scope, modularity and aqueous compatibility. Moreover, we also present the first validation of the distinct aggregation-caused quenching (ACQ) property of the tetraarylated furans beyond only phenyls as peripheral groups and disclose new mechanistic underpinnings for the same.

Gender-Neutral HPV Vaccine in India; Requisite for a Healthy Community: A Review.

Human papillomavirus (HPV) affects approximately 80% of individuals, irrespective of gender, and is implicated in various cancers. Existing HPV vaccines, while safe and effective, do not sufficiently protect males when administered solely to females. This review, triggered by the urgent need to address this gap and reduce the associated stigma, aims to evaluate the introduction of a gender-neutral HPV vaccine, GARDASIL-9, in India. The primary objective is to assess the necessity and feasibility of incorporating the gender-neutral HPV vaccine into India's national immunization program. This integration is crucial to ensure equitable access for all children and to mitigate the substantial burden of HPV. A literature search was conducted using databases such as Google Scholar, PubMed, government websites, and relevant publications. Keywords included "gender-neutral vaccine", "HPV vaccine", and "Indian population". The central research question guiding this review is: How necessary and feasible is the inclusion of a gender-neutral HPV vaccine in India's national immunization schedule to ensure equitable access for all children and reduce the HPV burden? The review inclusion criteria comprised studies addressing the prevalence of HPV infections, HPV vaccination awareness among both genders, the cost-effectiveness of gender-neutral vaccines, current HPV vaccination status, and future perspectives specific to India. Studies not meeting these criteria were excluded. The review highlights that introducing a gender-neutral HPV vaccine in India is imperative. Including males in vaccination efforts significantly reduces the overall disease burden and helps in reducing the stigma associated with HPV. A comprehensive vaccination program, bolstered by education and awareness campaigns, and its inclusion in the national immunization schedule is essential. This approach ensures equitable access to the vaccine for all children, fostering a healthier community, preventing HPV-related cancers, and enhancing public health outcomes in India.

HPV is contracted by approximately 80% of people, regardless of gender, and is linked to various cancers. Existing HPV vaccines are safe and effective, but female vaccination alone is insufficient to protect men. The introduction of a gender-neutral HPV vaccine, GARDASIL-9, in India aims to protect both young women and boys from nine HPV serotypes. This study evaluates the urgency of including the vaccine in India's national immunization schedule to reduce the significant HPV burden. A literature search was conducted on Google Scholar, PubMed, government websites, and relevant publications using keywords like "gender-neutral vaccine," "HPV vaccine," and "Indian population." The review focused on the HPV vaccine situation in India and related studies. Key findings were grouped into following themes: (1) Prevalence of HPV infections, (2) HPV vaccination knowledge among women and men, (3) Cost-effectiveness of gender-neutral HPV vaccines, (4) HPV vaccination status, and (5) Future perspective. A gender-neutral HPV vaccine in India is vital to combat HPV-related cancers. Including boys and men in vaccination efforts reduces disease burden. A comprehensive program with education and awareness campaigns fosters a healthier community, preventing HPV-related cancers and improving public health in India.

Dermoscopy of hypopigmented macules unveiling genetic diagnosis of tuberous sclerosis complex type 2 in an infant presenting with sacral chordoma.

A 2-month-old male with surgically resected sacral chordoma presented with multiple hypopigmented macules showing characteristic patchy, sharply demarcated areas of pigment network on dermoscopy. These dermoscopic findings were suggestive of the ash-leaf macules of tuberous sclerosis over other common hypopigmented macules in neonates. Chordomas presenting in early childhood in the sacral location have been reported as a rare manifestation of tuberous sclerosis complex. The combination of these findings led to a diagnosis of tuberous sclerosis, confirmed with the finding of a heterozygous TSC2 gene deletion; treatment with sirolimus resulted in regression of cardiac rhabdomyomas and hypopigmented macules.

Follicular Becker's nevi: A case series and review of literature.

The follicular variant of Becker's nevus is an under-reported entity. We present the rare occurrence of follicular Becker's nevus in 7 patients, confirmed through dermoscopy and histopathological examination. Dermoscopy shows perifollicular hypopigmentation surrounded by a well-defined net-like pigmentation corresponding clinically to the presence of folliculocentric macules. Histology shows prominent basal and suprabasal melanization surrounding the follicle, corresponding to well-defined net-like pigmentation seen on dermoscopy. However, the melanization does not extend along the entire length of the follicular epithelium leading to perifollicular hypopigmentation on dermoscopy. Though biopsy is confirmatory, it is not usually necessary.

Brønsted-Acid-Catalyzed One-Pot Synthesis of ß,ß-Diaryl Esters: Direct Regioselective Approach to Diverse Arrays of 3-Aryl-1-indanone Cores.

A three-component, solvent-dependent, Brønsted-acid-catalyzed reaction of benzaldehydes, silyl enolates and arene nucleophiles has been developed for the synthesis of potential drug candidate 3-aryl-1-indanones. This reaction features the formation of three C-C bonds, high regioselectivity in a one-pot strategy, broad substrate generality, facile scalability (1.04g), high functional group tolerance and viable substrates. The ß-O-silyl ethers generated in-situ from the Mukaiyama aldol reaction were subjected to acid-catalyzed benzylic arylation with strong as well as weak nucleophiles, and the resultant ß,ß-diaryl esters can undergo a third C-C bond formation with excellent regioselectivity through intramolecular cyclization to afford the indanone products in the same pot. Detailed mechanistic insight leads to a feasible reaction pathway. This transformation opens up a practical and adaptable approach to producing a variety of synthetically valuable transformations and enable the synthesis of medicinally valuable (R)-tolterodine and (+)-indatraline.

Practical Access to meta-Substituted Anilines by Amination of Quinone Imine Ketals Derived from Anisidines: Efficient Synthesis of Anti-Psychotic Drugs.

Reversing the conventional site-selectivity of C-H activation provides efficient retrosynthetic disconnections to otherwise unreactive bonds. Described herein is the Brønsted acid-catalyzed reaction that selectively performs meta-amination of anisidines with aliphatic-, heterocyclic- and aromatic amines in a one-pot procedure. In addition to dramatically simplifying the synthesis of meta-substituted anilines, our approach has the advantage of the scalability and remarkable functional group tolerance, including late-stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed computational analysis provide insight into the reaction mechanism and the origin of meta-selectivity. The protocol extended to the synthesis of challenging tri-aminated arenes and successfully applied for the efficient synthesis of 5-HT6 receptor antagonists, the anti-psychotic drugs viz.. SB-214111, SB-258510, and specifically, anti-schizophrenic drug SB-271046.

2022 AAHA Canine Vaccination Guidelines.

These guidelines are an update and extension of previous AAHA peer-reviewed canine vaccination guidelines published in 2017. Vaccination is a cornerstone of canine preventive healthcare and one of the most cost-effective ways of maintaining a dog's health, longevity, and quality of life. Canine vaccination also serves a public health function by forming a barrier against several zoonotic diseases affecting dogs and humans. Canine vaccines are broadly categorized as containing core and noncore immunizing antigens, with administration recommendations based on assessment of individual patient risk factors. The guidelines include a comprehensive table listing canine core and noncore vaccines and a recommended vaccination and revaccination schedule for each vaccine. The guidelines explain the relevance of different vaccine formulations, including those containing modified-live virus, inactivated, and recombinant immunizing agents. Factors that potentially affect vaccine efficacy are addressed, including the patient's prevaccination immune status and vaccine duration of immunity. Because animal shelters are one of the most challenging environments for prevention and control of infectious diseases, the guidelines also provide recommendations for vaccination of dogs presented at or housed in animal shelters, including the appropriate response to an infectious disease outbreak in the shelter setting. The guidelines explain how practitioners can interpret a patient's serological status, including maternally derived antibody titers, as indicators of immune status and suitability for vaccination. Other topics covered include factors associated with postvaccination adverse events, vaccine storage and handling to preserve product efficacy, interpreting product labeling to ensure proper vaccine use, and using client education and healthcare team training to raise awareness of the importance of vaccinations.

Knowledge, Attitude, and Practice on Cervical Cancer and Screening Among Women in India: A Review.

BACKGROUND: Cervical Cancer is the second most common cancer among women in the world leading to 90% deaths in low and middle income countries. About 96,922 new Cervical Cancer cases are diagnosed annually in India. OBJECTIVE: To study the knowledge, attitude and practice on Cervical Cancer and screening among women in India. MATERIALS AND METHODS: Health sciences electronic databases PubMed and Google Scholar were searched for studies published between 2012 to March 2020. Keywords used for the search were ("Cervical Cancer screening"), ("knowledge"),("attitude"), ("practice") AND ("India"). 19 articles were included in the review based on the eligibility criteria. Statistical software SPSS-V.23 was used for the statistical application. RESULTS: 7688 women were included in the study. Age of study participants ranged from 12-65 years. Overall knowledge on Cervical Cancer among women was 40.22%. Knowledge of risk factors and signs and symptoms was fairly adequate among the women. 32.68% of women knew that early age of marriage was a risk factor for Cervical Cancer followed by 23.01% women who mentioned that early age of initiation of sexual activity was a common risk factor for Cervical Cancer. Inter menstrual bleeding and foul smelling discharge was the most common sign and symptom reported in 30.75% and 28.86% women respectively. Knowledge, attitude and practice regarding Cervical Cancer screening was seen in 20.31%, 43.64% and 13.22% of women respectively. CONCLUSION: Effective information, education and communication strategies are required to improve the level of awareness of women on Cervical Cancer.

Internet Addiction, Sleep Quality and Depressive Symptoms Amongst Medical Students in Delhi, India.

Today, the internet has become an important element in people's lives, and owing to internet access becoming widespread, it has resulted in internet addiction. It is a major concern amongst medical students aiming to develop into health professionals. The implications of this addiction as well as its association with sleep and depression affects their studies, impacts their career goals and has detrimental consequences for society as a whole. The objectives of this study were to assess the proportion of medical undergraduate students and interns with internet addiction (IA), depressive symptoms and poor sleep quality and to study the association of IA with sleep quality and depressive symptoms. A cross-sectional questionnaire-based study was carried out in a medical college in Delhi. Universal sample consisting of all the medical students from first to final year (n = 185) and interns (n = 37) enrolled during the time of the study were included. Sleep quality, internet addiction and depressive symptoms in these students was assessed using Pittsburgh Sleep Quality Index (PSQI) Young's Internet Addiction Test (YIAT) and Patient Health Questionnaire-9 (PHQ) respectively. The average YIAT score was 33.16 ± 15.68. Overall 18%, 59.9%, 46.8% of students scored above validated cutoff scores for internet addiction, poor sleep quality and depression respectively. Prevalence of IA among males and females were 20.4% and 12.9% respectively. Significant correlations were found between potential IA, sleep quality and depression (p < 0.001). The study concluded a strong correlation between IA, disturbed sleep quality and depression. Identifying medical students with potential IA is important because this addiction often coexists with other psychological problems. Thus timely remedial actions and tailored interventions are required to combat IA among medical students.

An unusual variant of lichen nitidus: Generalized follicular spinous with perifollicular granulomas.

Several unusual variants of lichen nitidus are described in the literature. Spinous follicular lichen nitidus with perifollicular granulomas is one such variant characterized by generalized follicular as well as nonfollicular keratotic papules, which show perifollicular granulomas on histopathology as well as a lichenoid granulomatous tissue reaction typical of lichen nitidus. Owing to its atypical clinical and histopathologic manifestations, it raises several clinical possibilities and can be a diagnostic challenge. We report this rare variant of lichen nitidus in a 19-year-old female, and discuss its clinical and histopathological differential diagnosis.

Efficacy and Safety of a Novel Method of Insulated Intralesional Radiofrequency Ablation for Deep Dermal and Subcutaneous Lesions: A 3-Year Institutional Experience.

BACKGROUND: Although insulated intralesional radiofrequency ablation (IL-RFA) is being increasingly used in other specialties, not much information on its safety and efficacy in dermatology is available. OBJECTIVE: To describe our experience with insulated IL-RFA for various dermatological conditions. METHODS: This is a retrospective review of the patients who underwent IL-RFA in the past 3 years. Our technique involved creating a small window in the proximal end of plastic sheath of an intravenous cannula using a surgical blade, and then touching the RF probe to the cannula through the window to deliver the electric current. Information regarding diagnosis, number of sessions, adverse effects, and follow-up was recorded. Clinical improvement was assessed on a visual analog scale by the patient and 2 independent observers. RESULTS: Data on 19 patients with lymphangioma circumscriptum (n = 9), venous or capillary-venous malformation (n = 4), angiolymphoid hyperplasia with eosinophilia (n = 3), arteriovenous malformation, hidradenitis suppurativa, and hypertrophic scar (n = 1 each) was available. The mean number of IL-RFA sessions was 2.26 ± 1.61. The mean patient and physician global assessment scores were 7.6 ± 2.22 and 7.3 ± 2.42, respectively. Adverse effects were seen in 9 (47.4%) patients. All patients, except 1, had sustained improvement in the mean follow-up period of 11.4 ± 11.6 months. CONCLUSION: Insulated IL-RFA seems to be safe and effective in selectively targeting deep-seated cutaneous lesions.