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The present study is an attempt for treatment of aquaculture wastewater from indoor facilities such as hatcheries etc through integrated process. which comprises an anaerobic baffled reactor (ABR) packed with coconut coir fibre as bacterial support medium and an aerobic cascading step to aerate the effluent coming out of the anaerobic baffled reactor. The maximum COD removal obtained in coconut coir packed ABR was 96 % while in the control, it was 65 %. The maximumTotal Kjeldahl Nitrogenremoval in coconut coir packed ABR was 95 % while in the control ABR the removal was 61 %. The maximum percentage ammonia removal obtained in coconut coir packed ABR was 97 % while in the control ABR 95 % of ammonia removal was achieved. Therefore the study concludes that the process significantly reduces the nutrient load in the wastewater making it suitable for release into natural water bodies or for recirculation.

Laterally spreading tumors may sometimes evade detection by colonoscopy. This study aimed to evaluate the use of image-enhanced endoscopy for visualizing laterally spreading tumors of the nongranular type. We reviewed consecutive patients with 47 non-granular-type laterally spreading tumors that had been examined using white-light imaging, autofluorescence imaging, narrow-band imaging, and chromoendoscopy with indigo carmine. The quality of visualization was evaluated using a 5-point scale by less- and more-experienced endoscopists. Autofluorescence imaging provided significantly better visualization than white-light imaging for both less-experienced and experienced endoscopists. On the other hand, no significant differences were observed between the quality of visualization provided by white-light imaging and narrow-band imaging for less-experienced endoscopists. Autofluorescence imaging provides high-quality visualization of non-granular-type laterally spreading tumors on still images. Multicenter trials should be conducted to confirm the usefulness of autofluorescence imaging in detecting laterally spreading colorectal tumors.

The identification, establishment, and exploration of potential pharmacological drug targets are major steps of the drug development pipeline. Target validation requires diverse chemical tools that come with a spectrum of functionality, e.g., inhibitors, activators, and other modulators. Particularly tools with rare modes-of-action allow for a proper kinetic and functional characterization of the targets-of-interest (e.g., channels, enzymes, receptors, or transporters). Despite, functional innovation is a prime criterion for patentability and commercial exploitation, which may lead to therapeutic benefit. Unfortunately, data on new, and thus, undruggable or barely druggable targets are scarce and mostly available for mainstream modes-of-action only (e.g., inhibition). Here we present a novel cheminformatic workflow-computer-aided pattern scoring (C@PS)-which was specifically designed to project its prediction capabilities into an uncharted domain of applicability., (© 2024. The Author(s).)

Background: Uttar Pradesh (UP), the most populous state in India, has about 36 million people aged 50 years or older, spread across more than 100,000 villages. Among them, an estimated 3.5 million suffer from visual impairments, including blindness due to untreated cataracts. To achieve cataract backlog-free status, UP is required to screen this population at the community level and provide treatment to those suffering from cataracts. We envisioned an AI-powered primary screening app utilizing eye images, deployable to frontline health workers for community-level screening. This paper outlines insights gained from developing the AI mobile app "Roshni" for cataract screening., Method: The AI-based cataract classification model was developed using 13,633 eye images and finalized after three stages of experiments, detecting cataracts in images focused on the eye, iris, and pupil. Overall, 155 experiments were conducted using multiple deep learning algorithms, including ResNet50, ResNet101, YOLOv5, EfficientNetV2, and InceptionV3. We established a minimum threshold of 90 % specificity and sensitivity to ensure the algorithm's suitability for field use., Results: The cataract detection model for eye-focused images achieved 51.9 % sensitivity and 87.6 % specificity, while the model for iris-focused images, using a good/bad iris filter, achieved 52.4 % sensitivity and 93.3 % specificity. The classification model for segmented-pupil images, employing a good/bad pupil filter with UNet-based semantic segmentation model and EfficientNetV2, yielded 96 % sensitivity and 97 % specificity. Field testing with 302 beneficiaries (604 images) showed an overall sensitivity of 86.6 %, specificity of 93.3 %, positive predictive value of 58.4 %, and negative predictive value of 98.5 %., Conclusion: This paper details the development of an AI mobile app designed to facilitate community screening for cataracts by frontline health workers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Competing interests The authors have no competing interest to report., (Copyright © 2024. Published by Elsevier Inc.)

The state of Uttar Pradesh (UP), India, has one of the largest single public health systems globally, serving about 235 million people through more than 30,000 public health facilities with approximately 160,000 health personnel. Yet, the UP health system has a shortfall of public health facilities to meet the population's needs, a shortage of clinical and nonclinical health personnel, inequitable distribution of existing health personnel, and low utilization of public health facilities. A robust and effective electronic human resource management system (eHRMS) that provides real-time information about the lifecycle of all health professionals in UP may aid in improving the health workforce, resulting in better health services and improved health outcomes. The Government of UP rolled out Manav Sampada, a comprehensive eHRMS that complied with global norms and requirements. We describe the implementation of Manav Sampada at scale and elaborate on key learnings and adoption strategies. Manav Sampada was based on key principles of integration and data-sharing with other digital systems, included functional components, a minimum dataset, used a lifecycle-based approach, and a workflow-based system, all of which acted to improve human resource data quality. The eHRMS emerged as a valuable tool for key stakeholders in reviewing worker performance, identifying skill-building needs, and allocating resources for training, leading to improved availability and equity in the distribution of a few critical cadres. The eHRMS in UP is well positioned to become an integral part of the Ayushman Bharat Digital Mission, the backbone of India's integrated digital health infrastructure. Linking eHRMS to a planned beneficiary-centric unitized health service delivery system (capturing information at the individual level rather than the aggregate level) will enable the measurement of service delivery and quality, leading to improved workforce management., (© Jain et al.)

The human orphan G protein-coupled receptor GPR18, activated by Δ 9 -tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in β-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC 50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC 50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.

The identification of lead molecules and the exploration of novel pharmacological drug targets are major challenges of medical life sciences today. Genome-wide association studies, multi-omics, and systems pharmacology steadily reveal new protein networks, extending the known and relevant disease-modifying proteome. Unfortunately, the vast majority of the disease-modifying proteome consists of 'orphan targets' of which intrinsic ligands/substrates, (patho)physiological roles, and/or modulators are unknown. Undruggability is a major challenge in drug development today, and medicinal chemistry efforts cannot keep up with hit identification and hit-to-lead optimization studies. New 'thinking-outside-the-box' approaches are necessary to identify structurally novel and functionally distinctive ligands for orphan targets. Here we present a unique dataset that includes critical information on the orphan target ABCA1, from which a novel cheminformatic workflow - computer-aided pattern scoring (C@PS) - for the identification of novel ligands was developed. Providing a hit rate of 95.5% and molecules with high potency and molecular-structural diversity, this dataset represents a suitable template for general deorphanization studies., (© 2024. The Author(s).)

Background: Uttar Pradesh (UP) is the most populous state in India, with a historically lower level of family planning coverage than the national average. In recent decades, family planning coverage in UP has significantly increased, yet there are considerable geographic and socio-economic inequalities., Methods: The data used for the study is derived from a cross-sectional quantitative survey of 12,200 currently married women conducted during December 2020-February 2021 in UP by the Technical Support Unit. Univariate and bivariate analyses were performed and equiplots were used to make visualizing inequalities easy., Results: The findings of the study reveal significant variation in family planning coverage indicators amongst currently married women in reproductive ages by administrative divisions in UP. For instance, in the Jhansi division, it was 72.4%, while in Faizabad, it was 39.3%. Jhansi division experienced the highest modern contraceptive coverage with the lowest inequity compared to other divisions. However, the range of coverage within the division by Accredited Social Health Activist (ASHA) areas is 25% to 75%. In fact, for some ASHA areas in the Jhansi division, the family planning demand satisfied for modern contraception ranged from more than 85% to less than 22%. On the other hand, the Gonda division with the lowest coverage and lowest inequity for demand satisfied for modern contraception has some ASHA areas with less than 5% and some with more than 36%. The study also revealed intersectionality of education, wealth, place of residence and geographic divisions in identifying inequity patterns. For instance, in case of Mirzapur and Varanasi, the demand satisfied among the illiterates was 69% and the corresponding percentage for literates was 49%. With respect to place of residence, Basti division, where the coverage for modern contraception is extremely low, demand satisfied for modern contraceptive methods is 16.3% among rural residents compared to 57.9% in the case of urban residents., Conclusions: The findings showed inequality in the modern family planning methods coverage in UP in both best and worst performing divisions. The inequalities exist even in extremely small geographies such as ASHA areas. Within the geographies as well, the socio-economic inequalities persisted. These inequalities at multiple levels are important to consider for effective resource allocation and utilization., (© 2024. The Author(s).)

Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and β-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies., (© 2024. The Author(s).)

The MAS-related G q protein-coupled receptor X4 (MRGPRX4) is poorly investigated. MRGPRX4 has been proposed to be involved in pain transmission, itch, inflammation, wound healing, and cancer. However, so far only a few moderately potent, nonselective MRGPRX4 agonists have been described, most of which appear to preferably activate the minor receptor variant MRGPRX4-83L but not the main variant 83S. In the present study, we discovered a xanthine derivative bearing a phosphate substituent that activates the main variant of MRGPRX4. Optimization resulted in analogs with high potency and metabolic stability. The best compounds of the present series include 8-( m -methoxyphenethyl)-1-propargylxanthine substituted with a butyl linker in the 3-position containing a terminal phosphonate ( 30d , PSB-22034, EC 50 Ca 2+ assay/β-arrestin assay, 11.2 nM/32.0 nM) and its N7-methyl derivative 31d (PSB-22040, EC 50 , 19.2/30.0 nM) showing high selectivity versus all other MRGPRX subtypes. They present promising tool compounds for exploring the potential of MRGPRX4 as a future drug target.

The discovery of both distinctive lead molecules and novel drug targets is a great challenge in drug discovery, which particularly accounts for orphan diseases. Huntington's disease (HD) is an orphan, neurodegenerative disease of which the pathology is well-described. However, its pathophysiological background and molecular mechanisms are poorly understood. To date, only 2 drugs have been approved on the US and European markets, both of which address symptomatic aspects of this disease only. Although several hundreds of agents were described with efficacy against the HD phenotype in in vitro and/or in vivo models, a successful translation into clinical use is rarely achieved. Two major impediments are, first, the lack of awareness and understanding of the interactome-the sum of key proteins, cascades, and mediators-that contributes to HD initiation and progression; and second, the translation of the little gained knowledge into useful model systems. To counteract this lack of data awareness, we manually compiled and curated the entire modulator landscape of successfully evaluated pre-clinical small-molecule HD-targeting agents which are annotated with substructural molecular patterns, physicochemical properties, as well as drug targets, and which were linked to benchmark databases such as PubChem, ChEMBL, or UniProt. Particularly, the annotation with substructural molecular patterns expressed as binary code allowed for the generation of target-specific and -unspecific fingerprints which could be used to determine the (poly)pharmacological profile of molecular-structurally distinct molecules., (© 2023. The Author(s).)

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

Endoscopic screening is premised on the detection of pre-symptomatic, early-stage gastric neoplasia that enables curative resection. Endoscopic screening reduces gastric cancer mortality in high-incidence countries but is highly resource-intensive. Endoscopic surveillance of high-risk subgroups of intestinal metaplasia has gained traction in low and intermediate-incidence countries, and emerging evidence suggests that risk-stratified endoscopic surveillance may facilitate timely detection of cancer. However, outcome-based evidence is required to support its adoption. Yet the impact of an endoscopy-based strategy may well lie in heralding a paradigm that regards every routine diagnostic gastroscopy as an opportunity to screen for GC. Endoscopic surveillance also renders gastric intestinal metaplasia a de facto disease, and the ramification of this needs to be further elucidated., Competing Interests: The author declares that they have no competing interests.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2023 Namasivayam V.)

Gastroscopy is the reference standard for the diagnosis of gastric cancer, but it is operator-dependent and associated with missed gastric cancer. The proliferation of gastroscopic examinations, increasingly for the screening and detection of subtle premalignant lesions, has motivated scrutiny of quality in gastroscopy. The concept of a high-quality endoscopic examination for the detection of superficial gastric neoplasia has been defined by expert guidelines to improve mucosal visualization, engender a systematic examination process and detect superficial neoplasia. This review discusses the evidence supporting the components of a high-quality diagnostic gastroscopic examination in relation to the detection of gastric cancer, and their potential role as procedural quality indicators to drive a structured improvement in clinically meaningful outcomes., Competing Interests: None., (© 2023 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Orthomyxo- and bunyaviruses steal the 5' cap portion of host RNAs to prime their own transcription in a process called "cap snatching." We report that RNA modification of the cap portion by host 2'-O-ribose methyltransferase 1 (MTr1) is essential for the initiation of influenza A and B virus replication, but not for other cap-snatching viruses. We identified with in silico compound screening and functional analysis a derivative of a natural product from Streptomyces , called trifluoromethyl-tubercidin (TFMT), that inhibits MTr1 through interaction at its S -adenosyl-l-methionine binding pocket to restrict influenza virus replication. Mechanistically, TFMT impairs the association of host cap RNAs with the viral polymerase basic protein 2 subunit in human lung explants and in vivo in mice. TFMT acts synergistically with approved anti-influenza drugs.

Background: The sustainable development goals (SDG) aim at satisfying three-fourths of family planning needs through modern contraceptive methods by 2030. However, the traditional methods (TM) of family planning use are on the rise, along with modern contraception in Uttar Pradesh (UP), the most populous Indian state. This study attempts to explore the dynamics of rising TM use in the state., Methods: We used a state representative cross-sectional survey conducted among 12,200 Currently Married Women (CMW) aged 15-49 years during December 2020-February 2021 in UP. Using a multistage sampling technique, 508 primary sampling units (PSU) were selected. These PSU were ASHA areas in rural settings and Census Enumeration Blocks in urban settings. About 27 households from each PSU were randomly selected. All the eligible women within the selected households were interviewed. The survey also included the nearest public health facilities to understand the availability of family planning methods. Univariate and bivariate analyses were conducted. Appropriate sampling weights were applied., Results: Overall, 33.9% of CMW were using any modern methods and 23.7% any TM (Rhythm and withdrawal) at the time of survey. The results show that while the modern method use has increased by 2.2 percentage points, the TM use increased by 9.9 percentage points compared to NFHS-4 (2015-16). The use of TM was almost same across women of different socio-demographic characteristics. Of 2921 current TM users, 80.7% started with TM and 78.3% expressed to continue with the same in future. No side effects (56.9%), easy to use (41.7%) and no cost incurred (38.0%) were the main reasons for the continuation of TM. TM use increased despite a significant increase (66.1 to 81.3%) in the availability of modern reversible methods and consistent availability of limiting methods (84.0%) in the nearest public health facilities., Conclusion: Initial contraceptive method was found to have significant implications for current contraceptive method choice and future preferences. Program should reach young and zero-parity women with modern method choices by leveraging front-line workers in rural UP. Community and facility platforms can also be engaged in providing modern method choices to women of other parities to increase modern contraceptive use further to achieve the SDG goals., (© 2022. The Author(s).)

Aims: P2X receptors are ATP-gated ion channels which play a role in many pathophysiological conditions. They are considered as novel drug targets, particularly in the fields of pain, (neuro) inflammation, and cancer. Due to difficulties in developing drug-like orthosteric ligands that bind to the highly polar ATP binding site, the design of positive and negative allosteric modulators (PAMs and NAMs) is a promising strategy. The P2X4 receptor was proposed as a novel target for neuropathic and inflammatory pain (antagonists), and for the treatment of alcoholism (PAMs). So far, little is known about the allosteric binding site(s) of P2X4 receptors. The aim of this study was to identify the binding site(s) of the macrocyclic natural product ivermectin, the urea derivative BX430, and the antidepressant drug paroxetine that act as allosteric modulators of P2X4 receptors., Material and Methods: We generated chimeric receptors in which extracellular sequences of the human P2X4 receptor were exchanged for corresponding residues of the human P2X2 receptor, complemented by specific single amino acid residue mutants. Chimeric and mutated receptors were stably expressed in 1321N1 astrocytoma cells, and characterized by fluorimetric measurement of ATP-induced Ca 2+ -influx. In addition, docking studies utilizing a homology model of the human P2X4 receptor were performed., Key Findings: Our results suggest a common binding site for ivermectin and BX430 in an extracellular receptor domain, while paroxetine might bind to the cation pore., Significance: The obtained results provide a basis for the development of positive and negative allosteric P2X4 modulators with improved properties and will support future drug development efforts., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Biomolecular condensates are compartmentalized communities of biomolecules, which unlike traditional organelles, are not enclosed by membranes. Condensates play roles in diverse cellular processes, are dysfunctional in many disease states, and are often enriched in classically "undruggable" targets. In this review, we provide an overview for how drugs can modulate condensate structure and function by phenotypically classifying them as dissolvers (dissolve condensates), inducers (induce condensates), localizers (alter localization of the specific condensate community members) or morphers (alter the physiochemical properties). We discuss the growing list of bioactive molecules that function as condensate modifiers (c-mods), including small molecules, oligonucleotides, and peptides. We propose that understanding mechanisms of condensate perturbation of known c-mods will accelerate the discovery of a new class of therapies for difficult-to-treat diseases., Competing Interests: All authors are employees or board members of Dewpoint Therapeutics, a drug discovery company that studies condensates, and have a financial stake in the company., (Copyright © 2022 Patel, Mitrea, Namasivayam, Murcko, Wagner and Klein.)

MAS-related G protein-coupled receptors (GPCRs) of subfamily X, designated MRGPRX, are primate-specific orphan receptors that belong to the δ-branch of rhodopsin-like, class A GPCRs. Four distinct subtypes exist, MRGPRX1, -2, -3, and -4, MRGPRX2 having the lowest degree of similarity with the others. Due to their expression on sensory neurons and immune cells, and their roles in pain perception and transmission, itch, inflammation, immune defense, pseudo-allergic reactions, wound healing, and possibly cancer, they have recently attracted much attention as novel drug targets. In particular MRGPRX2 was identified as an important mast cell receptor, responsible for anaphylactoid drug reactions and involved in skin and mucosal diseases, e.g. urticaria, atopic dermatitis, rosacea, and allergic rhinitis. A major hurdle has been the lack of animal models for studying these primate-specific receptors. However, recently humanized mice have been created. Moreover, a mouse ortholog of MRGPRX2, MRGPRB2, was identified, both receptors having a certain degree of similarity. MRGPRX1 and -2 can be activated by various peptides and small (partly peptidomimetic) molecules. MRGPRX2 is additionally activated by a very broad range of basic molecules, positively charged at physiologic pH value of 7.4, including many drugs. MRGPRX4 is activated by small acidic molecules including bile acids. For MRGPRX3, no ligands have been reported yet. Antagonists with reasonable potency and selectivity have been described for MRGPRX1, and few antagonists also for MRGPRX2, but not for the other subtypes. The recent elucidation of cryogenic electron microscopy structures of MRGPRX2 and -4 is expected to facilitate and advance drug development for these receptors. Currently, research on MRGPRX is still in its infancy, and exciting discoveries can be awaited. These receptors have great potential as future drug targets., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

Alzheimer's disease (AD) is a devastating neurological disorder characterized by the pathological accumulation of macromolecular Aβ and tau leading to neuronal death. Drugs approved to treat AD may ameliorate disease symptoms, however, no curative treatment exists. Aβ peptides were discovered to be substrates of adenosine triphosphate-(ATP)-binding cassette (ABC) transporters. Activators of these membrane-bound efflux proteins that promote binding and/or translocation of Aβ could revolutionize AD medicine. The knowledge about ABC transporter activators is very scarce, however, the few molecules that were reported contain substructural features of multitarget (pan-)ABC transporter inhibitors. A cutting-edge strategy to obtain new drug candidates is to explore and potentially exploit the recently proposed multitarget binding site of pan-ABC transporter inhibitors as anchor point for the development of innovative activators to promote Aβ clearance from the brain. Molecular associations between functional bioactivities and physicochemical properties of small-molecules are key to understand these processes. This study provides an analysis of a recently reported unique multitarget dataset for the correlation between multitarget bioactivity and physicochemistry. Six novel pan-ABC transporter inhibitors were validated containing substructural features of ABC transporter activators, which underpins the relevance of the multitarget binding site for the targeted development of novel AD diagnostics and therapeutics., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

An effective health management information system (HMIS) that captures accurate, consistent, and relevant data in a timely fashion can enable better planning and monitoring of health programs and improved service delivery, in turn helping increase the impact of different interventions. In 2009, the Government of Uttar Pradesh (GOUP) implemented HMIS, India's national-level health information platform. However, key challenges, including difficulties in accessing the data through a web-based portal and its limited relevance to decision making and managerial needs, reduced its usability at the district and state levels. In 2015, with the support of the Uttar Pradesh Technical Support Unit, the GOUP created its own data platform, the Uttar Pradesh HMIS (UP-HMIS), to capture data elements missing from HMIS but important to UP decision makers. The UP-HMIS was redesigned to capture these data elements to holistically measure and monitor the performance of health programs and inform decision making at the district and state levels. In addition, the GOUP implemented complementary initiatives to improve data quality and data use processes. To improve HMIS data quality, the GOUP established data validation committee meetings at the block, district, and state levels. To promote the use of these validated data, in 2017, the GOUP developed and implemented the UP Health Dashboard, which ranks each of UP's 75 districts on a set of key HMIS priority health indicators. These policy guidelines have brought greater attention to UP-HMIS data quality and use; however, additional strengthening is required to improve the quality and use of HMIS data. There is a need to increase the overall capacity and understanding of HMIS data, not only for staff with specific data-related responsibilities but also for program managers and senior decision makers., (© Meghani et al.)

Multitarget datasets that correlate bioactivity landscapes of small-molecules toward different related or unrelated pharmacological targets are crucial for novel drug design and discovery. ATP-binding cassette (ABC) transporters are critical membrane-bound transport proteins that impact drug and metabolite distribution in human disease as well as disease diagnosis and therapy. Molecular-structural patterns are of the highest importance for the drug discovery process as demonstrated by the novel drug discovery tool 'computer-aided pattern analysis' ('C@PA'). Here, we report a multitarget dataset of 1,167 ABC transporter inhibitors analyzed for 604 molecular substructures in a statistical binary pattern distribution scheme. This binary pattern multitarget dataset (ABC_BPMDS) can be utilized for various areas. These areas include the intended design of (i) polypharmacological agents, (ii) highly potent and selective ABC transporter-targeting agents, but also (iii) agents that avoid clearance by the focused ABC transporters [e.g., at the blood-brain barrier (BBB)]. The information provided will not only facilitate novel drug prediction and discovery of ABC transporter-targeting agents, but also drug design in general in terms of pharmacokinetics and pharmacodynamics., (© 2022. The Author(s).)

Gastric cancer (GC) has a good prognosis, if detected at an early stage. The intestinal subtype of GC follows a stepwise progression to carcinoma, which is treatable with early detection and intervention using high-quality endoscopy. Premalignant lesions and gastric epithelial polyps are commonly encountered in clinical practice. Surveillance of patients with premalignant gastric lesions may aid in early diagnosis of GC, and thus improve chances of survival. An expert professional workgroup was formed to summarise the current evidence and provide recommendations on the management of patients with gastric premalignant lesions in Singapore. Twenty-five recommendations were made to address screening and surveillance, strategies for detection and management of gastric premalignant lesions, management of gastric epithelial polyps, and pathological reporting of gastric premalignant lesions.

For emerging and re-emerging epidemic infections, researchers face challenges to develop broad-spectrum antivirals as well as reducing development time and costs, and drug resistance. Drug repurposing is a reliable strategy for rapidly discovering potent new antiviral agents, reducing the need for clinical trials. In this review, we outline antiviral drug candidates identified using the drug repurposing approach, with their potential modes of action and biological responses against various epidemic viral infectious diseases., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Although community health workers (CHWs) are effective at mobilizing important health behaviors, there is limited evidence on how financial incentive systems can best be designed to drive their effectiveness. This study intends to bridge this evidence gap by analyzing the compensation model of India's accredited social health activist (ASHA) program and identifying areas of improvement in the system's design and implementation., Methods: We analyze the ASHA program in Uttar Pradesh, India. ASHAs receive compensation through a mix of program-linked, performance-based, and routine activity-based incentive structures. Using multiple data sources, including a novel linked household and ASHA survey, we estimate ASHA performance-linked incentive earnings under different scenarios of ASHA actions and household behaviors. Juxtaposing statistical projection models and actual government payments, we identified which incentives promised the highest payments, which were claimed or not, which could be claimed more by increasing ASHA actions, and which were paid despite not meeting payment criteria. We also report findings on ASHA awareness of and experiences with claiming incentives., Results: We find crucial gaps and implementation challenges in the ASHA incentive structure. ASHAs could double their earnings by completing certain tasks within their control. ASHAs may also be paid for partial completion of activities, as incentives are paid in lump sums for a series of activities rather than for each activity. Family planning incentives have the largest gap between potential and actual earnings. Incentivizing ASHAs for achieving certain health outcomes is inefficient, as no clear linkage was found between the achievability of such health outcomes and the claim amounts., Conclusion: There are several opportunities for improving CHW compensation, from improving the incentive claims process to shifting focus to achievable outcomes. Optimizing incentive system designs can further enhance CHW effectiveness globally to affect key health behaviors., (© Jain et al.)

This review provides an overview of organic compounds detected in non-avian dinosaur fossils to date. This was enabled by the development of sensitive analytical techniques. Non-destructive methods and procedures restricted to the sample surface, e.g., light and electron microscopy, infrared (IR) and Raman spectroscopy, as well as more invasive approaches including liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), time-of-flight secondary ion mass spectrometry, and immunological methods were employed. Organic compounds detected in samples of dinosaur fossils include pigments (heme, biliverdin, protoporphyrin IX, melanin), and proteins, such as collagens and keratins. The origin and nature of the observed protein signals is, however, in some cases, controversially discussed. Molecular taphonomy approaches can support the development of suitable analytical methods to confirm reported findings and to identify further organic compounds in dinosaur and other fossils in the future. The chemical properties of the various organic compounds detected in dinosaurs, and the techniques utilized for the identification and analysis of each of the compounds will be discussed.

In the tumor microenvironment, cancer cells experience hypoxia resulting in the accumulation of misfolded/unfolded proteins largely in the endoplasmic reticulum (ER). Consequently, ER proteotoxicity elicits unfolded protein response (UPR) as an adaptive mechanism to resolve ER stress. In addition to canonical UPR, proteotoxicity also stimulates the selective, autophagy-dependent, removal of discrete ER domains loaded with misfolded proteins to further alleviate ER stress. These mechanisms can favor cancer cell growth, metastasis, and long-term survival. Our investigations reveal that during hypoxia-induced ER stress, the ER-phagy receptor FAM134B targets damaged portions of ER into autophagosomes to restore ER homeostasis in cancer cells. Loss of FAM134B in breast cancer cells results in increased ER stress and reduced cell proliferation. Mechanistically, upon sensing hypoxia-induced proteotoxic stress, the ER chaperone BiP forms a complex with FAM134B and promotes ER-phagy. To prove the translational implication of our mechanistic findings, we identified vitexin as a pharmacological agent that disrupts FAM134B-BiP complex, inhibits ER-phagy, and potently suppresses breast cancer progression in vivo., (© 2022. The Author(s).)

The human ATP- and UTP-activated P2Y 2 receptor (P2Y 2 R) is a G q protein-coupled receptor involved in several pathophysiological conditions including acute and chronic inflammation, cancer, and pain. Despite its potential as a novel drug target, only few P2Y 2 R antagonists have been developed so far, all of which suffer from severe drawbacks. These include (i) high polarity due to one or several negative charges resulting in low oral bioavailability, (ii) metabolic instability and generally poor pharmacokinetic properties, and/or (iii) lack of selectivity, which limits their utility for in vitro and in vivo studies aimed at target validation. In search of new druglike scaffolds for P2Y 2 R antagonists, we employed a structure-based virtual high-throughput screening approach utilizing the complex of a P2Y 2 R homology model with one of the most potent and selective orthosteric antagonists described so far, AR-C118925 ( 10 ). After virtual screening of 3.2 million molecules, 58 compounds were purchased and pharmacologically evaluated. Several novel antagonist scaffolds were discovered, and their binding modes at the human P2Y 2 R were analyzed by molecular docking studies. The investigated antagonists likely share a similar binding mode with 10 which includes accommodation of bulky, lipophilic groups in the putative orthosteric binding site of the P2Y 2 R. The discovered scaffolds and the elucidated structure-activity relationships provide a basis for the development of future drug candidates for the P2Y 2 R which have great potential as novel drugs.

Motivation: Multitargeting features of small molecules have been of increasing interest in recent years. Polypharmacological drugs that address several therapeutic targets may provide greater therapeutic benefits for patients. Furthermore, multitarget compounds can be used to address proteins of the same (or similar) protein families for their exploration as potential pharmacological targets. In addition, the knowledge of multitargeting features is of major importance in the drug selection process; particularly in ultra-large virtual screening procedures to gain high-quality compound collections. However, large-scale multitarget modulator landscapes are almost non-existent., Results: We implemented a specific feature-driven computer-aided pattern analysis (C@PA) to extract molecular-structural features of inhibitors of the model protein family of ATP-binding cassette (ABC) transporters. New molecular-structural features have been identified that successfully expanded the known multitarget modulator landscape of pan-ABC transporter inhibitors. The prediction capability was biologically confirmed by the successful discovery of pan-ABC transporter inhibitors with a distinct inhibitory activity profile., Availability and Implementation: The multitarget dataset is available on the PANABC web page (http://www.panabc.info) and its use is free of charge., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

The P2X7 receptor has been proposed as a novel drug target for different types of diseases associated with inflammation, including brain diseases, peripheral inflammation, and cancers. Structurally diverse P2X7 receptor antagonists, mainly negative allosteric modulators (NAMs), have been developed in recent years, and several P2X7 receptor antagonists are currently evaluated in clinical trials. The P2X7 receptor requires high micro- to even millimolar ATP concentrations to be activated. Selective agonists for the P2X7 receptor are not available. Positive allosteric modulators (PAMs) have been described, but PAMs with high potency and selectivity are still lacking. This chapter discusses medicinal chemistry approaches toward the development of P2X7 receptor modulators and presents a selection of recommended tool compounds for studying P2X7 receptors in humans and rodents., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

This review article presents a collection of tool compounds that selectively block and are recommended for studying P2Y and P2X receptor subtypes, investigating their roles in physiology and validating them as future drug targets. Moreover, drug candidates and approved drugs for P2 receptors will be discussed., (© 2021. The Author(s).)

The antithrombotic prodrugs ticlopidine and clopidogrel are thienotetrahydro-pyridine derivatives that are metabolized in the liver to produce thiols that irreversibly block adenosine diphosphate (ADP)-activated P2Y 12 receptors on thrombocytes. In their native, nonmetabolized form, both drugs were reported to act as inhibitors of ectonucleoside triphosphate diphosphohydrolase-1 (NTPDase1, CD39). CD39 catalyzes the extracellular hydrolysis of nucleoside tri- and diphosphates, mainly adenosine 5'-triphosphate (ATP) and ADP, yielding adenosine monophosphate, which is further hydrolyzed by ecto-5'-nucleotidase (CD73) to produce adenosine. While ATP has proinflammatory effects, adenosine is a potent anti-inflammatory, immunosuppressive agent. Inhibitors of CD39 and CD73 have potential as novel checkpoint inhibitors for the immunotherapy of cancer and infection. In the present study, we investigated 2-substituted thienotetrahydropyridine derivatives, structurally related to ticlopidine, as CD39 inhibitors. Due to their substituent on the 2-position, they will not be metabolically transformed into reactive thiols and can, therefore, be expected to be devoid of P2Y 12 receptor-antagonistic activity in vivo. Several of the investigated 2-substituted thienotetrahydropyridine derivatives showed concentration-dependent inhibition of CD39. The most potent derivative, 32, showed similar CD39-inhibitory potency to ticlopidine, both acting as allosteric inhibitors. Compound 32 showed an improved selectivity profile: While ticlopidine blocked several NTPDase isoenzymes, 32 was characterized as a novel dual inhibitor of CD39 and CD73., (© 2021 The Authors. Archiv der Pharmazie published by Wiley-VCH Verlag GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Population-based serological antibody test for SARS-CoV-2 infection helps in estimating the exposure in the community. We present the findings of the first district representative seroepidemiological survey conducted between 4 and 10 September 2020 among the population aged 5 years and above in the state of Uttar Pradesh, India. Multi-stage cluster sampling was used to select participants from 495 primary sampling units (villages in rural areas and wards in urban areas) across 11 selected districts to provide district-level seroprevalence disaggregated by place of residence (rural/urban), age (5-17 years/aged 18 +) and gender. A venous blood sample was collected to determine seroprevalence. Of 16,012 individuals enrolled in the study, 22.2% [95% CI 21.5-22.9] equating to about 10.4 million population in 11 districts were already exposed to SARS-CoV-2 infection by mid-September 2020. The overall seroprevalence was significantly higher in urban areas (30.6%, 95% CI 29.4-31.7) compared to rural areas (14.7%, 95% CI 13.9-15.6), and among aged 18 + years (23.2%, 95% CI 22.4-24.0) compared to aged 5-17 years (18.4%, 95% CI 17.0-19.9). No differences were observed by gender. Individuals exposed to a COVID confirmed case or residing in a COVID containment zone had higher seroprevalence (34.5% and 26.0%, respectively). There was also a wide variation (10.7-33.0%) in seropositivity across 11 districts indicating that population exposed to COVID was not uniform at the time of the study. Since about 78% of the population (36.5 million) in these districts were still susceptible to infection, public health measures remain essential to reduce further spread., (© 2021. The Author(s).)

The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

G proteins represent intracellular switches that transduce signals relayed from G protein-coupled receptors. The structurally related macrocyclic depsipeptides FR900359 (FR) and YM-254890 (YM) are potent, selective inhibitors of the Gα q protein family. We recently discovered that radiolabeled FR and YM display strongly divergent residence times, which translates into significantly longer antiasthmatic effects of FR. The present study is aimed at investigating the molecular basis for this observed disparity. Based on docking studies, we mutated amino acid residues of the Gα q protein predicted to interact with FR or YM, and recombinantly expressed the mutated Gα q proteins in cells in which the native Gα q proteins had been knocked out by CRISPR-Cas9. Both radioligands showed similar association kinetics, and their binding followed a conformational selection mechanism, which was rationalized by molecular dynamics simulation studies. Several mutations of amino acid residues near the putative binding site of the "lipophilic anchors" of FR, especially those predicted to interact with the isopropyl group present in FR but not in YM, led to dramatically accelerated dissociation kinetics. Our data indicate that the long residence time of FR depends on lipophilic interactions within its binding site. The observed structure-kinetic relationships point to a complex binding mechanism of FR, which likely involves snap-lock- or dowel-like conformational changes of either ligand or protein, or both. These experimental data will be useful for the design of compounds with a desired residence time, a parameter that has now been recognized to be of utmost importance in drug development., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Timely and skilled care is key to reducing maternal and neonatal mortality. Birth preparedness involves preparation for safe childbirth during the antenatal period to reach the appropriate health facility for ensuring safe delivery. Hence, understanding the factors associated with birth preparedness and its significance for safe delivery is essential. This paper aims to assess the levels of birth preparedness, its determinants and association with institutional deliveries in High Priority Districts of Uttar Pradesh, India., Methods: A community-based cross-sectional survey was conducted between June-October 2018 in the rural areas of 25 high priority districts of Uttar Pradesh, India. Simple random sampling was used to select 40 blocks among 294 blocks in 25 districts and 2646 primary sampling units within the selected blocks. The survey interviewed 9458 women who had a delivery 2 months prior to the survey. Descriptive statistics were included to characterize the study population. Multivariable logistic regression analyses were performed to identify the determinants of birth preparedness and to examine the association of birth preparedness with institutional delivery., Results: Among the 9458 respondents, 61.8% had birth preparedness (both facility and transportation identified) and 79.1% delivered in a health facility. Women in other caste category (aOR = 1.24, CI 1.06-1.45) and those with 10 or more years of education (aOR = 1.68, CI 1.46-1.92) were more likely to have birth preparedness. Antenatal care (ANC) service uptake related factors like early registration for ANC (aOR = 1.14, CI 1.04-1.25) and three or more front line worker contacts (aOR = 1.61, CI 1.46-1.79) were also found to be significantly associated with birth preparedness. The adjusted multivariate model showed that those who identified both facility and transport were seven times more likely to undergo delivery in a health facility (aOR = 7.00, CI 6.07-8.08)., Conclusion: The results indicate the need for focussing on marginalized groups for improving birth preparedness. Increasing ANC registration in the first trimester of pregnancy, improving frontline worker contact, and optimum utilization of antenatal care check-ups for effective counselling on birth preparedness along with system level improvements could improve birth preparedness and consequently institutional delivery rates in Uttar Pradesh, India., (© 2021. The Author(s).)

This study investigates the implementation of a recent health management information systems (HMIS) policy reform in Uttar Pradesh, India, which aims to improve the quality and use of HMIS data in decision-making. Through in-depth interviews, meeting observations and a policy document review, this study sought to capture the experiences of district-level staff (street-level bureaucrats) who were responsible for HMIS policy implementation. Findings revealed that issues of weak HMIS implementation were partly due to human resources shortages both in number and technical skill. Delays in recruitment and the presence of inactive staff overburdened existing staff and weakened the implementation of HMIS activities at the block- and district-levels. District staff also explained how inadequate computer literacy and limited technical understanding further contributed to low HMIS data quality. The organizational culture was even more constraining: working within a very rigid and hierarchical organization was challenging for district data staff, who were expected to manage day-to-day HMIS activities, but lacked the discretion and authority to do so effectively. Consequently, they had to escalate minor issues to district leadership for action and were expected to follow their supervisors' directives- even if they contradicted HMIS policy guidelines. High performance pressures associated with achieving top district rankings deviated focus away from HMIS data quality issues. Many district-level respondents described their superiors' "fixation" with becoming a top-ranking district often resulted in disregard for the quality of data informing district rankings. Furthermore, the review of district rankings only partially encouraged district-level leadership to investigate reasons for low-performing indicators. Instead, low district rankings often resulted in punitive action. The study recommends the importance of incorporating the perspectives of district staff, and recognizing their discretion, and authority when designing policy implementation processes, and finally concludes with potential strategies for strengthening the current HMIS policy reform., (Copyright © 2021. Published by Elsevier Ltd.)