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An organobase assisted approach is adopted to synthesize pyranopyrazole derivatives in one pot. Three-component condensation reaction of 3-methylpyrazolin-5-ones, aromatic aldehydes and malononitrile were catalyzed by 5 mol% of 4-dimethylaminopyridine (DMAP) in ethanol at room temperature. Key aspects of this approach are simple filtration without the need of time-consuming column purification; good yields; cost-effectiveness and use of easily available solid organo-base as a catalyst. A broad substrate scope and variety of functional group tolerance permit diversity generation in a one pot operation. In silico, molecular-docking studies of the compounds were performed with anti-inflammatory active drugs i.e. indomethacin and celecoxib and the compounds were also studied for their pharmacokinetic properties absorption, distribution, metabolism, and excretion (ADME). The results obtained for most of the synthesized compounds are promising and all of them comply well satisfying the Lipinski rule of 5 (RO5) with 0 violation.

NIV (Non-invasive ventilation) and HFNC (High Flow nasal cannula) are being used in patients with acute respiratory failure. HACOR score has been exclusively calculated for patients on NIV, on other hand ROX index is being used for patients on HFNC. This is first study where ROX index has been used in patients on NIV to predict failure.

T Karuna,1 Rahul Garg,2 Shweta Kumar,2 Gyanendra Singh,3 Lakshmi Prasad,4 Kawal Krishen Pandita,4 Abhijit Pakhare,3 Saurabh Saigal,5 Alkesh Kumar Khurana,6 Rajnish Joshi,2 Kamini Walia,7 Sagar Khadanga2 1Department of Microbiology, AIIMS, Bhopal, Madhya Pradesh, India; 2Department of General Medicine, AIIMS, Bhopal, Madhya Pradesh, India; 3Department of Community and Family Medicine, AIIMS, Bhopal, Madhya Pradesh, India; 4Department of Hospital Administration, AIIMS, Bhopal, Madhya Pradesh, India; 5Department of Critical Care, AIIMS, Bhopal, Madhya Pradesh, India; 6Department of Pulmonary Medicine & TB, AIIMS, Bhopal, Madhya Pradesh, India; 7Indian Council of Medical Research, New Delhi, IndiaCorrespondence: Sagar Khadanga, Department of General Medicine, AIIMS, Bhopal, Madhya Pradesh, India, Email drsagarkhadanga@gmail.comPurpose: Secondary infections (SI) in COVID-19 have been documented from 3.6% to 72% in various studies with mortality ranging from 8.1% to 57.6%. There is a gap in knowledge for clinico–epidemio-microbilogical association among COVID-19 patients with concomitant SI.Patients and Methods: This is a retrospective chart review, in central India. The study was undertaken for hospitalized adult patients during 1st June 2020 to 30th November 2020, with laboratory proven COVID-19 infection and secondary infection.Results: Out of the total 2338 number of patients, only 265 (11.3%) patients were investigated for microbiological identification of SI. Male gender was predominant (76.8%) and the mean age was 53.7 ± 17.8 years. Only 3.5% (82/2338) of patients were having microbiologically confirmed (bacterial or fungal) SI. The overall mortality was 50.9% (54/82) with a differential mortality of 88.8% (48/54) in high-priority areas and 21.4% (6/28) in low-priority areas. Blood was the most commonly investigated sample (56%) followed by urine (20.7%) and respiratory secretion (15.8%). A. baumanii complex (20/82, 24.3%) was the most common bacteria isolated followed by K. pneumonia (12/82, 14.6%) and E. coli (11/82, 13.4%). Candida spp. (20/82, 24.3%) was the most common fungal pathogen isolated. Sixty percent (12/20) of Acinetobacter spp. were carbapenam-resistant and 70.3% of Enterobacterales were carbapenam-resistant. Fluconazole resistant Candida spp. was isolated only in 10% (2/20) of cases. Diabetes was the most common co-morbidity 54.8% (45/82) followed by hypertension (41.4%) and chronic heart disease (13.4%). The negative predictors of secondary infections are urinary catheterization, placement of central line and mechanical ventilation (invasive and non-invasive).Conclusion: There is an urgent need of better anti-microbial stewardship practices in India (institutional and extra institutional) for curtailment of secondary infection rates particularly among COVID-19 patients.Keywords: COVID-19, secondary infection, anti-microbial stewardship practice, mortality, predictor

John D Rodriguez,1 Keith Lane,1 David A Hollander,1,2 Aron Shapiro,1 Sunita Saigal,1 Andrew J Hertsenberg,1 Garrick Wallstrom,3 Divya Narayanan,1 Endri Angjeli,1 Mark B Abelson1,4 1Ora, Inc., Andover, MA, USA; 2Jules Stein Eye Institute, University of California, Los Angeles, CA, USA; 3Statistics and Data Corporation, Tempe, AZ, USA; 4Department of Ophthalmology, Harvard Medical School, Boston, MA, USA Purpose: To identify parameters from cone function and recovery after photostress that detect functional deficits in early non-exudative age-related macular degeneration (AMD) and to determine the repeatability of these parameters. Methods: Cone-mediated visual function recovery after photostress was examined in three groups of subjects: young normal subjects (ages 20–29; N=8), older normal subjects (ages 50–90; N=9), and early non-exudative AMD subjects (ages 50–90; N=12). Eight AMD and four normal subjects were retested 1 year after the initial evaluation. Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) and parameters of cone function (baseline cone sensitivity and cone recovery half-life following photobleach) were measured and compared between AMD and normal subjects. Short-term repeatability was assessed for each subject’s initial evaluation. Long-term repeatability was assessed by comparing outcomes from the initial evaluation and 1-year follow-up. Results: The mean baseline cone threshold was significantly worse in subjects with early AMD compared to older normal subjects (-1.80±0.04 vs -1.57±0.06 log cd/m2 p=0.0027). Moreover, the baseline cone threshold parameter exhibited good short-term (intraclass correlation coefficient [ICC]=0.88) and long-term (ICC=0.85) repeatability in all subjects. The cone intercept parameter and ETDRS VA were not significantly different between AMD and older normal subject groups. Cone recovery half-life was significantly different between older normal and AMD subject groups (p=0.041). Neither ETDRS VA nor cone function parameters were significantly different for any group at the 1-year follow-up. Conclusion: The baseline cone threshold shows potential as a novel parameter to assess visual dysfunction in early AMD. This outcome consistently detected deficits in AMD subjects, and differentiated them from age-matched controls with high test–retest repeatability. Keywords: AMD, photobleach, photoreceptor, cone recovery, Ora LUX

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

STUDY DESIGN: Clinical practice guideline development. OBJECTIVES: Acute spinal cord injury (SCI) can result in devastating motor, sensory, and autonomic impairment; loss of independence; and reduced quality of life. Preclinical evidence suggests that early decompression of the spinal cord may help to limit secondary injury, reduce damage to the neural tissue, and improve functional outcomes. Emerging evidence indicates that early surgical decompression completed within 24 hours of injury also improves neurological recovery in patients with acute SCI. The objective of this clinical practice guideline (CPG) is to update the 2017 recommendations on the timing of surgical decompression and to evaluate the evidence with respect to ultra-early surgery (in particular, but not limited to,

STUDY DESIGN: Clinical practice guideline development following the GRADE process. OBJECTIVES: Hemodynamic management is one of the only available treatment options that likely improves neurologic outcomes in patients with acute traumatic spinal cord injury (SCI). Augmenting mean arterial pressure (MAP) aims to improve blood perfusion and oxygen delivery to the injured spinal cord in order to minimize secondary ischemic damage to neural tissue. The objective of this guideline was to update the 2013 AANS/CNS recommendations on the hemodynamic management of patients with acute traumatic SCI, acknowledging that much has been published in this area since its publication. Specifically, we sought to make recommendations on 1. The range of mean arterial pressure (MAP) to be maintained by identifying an upper and lower MAP limit; 2. The duration of such MAP augmentation; and 3. The choice of vasopressor. Additionally, we sought to make a recommendation on spinal cord perfusion pressure (SCPP) targets. METHODS: A multidisciplinary guideline development group (GDG) was formed that included health care professionals from a wide range of clinical specialities, patient advocates, and individuals living with SCI. The GDG reviewed the 2013 AANS/CNS guidelines and voted on whether each recommendation should be endorsed or updated. A systematic review of the literature, following PRISMA standards and registered in PROSPERO, was conducted to inform the guideline development process and address the following key questions: (i) what are the effects of goal-directed interventions to optimize spinal cord perfusion on extent of neurological recovery and rates of adverse events at any time point of follow-up? and (ii) what are the effects of particular monitoring techniques, perfusion ranges, pharmacological agents, and durations of treatment on extent of neurological recovery and rates of adverse events at any time point of follow-up? The GDG combined the information from this systematic review with their clinical expertise in order to develop recommendations on a MAP target range (specifically an upper and lower limit to target), the optimal duration for MAP augmentation, and the use of vasopressors or inotropes. Using methods outlined by the GRADE working group, recommendations were formulated that considered the balance of benefits and harms, financial impact, acceptability, feasibility and patient preferences. RESULTS: The GDG suggested that MAP should be augmented to at least 75-80 mmHg as the lower limit, but not actively augmented beyond an upper limit of 90-95 mmHg in order to optimize spinal cord perfusion in acute traumatic SCI. The quality of the evidence around the target MAP was very low, and thus the strength of this recommendation is weak. For duration of hemodynamic management, the GDG suggested that MAP be augmented for a duration of 3-7 days. Again, the quality of the evidence around the duration of MAP support was very low, and thus the strength of this recommendation is also weak. The GDG felt that a recommendation on the choice of vasopressor or the use of SCPP targets was not warranted, given the dearth of available evidence. CONCLUSION: We provide new recommendations for blood pressure management after acute SCI that acknowledge the limitations of the current evidence on the relationship between MAP and neurologic recovery. It was felt that the low quality of existing evidence and uncertainty around the relationship between MAP and neurologic recovery justified a greater range of MAP to target, and for a broader range of days post-injury than recommended in previous guidelines. While important knowledge gaps still remain regarding hemodynamic management, these recommendations represent current perspectives on the role of MAP augmentation for acute SCI.

STUDY DESIGN: Development of a clinical practice guideline following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) process. OBJECTIVE: The objectives of this study were to develop guidelines that outline the utility of intraoperative neuromonitoring (IONM) to detect intraoperative spinal cord injury (ISCI) among patients undergoing spine surgery, to define a subset of patients undergoing spine surgery at higher risk for ISCI and to develop protocols to prevent, diagnose, and manage ISCI. METHODS: All systematic reviews were performed according to PRISMA standards and registered on PROSPERO. A multidisciplinary, international Guidelines Development Group (GDG) reviewed and discussed the evidence using GRADE protocols. Consensus was defined by 80% agreement among GDG members. A systematic review and diagnostic test accuracy (DTA) meta-analysis was performed to synthesize pooled evidence on the diagnostic accuracy of IONM to detect ISCI among patients undergoing spinal surgery. The IONM modalities evaluated included somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), electromyography (EMG), and multimodal neuromonitoring. Utilizing this knowledge and their clinical experience, the multidisciplinary GDG created recommendations for the use of IONM to identify ISCI in patients undergoing spine surgery. The evidence related to existing care pathways to manage ISCI was summarized and based on this a novel AO Spine-PRAXIS care pathway was created. RESULTS: Our recommendations are as follows: (1) We recommend that intraoperative neurophysiological monitoring be employed for high risk patients undergoing spine surgery, and (2) We suggest that patients at high risk for ISCI during spine surgery be proactively identified, that after identification of such patients, multi-disciplinary team discussions be undertaken to manage patients, and that an intraoperative protocol including the use of IONM be implemented. A care pathway for the prevention, diagnosis, and management of ISCI has been developed by the GDG. CONCLUSION: We anticipate that these guidelines will promote the use of IONM to detect and manage ISCI, and promote the use of preoperative and intraoperative checklists by surgeons and other team members for high risk patients undergoing spine surgery. We welcome teams to implement and evaluate the care pathway created by our GDG.

BACKGROUND: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). METHODS: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. RESULTS: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal sentinel surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. CONCLUSIONS: The consortiums aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies. FUNDING: No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

Purpose: To compare the efficacy and safety of subconjunctival and intrascleral applications of mitomycin C (MMC) in trabeculectomy for high-risk glaucomas. Methodology: A randomized prospective clinical study was conducted on 41 consecutive eyes with a high risk of glaucoma surgery failure. Patients were randomized to trabeculectomy and application of subconjunctival MMC or to trabeculectomy and application of intrascleral MMC. MMC solution 0.2 mg/ml was applied for 3 minutes under the conjunctival flap overlying the proposed site of trabeculectomy in Group 1 (n=21), or intrasclerally under the superficial scleral flap in Group II (n=20) Results: After a follow-up of one year, the intraocular pressure (IOP) decreased from a mean basal IOP of 33.0 ± 8.4 mm Hg to 12.56 ± 2.54 mm Hg in Group I and from 30.9 ± 6.6 mm Hg to 11.6 ± 2.21 mm Hg in Group II. The IOP was 6 - 21 mmHg, without medication, in 90.5 % of the eyes in Group I and 75 % of the eyes Group II. Ocular hypotony, hypotony maculopathy, choroidal detachment and a shallow anterior chamber were more frequent with the intrascleral application of MMC during trabeculectomy, but the difference was not statistically significant. The overall success of the surgery at one year, i.e., achieving an IOP of 6 - 21 mmHg and a stable vision, (reduction in visual acuity of ≤2 lines), was 90.5% in Group I and 75 % in Group II. Conclusion: No significant difference was seen in overall success or complication between subconjunctival and intrascleral application of MMC-augmented trabeculectomies in glaucomatous eyes at high risk of surgical failure.

PURPOSE: Postoperative radiation therapy (RT) is an underused standard-of-care intervention for patients with prostate cancer and recurrence/adverse pathologic features after radical prostatectomy. Although stereotactic body RT (SBRT) is a well-studied and convenient option for definitive treatment, data on the postprostatectomy setting are extremely limited. The purpose of this study was to evaluate short-term physician-scored genitourinary (GU) and gastrointestinal (GI) toxicities and patient-reported outcomes after postprostatectomy SBRT. METHODS AND MATERIALS: The SCIMITAR trial was a phase 2, dual-center, open-label, single-arm trial that enrolled patients with postoperative prostate-specific antigen >0.03 ng/mL or adverse pathologic features. Coprimary endpoints were 4-year biochemical recurrence-free survival, physician-scored acute and late GU and GI toxicities by the Common Terminology Criteria for Adverse Events (version 4.03) scale, and patient-reported quality-of-life (QOL) outcomes, as represented by the Expanded Prostate Cancer Index-26 and the International Prostate Symptom Score. Patients received SBRT 30 to 34 Gy/5 fractions to the prostate bed ± bed boost ± pelvic nodes with computed tomography (CTgRT) or magnetic resonance imaging guidance (MRgRT) in a nonrandomized fashion. Physician-scored toxicities and patient-reported QOL outcomes were collected at baseline and at 1, 3, and 6 months of follow-up. Univariable and multivariable analyses were performed to evaluate predictors of toxicities and QOL outcomes. RESULTS: One hundred participants were enrolled (CTgRT, n = 69; MRgRT, n = 31). The median follow-up was 29.5 months (CTgRT: 33.3 months, MRgRT: 22.6 months). The median (range) prostate bed dose was 32 (30-34) Gy. Acute and late grade 2 GU toxicities were both 9% while acute and late grade 2 GI toxicities were 5% and 0%, respectively. Three patients had grade 3 toxicity (n = 1 GU, n = 2 GI). No patient receiving MRgRT had grade 3 GU or grade ≥2 GI toxicity. Compared with CTgRT, MRgRT was associated with a 30.5% (95% confidence interval, 11.6%-49.5%) reduction in any-grade acute GI toxicity (P = .006). MRgRT was independently associated with improved any-grade GI toxicity and improved bowel QOL. CONCLUSIONS: Postprostatectomy SBRT was well tolerated at short-term follow-up. MRgRT may decrease GI toxicity. Longer toxicity and/or efficacy follow-up and randomized studies are needed.