Molecular dynamics investigation of the influenza hemagglutinin conformational changes in acidic pH.

The surface protein hemagglutinin (HA) of the influenza virus plays a pivotal role in facilitating viral infection by binding to sialic acid receptors on host cells. Its conformational state is pH-sensitive, impacting its receptor-binding ability and evasion of the host immune response. In this study, we conducted extensive equilibrium microsecond-level all-atom molecular dynamics (MD) simulations of the HA protein to explore the influence of low pH on its conformational dynamics. Specifically, we investigated the impact of protonation on conserved histidine residues (His106 2 ) located in the hinge region of HA2. Our analysis encompassed comparisons between non-protonated (NP), partially protonated (1P, 2P), and fully-protonated (3P) conditions. Our findings reveal substantial pH-dependent conformational alterations in the HA protein, affecting its receptor-binding capability and immune evasion potential. Notably, the non-protonated form exhibits greater stability compared to protonated states. Conformational shifts in the central helices of HA2 involve outward movement, counterclockwise rotation of protonated helices, and fusion peptide release in protonated systems. Disruption of hydrogen bonds between the fusion peptide and central helices of HA2 drives this release. Moreover, HA1 separation is more likely in the fully-protonated system (3P) compared to non-protonated systems (NP), underscoring the influence of protonation. These insights shed light on influenza virus infection mechanisms and may inform the development of novel antiviral drugs targeting HA protein and pH-responsive drug delivery systems for influenza.

Analytical and Clinical Validation of a Non-Ristocetin Based VWF Assay on 2 Automated Analyzers in a Large Reference Laboratory.

BACKGROUND: Historically, von Willebrand factor (VWF) activity assays utilized ristocetin despite limitations including poor limits of detection and high imprecision. Newer VWF activity assays such as the INNOVANCE® VWF Ac assay, however, do not rely on ristocetin to measure platelet-dependent VWF function. The purpose of this study was to evaluate the analytical and clinical performance of the Siemens Healthineers INNOVANCE VWF Ac Assay on the Siemens BCS® XP and the Sysmex® CS-2500 systems in a large reference laboratory setting. METHODS: Performance indicators for the INNOVANCE VWF Ac assay were the limit of quantitation (LoQ), precision, and method comparison. Method comparison studies were performed using remnant plasma patient samples from routine coagulation tests and analyzed using both the INNOVANCE VWF Ac assay and the Siemens Healthineers ristocetin-dependent BC von Willebrand Reagent. RESULTS: Evaluation of the INNOVANCE VWF Ac assay on the BCS® XP and CS-2500 systems demonstrated good precision and a lower LoQ compared to the BC von Willebrand Reagent. Method comparisons support the use of the INNOVANCE VWF Ac assay on the BCS® XP and CS-2500 systems to measure platelet-dependent VWF function. The INNOVANCE VWF Ac assay was able to further assist in von Willebrand disease classification in 6/7 (86%) samples when the result was below the LoQ for the BC von Willebrand Reagent (ristocetin cofactor activity). CONCLUSIONS: These data are consistent with the 2021 American Society of Hematology/International Society on Thrombosis and Haemostasis/National Hemophilia Foundation/World Federation of Hemophilia von Willebrand disease guidelines that suggest using newer assays such as the INNOVANCE VWF Ac assay in place of ristocetin cofactor activity assays.

Point-of-care diagnostic devices for periodontitis - current trends and urgent need.

Point of care (POC) diagnostic devices provide a method for rapid accurate identification of disease through analysis of biologically relevant substances. This review focuses on the utility of POC testing for early detection of periodontitis, a critical factor in treating the disease. Accessing the oral cavity for biological sampling is less invasive when compared to other internal test sites, and oral fluids contain biomarkers indicative of periodontitis. The ease of access makes the mouth an excellent target location for the development of POC devices. In this review, accepted standards in industry by which these devices must adhere, provided by the World Health Organization such as REASSURED and CLIA, are discussed. An overview is provided for many periodontal biomarkers currently being investigated as a means of predicting periodontal disease and its progression. POC devices currently being investigated for the identification and monitoring of periodontal disease such as paper-based and lab-on-a-chip based devices are outlined. Limitations of current POC devices on the market are provided and future directions in leveraging biomarkers as an adjunctive method for oral diagnosis along with AI-based analysis systems are discussed. Here, we present the ESSENCE sensor platform, which combines a porous non-planar electrode with enhanced shear flow to achieve unprecedented sensitivity and selectivity. The combination of the ESENCE chip with an automated platform allows us to meet the WHO's ASSURED criteria. This platform promises to be an exciting POC candidate for early detection of periodontitis.

Effect of digital tools to promote hospital quality and safety on adverse events after discharge.

OBJECTIVES: Post-discharge adverse events (AEs) are common and heralded by new and worsening symptoms (NWS). We evaluated the effect of electronic health record (EHR)-integrated digital tools designed to promote quality and safety in hospitalized patients on NWS and AEs after discharge. MATERIALS AND METHODS: Adult general medicine patients at a community hospital were enrolled. We implemented a dashboard which clinicians used to assess safety risks during interdisciplinary rounds. Post-implementation patients were randomized to complete a discharge checklist whose responses were incorporated into the dashboard. Outcomes were assessed using EHR review and 30-day call data adjudicated by 2 clinicians and analyzed using Poisson regression. We conducted comparisons of each exposure on post-discharge outcomes and used selected variables and NWS as independent predictors to model post-discharge AEs using multivariable logistic regression. RESULTS: A total of 260 patients (122 pre, 71 post [dashboard], 67 post [dashboard plus discharge checklist]) enrolled. The adjusted incidence rate ratios (aIRR) for NWS and AEs were unchanged in the post- compared to pre-implementation period. For patient-reported NWS, aIRR was non-significantly higher for dashboard plus discharge checklist compared to dashboard participants (1.23 [0.97,1.56], P = .08). For post-implementation patients with an AE, aIRR for duration of injury (>1 week) was significantly lower for dashboard plus discharge checklist compared to dashboard participants (0 [0,0.53], P < .01). In multivariable models, certain patient-reported NWS were associated with AEs (3.76 [1.89,7.82], P < .01). DISCUSSION: While significant reductions in post-discharge AEs were not observed, checklist participants experiencing a post-discharge AE were more likely to report NWS and had a shorter duration of injury. CONCLUSION: Interventions designed to prompt patients to report NWS may facilitate earlier detection of AEs after discharge. CLINICALTRIALS.GOV: NCT05232656.

Pro- and anti-inflammatory cytokines signatures at different severity of dengue infection.

Context: Dengue disease severity and progression are determined by the host immune response, with both pro- and anti-inflammatory cytokines are key mediators. Aims: To study pro- and anti-inflammatory cytokines across dengue severity and as a biomarker for predicting severe dengue infection. Settings and Design: Hospital-based cross-sectional study was conducted on 125 dengue-positive subjects across the 5-60 years age group of either gender in 2022. Methods and Materials: Haematological parameters and blood samples were drawn to measure cytokines IL6, IL-10 and TNF alpha using the ELISA technique. Statistical Analysis: One-way ANOVA and the Kruskal - Wallis test were used to compare the dependent variables across categories of the dengue spectrum. Receiver operating characteristic curve was drawn to calculate the predictability of the cytokines as a predictor of severe dengue. A P < 0.05 was considered significant. Results: 34.4% of cases had severe dengue infection with 53.2% of severe cases reported in >40 years of age. Only IL-6 levels significantly increased (P < 0.01) across the spectrum of dengue infection across age groups >20 years with a consistent and significant fall in platelet levels (P < 0.01). The accuracy of IL-6 to predict severe dengue was 74.4% and platelet count was 16.2%. Conclusions: Only IL-6 cytokine levels were significantly increased across the spectrum of dengue infection observed in age >20 years and can significantly predict the probability of severe dengue by 74% (sensitivity 81.4%). A significant decrease in platelet values is consistent with the severity but is not a good predictor for severe dengue infection.

Visual detection of seizures in mice using supervised machine learning.

Seizures are caused by abnormally synchronous brain activity that can result in changes in muscle tone, such as twitching, stiffness, limpness, or rhythmic jerking. These behavioral manifestations are clear on visual inspection and the most widely used seizure scoring systems in preclinical models, such as the Racine scale in rodents, use these behavioral patterns in semiquantitative seizure intensity scores. However, visual inspection is time-consuming, low-throughput, and partially subjective, and there is a need for rigorously quantitative approaches that are scalable. In this study, we used supervised machine learning approaches to develop automated classifiers to predict seizure severity directly from noninvasive video data. Using the PTZ-induced seizure model in mice, we trained video-only classifiers to predict ictal events, combined these events to predict an univariate seizure intensity for a recording session, as well as time-varying seizure intensity scores. Our results show, for the first time, that seizure events and overall intensity can be rigorously quantified directly from overhead video of mice in a standard open field using supervised approaches. These results enable high-throughput, noninvasive, and standardized seizure scoring for downstream applications such as neurogenetics and therapeutic discovery.

Clarifying the Dominant Role of Crystallinity and Molecular Orientation in Differently Processed Thin Films of Regioregular Poly(3-hexylthiophene).

Conjugated polymers (CPs) offer the potential for sustainable semiconductor devices due to their low cost and inherent molecular self-assembly. Enhanced crystallinity and molecular orientation in thin films of solution-processable CPs have significantly improved organic electronic device performance. In this work, three methods, namely spin coating, dip coating, and unidirectional floating-film transfer method (UFTM), were utilized with their parametric optimization for fabricating RR-P3HT films. These films were then utilized for their characterization via optical and microstructural analysis to elucidate dominant roles of molecular orientation and crystallinity in controlling charge transport in organic field-effect transistors (OFETs). OFETs fabricated by RR-P3HT thin films using spin coating and dip coating displayed field-effect mobility (µ) of 8.0 × 10-4 cm2V-1s-1 and 1.3 × 10-3 cm2V-1s-1, respectively. This two-time enhancement in µ for dip-coated films was attributed to its enhanced crystallinity. Interestingly, UFTM film-based OFETs demonstrated µ of 7.0 × 10-2 cm2V-1s-1, >100 times increment as compared to its spin-coated counterpart. This superior device performance is attributed to the synergistic influence of higher crystallinity and molecular orientation. Since the crystallinity of dip-coated and UFTM-thin films are similar, ~50 times improved µ of UFTM thin films, this suggests a dominant role of molecular orientation as compared to crystallinity in controlling the charge transport.

The Future of Kidney Care in Low- and Middle-Income Countries: Challenges, Triumphs, and Opportunities.

CKD affects about 850 million people worldwide and is projected to be the fifth leading cause of death by 2040. Individuals from low- and middle-income countries (LMICs) bear the bulk of CKD. They face challenges including lack of awareness among the general population, as well as health care providers, unique risk factors such as genetic predispositions, infectious diseases, and environmental toxins, limited availability and affordability of diagnostic tests and medications, and limited access to KRTs. The inadequate health system infrastructure, human resources, and financing mechanisms to support comprehensive and integrated kidney care worsen the situation. Overcoming these challenges needs concerted efforts toward early detection, intervention, and multidisciplinary follow-up, policy, collaboration, advocacy, and financing. To achieve this, there is need for individual governments to include kidney health among the key health priorities and build capacity toward resilient health care systems. Integrating kidney care using the roadmaps of well-established management systems for other chronic diseases, such as HIV, has the potential to expedite the widespread adoption of kidney health. The aim of this article is to provide an overview of the current state and future prospects of kidney care in LMICs, highlighting the main challenges, ongoing efforts, and opportunities for improvement. We present case studies of exemplary efforts from three continents of the world with the highest densities of LMICs and propose potential strategies for a sustainable solution.

Manifestation of anharmonicities in terms of Fano scattering and phonon lifetime of scissors modes in α-MoO3.

α-MoO3 exhibits promising potential in the field of infrared detection and thermoelectricity owing to its exceptional characteristics of ultra-low-loss phonon polaritons (PhPs). It is of utmost importance to comprehend the phonon interaction exhibited by α-MoO3 in order to facilitate the advancement of phonon-centric devices. The intriguing applications of α-MoO3 for phonon-centric technology are found to be strongly dependent on scissors Raman modes. In this study, we have investigated the temperature-dependent asymmetric Raman line-shape characteristics of two scissors modes, Ag(1) and B1g(1), in the orthorhombic phase of bulk α-MoO3 within a temperature range spanning from 138 K to 498 K at 633 nm excitation wavelength. The Fano-Raman line-shape function was employed to analyze the asymmetry in terms of electron-phonon coupling strength, which varies from 0.050 to 0.313 and -0.017 to -0.192 for Ag(1) and B1g(1) modes, respectively, with temperature. This asymmetric behavior of Ag(1) and B1g(1) scissors modes are attributed to interference between the electronic energy continuum and discrete TO and LO phonon states, respectively. Therefore, the line-shape asymmetry in two scissors modes with increasing temperature stemming from the Fano resonance is also consistent with a 488 nm excitation wavelength. Additionally, anharmonicity caused by temperature results in redshift, and linewidth broadening of these two scissors modes through cubic-phonon decay has been observed. Moreover, the ultrashort lifetime of these optical phonons diminishes from ∼1.37 ps to ∼0.53 ps with increasing temperature due to the dominance of cubic-phonon decay over quartic-phonon decay. Our findings strongly emphasize the significance of investigating anharmonic interactions with Fano resonance to acquire an extensive comprehension of the vibrational characteristics of α-MoO3 for novel functionalities.

Towards realizing nano-enabled precision delivery in plants.

Nanocarriers (NCs) that can precisely deliver active agents, nutrients and genetic materials into plants will make crop agriculture more resilient to climate change and sustainable. As a research field, nano-agriculture is still developing, with significant scientific and societal barriers to overcome. In this Review, we argue that lessons can be learned from mammalian nanomedicine. In particular, it may be possible to enhance efficiency and efficacy by improving our understanding of how NC properties affect their interactions with plant surfaces and biomolecules, and their ability to carry and deliver cargo to specific locations. New tools are required to rapidly assess NC-plant interactions and to explore and verify the range of viable targeting approaches in plants. Elucidating these interactions can lead to the creation of computer-generated in silico models (digital twins) to predict the impact of different NC and plant properties, biological responses, and environmental conditions on the efficiency and efficacy of nanotechnology approaches. Finally, we highlight the need for nano-agriculture researchers and social scientists to converge in order to develop sustainable, safe and socially acceptable NCs.

The prognostic and predictive value of homologous recombination deficiency status in patients with advanced stage epithelial ovarian carcinoma after first-line platinum-based chemotherapy.

Objective: Homologous recombination (HR) comprises series of interrelated pathways that repair double-stranded DNA breaks and inter-strand crosslinks. It provides support for DNA replication to recover stalled or broken replication forks. Compared with homologous recombination proficiency (HRP), cancers with homologous recombination deficiency (HRD) are more likely to undergo cell death when treated with DNA-damaging agents, such as platinum agents, and have better disease control. Methods: Patients diagnosed with stage III/IV ovarian cancer, early stages with recurrence, who received adjuvant chemotherapy after debulking surgery, and who also had known HR status were eligible. Results: Forty-four patients were included, with 21 in the HRD group (including 8 with germline mutations) and 23 in the HRP group. The HRD group was composed predominantly of serous carcinoma (95.2%), while mucinous (n=3) and clear cell (n=1) cases were all found in the HRP group. Stage III/IV disease was 66.7% and 91.3% in HRD and HRP groups, respectively (p=0.064). Patients who were optimally debulked to no residual disease was 90.0% and 72.7% (p=0.243), respectively. Late line use of PARP inhibitors was 33.3% and 17.4% (p=0.303). Median PFS was 22.5 months (95% CI, 18.5 - 66.6) and 21.5 months (95% CI, 18.3-39.5) (p=0.49) in HRD and HRP respectively. Median platinum free interval (PFI) was 15.8 months (95% CI 12.4-60.4) and 15.9 months (95% CI 8.3-34.1) (p=0.24), respectively. Median OS was 88.2 months (95% CI 71.2-NA) and 49.7 months (95% CI 35.1-NA) (p=0.21). The PFS of the patients with germline BRCA mutations (n=5) was 54.3 months (95% CI 23.1-NA) and 21.5 months (95% CI 18.3-39.5) in the HRP group (p=0.095); the PFI difference was 47.7 months (95% CI 17.6-NA) in the BRCA mutation group, and 15.9 months (95% CI 12.4-60.4) in HRP, showing statistical significance (p=0.039); while the median OS was NA and 49.7 months (95% CI 35.1-NA) respectively (p=0.051). When adding two additional patients with somatic BRCA mutations to the germline BRCA mutation carriers, the median OS is NA (95% CI 73, NA) versus 49.7 months (95% CI 35.1, NA) for HRP (p=0.045). Conclusions: HRD status was not associated with longer PFS or PFI in advanced ovarian cancer who received first line adjuvant platinum-based chemotherapy. Its role as a prognostic marker for overall survival is suggested, particularly in the subgroup with germline and somatic BRCA mutations.

The dopant (n- and p-type)-, band gap-, size- and stress-dependent field electron emission of silicon nanowires.

This study investigates the electron field emission (EFE) of vertical silicon nanowires (Si NWs) fabricated on n-type Si (100) and p-type Si (100) substrates using catalyst-induced etching (CIE). The impact of dopant types (n- and p-types), optical energy gap, crystallite size and stress on EFE parameters has been explored in detail. The surface morphology of grown SiNWs has been characterized by field emission scanning electron microscopy (FESEM), showing vertical, well aligned SiNWs. Optical absorption and Raman spectroscopy confirmed the presence of the quantum confinement (QC) effect. The EFE performance of the grown nanowire arrays has been examined through recorded J-E measurements under the Fowler-Nordheim framework. The Si NWs grown on p-type Si showed a minimum turn-on field and also a higher field enhancement factor. The band-bending diagram also suggests a lower barrier height of p-type Si NWs compared to n-type Si NWs, which plays a key role in enhancing the EFE performance. These investigations suggest that dopant types (n- and p-types), band gap, crystallite size and stress influence the EFE parameters and Si NWs grown on p-type Si (100) substrates are much more favorable for the investigation of EFE properties.

VeXUS: Do Not Drown in the ExCESS.

How to cite this article: Kumar V. VeXUS: Do Not Drown in the ExCESS. Indian J Crit Care Med 2024;28(5):419-421.

Biofortification as a solution for addressing nutrient deficiencies and malnutrition.

Malnutrition, defined as both undernutrition and overnutrition, is a major global health concern affecting millions of people. One possible way to address nutrient deficiency and combat malnutrition is through biofortification. A comprehensive review of the literature was conducted to explore the current state of biofortification research, including techniques, applications, effectiveness and challenges. Biofortification is a promising strategy for enhancing the nutritional condition of at-risk populations. Biofortified varieties of basic crops, including rice, wheat, maize and beans, with elevated amounts of vital micronutrients, such as iron, zinc, vitamin A and vitamin C, have been successfully developed using conventional and advanced technologies. Additionally, the ability to specifically modify crop genomes to improve their nutritional profiles has been made possible by recent developments in genetic engineering, such as CRISPR-Cas9 technology. The health conditions of people have been shown to improve and nutrient deficiencies were reduced when biofortified crops were grown. Particularly in environments with limited resources, biofortification showed considerable promise as a long-term and economical solution to nutrient shortages and malnutrition. To fully exploit the potential of biofortified crops to enhance public health and global nutrition, issues such as consumer acceptance, regulatory permitting and production and distribution scaling up need to be resolved. Collaboration among governments, researchers, non-governmental organizations and the private sector is essential to overcome these challenges and promote the widespread adoption of biofortification as a key part of global food security and nutrition strategies.

Acid mine drainage from coal mines in the eastern Himalayan sub-region: Hydrogeochemical processes, seasonal variations and insights from hydrogen and oxygen stable isotopes.

Uncontrolled coal mining using non-scientific methods has presented a major threat to the quality of environment, particularly the water resources in eastern himalayan sub-region of India. Water bodies in the vicinity of mining areas are contaminated by acid mine drainage (AMD) that is released into streams and rivers. This study attempted to assess the impact of AMD, deciphering hydrogeochemical processes, seasonal fluctuations, and stable isotope features of water bodies flowing through and around coal mining areas. Self-organizing maps (SOMs) used to separate and categorize AMD, AMD-impacted and non-AMD impacted water from the different study locations for two sampling seasons revealed four clusters (C), with C1 and C2 impacted by AMD, C3 and C4 showing negligible to no impact of AMD. AMD impacted water was SO42- - Mg2+- Ca2+ hydrochemical type with sulphide oxidation and evaporation dominating water chemistry, followed by silicate weathering during both the sampling seasons. Water with negligible-to-no AMD-impact was Mg2+- Ca2+- SO42- to Ca2+ - HCO3- to mixed hydrochemical type with rock weathering and dissolution, followed by ion exchange as major factors controlling water chemistry during both the sampling seasons. Most of physicochemical parameters of C1 and C2 exceeded the prescribed limits, whereas in C3 and C4 water samples, parameters were found within the prescribed limits. Stable isotopes of hydrogen (δ2H) and oxygen (δ18O) during post-monsoon (PoM) varied between -41.04 ‰ and -29.98 ‰, and -6.60 ‰ to -3.94 ‰; and during pre-monsoon (PrM) varied between -58.18 ‰ and - 33.76 ‰ and -8.60 ‰ to -5.46 ‰. Deuterium excess (d-excess) ranged between 1.57 ‰ and 12.47 ‰ during PoM and 5.70 ‰ to 15.17 ‰ during PrM season. The stable isotopes analysis revealed that evaporation, mineral dissolution and mixing with rainwater are the key factors in study area.

Long Term Surgical and Radiological Outcome of Discoid Lateral Meniscus: An Updated Systematic Review.

Purpose of the study: This study aimed to reach a consensus for ideal surgical treatment of discoid lateral meniscus (DLM) and to evaluate its long term surgical and radiological outcome. Methods: All authors independently searched for peer reviewed publications with keywords like discoid lateral meniscus, tibial menisci abnormalities, tibial menisci surgery and clinical outcome and their representative Medical Subjects Headings (MeSH) in databases of PubMed, EBSCO, Cochrane Central Register of Controlled Trials, from inception to December 2022. Original articles in English language on discoid lateral meniscus reporting clinical, surgical, or radiological outcomes with five or more years of follow-up were included in this systematic review. Study details and outcome data were analysed according to the age, follow-up period, kind of surgery, DLM type, and alignment. Results: Our search strategy yielded 654 articles in PubMed, 222 articles in EBSCO and 5 articles in CENTRAL i.e. a total of 881 articles. After detailed assessment and screening, 12 articles were included in the final analysis, which included 444 DLM cases. The mean patient age at surgery ranged from 9.9 to 35.9 years, and the mean follow-up period ranged from 5.2 to 16 years. Partial meniscectomy and meniscoplasty are the recommended treatment because of the concerns of degenerative arthritis development after the total and subtotal meniscectomies. Two studies have documented better results with meniscal allograft transplantation. Conclusion: Satisfactory clinico-radiological outcome can be obtained after surgical treatment of discoid lateral meniscus with meniscus reshaping and repair of peripheral unstable part. Meniscal allograft transplantation (MAT) is gaining popularity in patients with total meniscectomy with satisfactory long term functional outcome.

Prototyping a wearable and stretchable graphene-on-PDMS sensor for strain detection on human body physiological and joint movements.

In the era of wearable electronic devices, which are quite popular nowadays, our research is focused on flexible as well as stretchable strain sensors, which are gaining humongous popularity because of recent advances in nanocomposites and their microstructures. Sensors that are stretchable and flexible based on graphene can be a prospective 'gateway' over the considerable biomedical speciality. The scientific community still faces a great problem in developing versatile and user-friendly graphene-based wearable strain sensors that satisfy the prerequisites of susceptible, ample range of sensing, and recoverable structural deformations. In this paper, we report the fabrication, development, detailed experimental analysis and electronic interfacing of a robust but simple PDMS/graphene/PDMS (PGP) multilayer strain sensor by drop casting conductive graphene ink as the sensing material onto a PDMS substrate. Electrochemical exfoliation of graphite leads to the production of abundant, fast and economical graphene. The PGP sensor selective to strain has a broad strain range of ⁓60%, with a maximum gauge factor of 850, detection of human physiological motion and personalized health monitoring, and the versatility to detect stretching with great sensitivity, recovery and repeatability. Additionally, recoverable structural deformation is demonstrated by the PGP strain sensors, and the sensor response is quite rapid for various ranges of frequency disturbances. The structural designation of graphene's overlap and crack structure is responsible for the resistance variations that give rise to the remarkable strain detection properties of this sensor. The comprehensive detection of resistance change resulting from different human body joints and physiological movements demonstrates that the PGP strain sensor is an effective choice for advanced biomedical and therapeutic electronic device utility.

Use of Paracetamol for Treatment of Patent Ductus Arteriosus in Preterm Neonates: A 5-Year Experience From a Tertiary Hospital in India.

OBJECTIVE: We evaluated ductal closure rates in preterm neonates with hemodynamically significant patent ductus arteriosus (hsPDA) who received paracetamol (PCM) as first-line therapy. METHODS: In this retrospective chart review, we included inborn preterm (< 37 weeks) neonates (January 2017-December 2021) with hsPDA (ductal diameter > 1.5 mm and left atrium-to-aortic root ratio (La/Ao > 1.4) who were treated with oral or intravenous PCM. Primary outcome was hsPDA closure (defined as small or no PDA) following 3-day treatment. Secondary outcomes were need for retreatment and surgical ligation, pulmonary hypertension (PH), and in-hospital morbidities. RESULTS: Out of 2784 preterm birth, 117 neonates were diagnosed with hsPDA. Out of 96 neonates who received PCM in the first course, 20 died before the completing the first course. The median (IQR) gestation and birth weight of neonates who received PCM were 28 (26, 29) weeks and 841 (714, 1039) g, respectively. Out of 76 neonates who completed treatment with first course of PCM (57 intravenous, 19 oral), 43 (56.6%) achieved successful closure and five (6.6%) developed PH. Out of 14 neonates who received a second course of PCM, 10 achieved closure of hsPDA while one neonate expired. CONCLUSION: Paracetamol is associated with successful closure of hsPDA in 56.6% of preterm neonates after one course and 70% of premies after two courses.

Digitalization of toxicology: improving preclinical to clinical translation.

Though the portfolio of medicines that are extending and improving the lives of patients continues to grow, drug discovery and development remains a challenging business on its best day. Safety liabilities are a significant contributor to development attrition where the costliest liabilities to both drug developers and patients emerge in late development or post-marketing. Animal studies are an important and influential contributor to the current drug discovery and development paradigm intending to provide evidence that a novel drug candidate can be used safely and effectively in human volunteers and patients. However, translational gaps-such as toxicity in patients not predicted by animal studies-have prompted efforts to improve their effectiveness, especially in safety assessment. More holistic monitoring and "digitalization" of animal studies has the potential to enrich study outcomes leading to datasets that are more computationally accessible, translationally relevant, replicable, and technically efficient. Continuous monitoring of animal behavior and physiology enables longitudinal assessment of drug effects, detection of effects during the animal's sleep and wake cycles and the opportunity to detect health or welfare events earlier. Automated measures can also mitigate human biases and reduce subjectivity. Reinventing a conservative, standardized, and traditional paradigm like drug safety assessment requires the collaboration and contributions of a broad and multi-disciplinary stakeholder group. In this perspective, we review the current state of the field and discuss opportunities to improve current approaches by more fully leveraging the power of sensor technologies, artificial intelligence (AI), and animal behavior in a home cage environment.