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Aryl fluorosulfates of varying complexities have been used in amination reactions in water using a new Pd oxidative addition complex (OAC-1) developed specifically to match the needs of the fine chemicals industry, not only in terms of functional group tolerance, but also reflecting time considerations associated with these important C-N couplings. Also especially noteworthy is that they replace both PFAS-related triflates and nonaflates, which are today out of favor due to recent government regulations. The new complex based on the BippyPhos ligand is used at low loadings and under aqueous micellar conditions. Moreover, it is easily prepared and stable to long term storage. DFT calculations on the OAC precatalyst compare well with the X-ray structure of the crystals with π-complexation to the aromatic system of the ligand and also confirm the NMR data showing a mixture of conformers in solution that differ from the X-ray structure in rotation of the phenyl and t-butyl ligand substituents. An extensive variety of coupling partners, including pharmaceutically relevant APIs, readily participate under mild and environmentally responsible reaction conditions.

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Background and Aims: Magnesium sulfate (MgSO4) has been demonstrated to have analgesic property in various clinical settings. This study explores if addition of MgSO4 to ropivacaine increases its analgesic efficacy when infiltrated continuously in the postsurgical wound following total abdominal hysterectomy. Material and Methods: This randomized controlled trial was conducted at a tertiary care referral hospital in New Delhi, India. Fifty-two patients were randomized into two groups to receive the intervention of which 48 were able to complete the study. The first group (n = 26) received 0.25% ropivacaine infiltration and the second group (n = 26) received 0.25% ropivacaine with 5% MgSO4 at the incision site for 48 h postoperatively. Primary objective was to compare the total postoperative opioid (morphine) consumption by the study participants in both the groups and the secondary objectives were pain scores at rest and at movement, patient satisfaction score, and wound quality of life on the 7th postoperative day among the two groups. Results: Both the groups were comparable in their demographic characteristics. The median morphine consumed at 48 h postoperatively was 16.5 [0-77] mg in the ropivacaine group and 13[1-45] mg in the ropivacaine with MgSO4 group and the difference was statistically insignificant (P = 0.788). There was no statistical difference between the groups with respect to the pain scores, patient satisfaction, or wound quality of life at 7 days. Conclusion: The addition of MgSO4 to ropivacaine does not confer any additional postoperative analgesic benefits over ropivacaine alone in continuous wound infiltration following total abdominal hysterectomy.

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Sustainable technology for constructing Pd-catalyzed C-N bonds involving aliphatic amines is reported. A catalytic system that relies on low levels of recyclable precious metal, a known and commercially available ligand, and a recyclable aqueous medium are combined, leading to a newly developed procedure. This new technology can be used in ocean water with equal effectiveness. Applications involving highly challenging reaction partners constituting late-stage functionalization are documented, as is a short but efficient synthesis of the drug naftopidil. Comparisons with existing aminations highlight the many advances being offered.

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A general protocol employing heterogeneous catalysis has been developed that enables ppm of Pd-catalyzed C-N cross-coupling reactions under aqueous micellar catalysis. A new nanoparticle catalyst containing specifically ligated Pd, in combination with nanoreactors composed of the designer surfactant Savie, a biodegradable amphiphile, catalyzes C-N bond formations in recyclable water. A variety of coupling partners, ranging from highly functionalized pharmaceutically relevant APIs to educts from the Merck Informer Library, readily participate under these environmentally responsible, sustainable reaction conditions. Other key features associated with this report include the low levels of residual Pd found in the products, the recyclability of the aqueous reaction medium, the use of ocean water as an alternative source of reaction medium, options for the use of pseudohalides as alternative reaction partners, and associated low E factors. In addition, an unprecedented 5-step, one-pot sequence is presented, featuring several of the most widely used transformations in the pharmaceutical industry, suggesting potential industrial applications.

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BACKGROUND: The impact of intraoperative starch-based fluid therapy on postoperative kidney dysfunction in patients undergoing major abdominal surgery is uncertain. Low molecular weight starch is expected to cause less postoperative kidney dysfunction. METHODS: This retrospective study evaluated the impact of intraoperative 6% hydroxyethyl starch on postoperative renal dysfunction. The primary outcome of this study was postoperative acute kidney injury as per KDIGO definition within 72 hours of surgery. RESULTS: This study analysed data from 461 patients with a median (interquartile range) age of 45 (33-58) years, and 48.2% of all patients were female. The proportion (95% confidence interval) of patients who developed acute kidney injury was 0.18 (0.14-0.21); 62.9% of patients had acute kidney injury stage I, 32% had acute kidney injury stage II, and the rest were acute kidney injury stage III. In the propensity score-matched sample, the average treatment effect of intraoperative colloid use on postoperative serum creatinine at day 3 (p = 0.32), duration of postoperative intensive care unit stay (p = 0.97), duration of hospital stay (p = 0.37), postoperative worst international normalised ratio (p = 0.92), and postoperative transfusion requirement (p = 0.40) were not statistically significant. CONCLUSION: Intraoperative use of low molecular weight hydroxyethyl starch use was not associated with postoperative kidney dysfunction and coagulopathy in adult patients undergoing major open abdominal surgery.

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A 6-step synthesis of the antimalarial drug candidate MMV688533 is reported. Key transformations carried out under aqueous micellar conditions include two Sonogashira couplings and amide bond formation. Compared with the first-generation manufacturing process reported by Sanofi, the current route features ppm levels of palladium loading, less material input, less organic solvent, and no traditional amide coupling reagents. The overall yield is improved ten-fold, from 6.4% to 67%.

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OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.

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Pfizer's drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.

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BACKGROUND: Optimum procedural sedation is very essential for conducting non-operating room procedures such as endoscopic retrograde cholangiopancreatography (ERCP). The combination of ketamine and dexmedetomidine (KD) is expected to balance out the undesirable effects of either drug and provide smooth sedation. Together ketamine and propofol (KP) also provide synergistic sedation with stable hemodynamics. This prospective, single-blinded randomized study aimed to compare the effect of both the combinations during ERCP in terms of oxygen desaturation, respiratory depression, hemodynamic parameters, analgesia, recovery time, and ease with which the endoscopist could perform the endoscopy. METHODS: This prospective, single-blinded randomized study (CTRI/2019/08/020625) was conducted on 84, ASA (American Society of Anesthesiologists) physical status I or II patients, of age 18-65 years presenting for ERCP in a tertiary care center. They were randomized to receive either KD (n=42) or KP (n=42) combination during ERCP. Mean SPO2 at the end of the procedure was compared between the groups. Apart from these periprocedural hemodynamic and respiratory parameters, pain scores on arrival in the recovery room (t0), 15 minutes (t15), and 30 minutes (t30), recovery time, and endoscopist's satisfaction as per a Likert's scale were recorded. RESULTS: The mean SpO2 (SpO2 recorded every minute during the procedure and averaged over procedure time in minutes) in group KP (97.7 [96.1-98.6]) was significantly lower than group KD (98.5 [98.1-98.8]) (p=0.005). The post-procedure pain scores measured at t0 and t15 were higher in group KP (p<0.001 and p=0.043), and comparable at t30 in both the groups (p=0.711). The time to achieve Modified Aldrete score (MAS) ≥ 9 was significantly more in group KD (p<0.001). The lowest mean arterial pressure and heart rate in group KD were significantly lower than in group KP (p<0.001, p=0.006, respectively). The overall endoscopist satisfaction was better in group KP compared to group KD (p= 0.011). CONCLUSIONS: The combination of ketamine-dexmedetomidine for procedural sedation during ERCP is a safe alternative to ketamine-propofol with a better respiratory profile. CLINICAL TRIAL NUMBER AND REGISTRY URL: CTRI/2019/08/020625 ( www.ctri.nic.in ).

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A newly devised route to the Pfizer drug nirmatrelvir is reported that reduces the overall sequence to a 1-pot process and relies on a commercially available, green coupling reagent, T3P. The overall yield of the targeted material, isolated as its MTBE solvate, is 64%.

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PURPOSE: To evaluate the presence of SARS-CoV-2 RNA in the conjunctival swab sample of positive confirmed COVID-19 patients and to find out its association with comorbidity and severity of COVID-19 disease. METHODS: We conducted an observational cross-sectional study at a dedicated tertiary COVID-19 hospital in central India for a period of 8 weeks from February 2021to March 2021. We included patients who tested positive for SARS-CoV-2 RNA through nasopharyngeal swab and were above 18 years of age. Swab samples have been collected within 48 h of admission. Conjunctival swab was taken from the lower fornix of both eyes and sent to microbiology laboratory for real-time- polymerase chain reaction (RT-PCR). RESULTS: Out of 150 patients, conjunctival swab RT-PCR was positive in five patients (3.33%). Two patients had conjunctival manifestations in the form of conjunctivitis but conjunctival swab RT-PCR was negative in those patients. Among the RT-PCR positive patients, two (40%) were from mild, one (20%) was from moderate, and two (40%) were from severe category. No association could be established between conjunctival swab RT-PCR positivity and severity of the disease or associated comorbidity. CONCLUSION: Our study provides evidence that SARS-CoV-2 RNA could be detected in conjunctival secretions, and though the risk is relatively low, the eye may act as source of transmission. Extra caution should be taken by healthcare workers, and use of proper precautions like face shields and goggles should be encouraged.

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Highly valued products resulting from reductive aminations utilizing shelf-stable bisulfite addition compounds of aldehydes can be made under aqueous micellar catalysis conditions. Readily available α-picolineborane serves as the stoichiometric hydride source. Recycling of the aqueous reaction medium is easily accomplished, and several applications to targets in the pharmaceutical industry are documented.

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BACKGROUND AND OBJECTIVE: A large number of studies describing the clinicoepidemiological features of coronavirus disease-2019 (COVID-19) patients are available but very few studies have documented similar features of the deceased. This study was aimed to describe the clinicoepidemiological features and the causes of mortality of COVID-19 deceased patients admitted in a dedicated COVID center in India. METHODOLOGY: This was a retrospective study done in adult deceased patients admitted in COVID ICU from April 4 to July 24, 2020. The clinical features, comorbidities, complications, and causes of mortality in these patients were analyzed. Pediatric deceased were analyzed separately. RESULTS: A total of 654 adult patients were admitted in the ICU during the study period and ICU mortality was 37.7% (247/654). Among the adult deceased, 65.9% were males with a median age of 56 years [interquartile range (IQR), 41.5-65] and 94.74% had one or more comorbidities, most common being hypertension (43.3%), diabetes mellitus (34.8%), and chronic kidney disease (20.6%). The most common presenting features in these deceased were fever (75.7%), cough (68.8%), and shortness of breath (67.6%). The mean initial sequential organ failure assessment score was 9.3 ± 4.7 and 24.2% were already intubated at the time of admission. The median duration of hospital stay was 6 days (IQR, 3-11). The most common cause of death was sepsis with multi-organ failure (55.1%) followed by severe acute respiratory distress syndrome (ARDS) (25.5%). All pediatric deceased had comorbid conditions and the most common cause of death in this group was severe ARDS. CONCLUSION: In this cohort of adult deceased, most were young males with age less than 65 years with one or more comorbidities, hypertension being the most common. Only 5% of the deceased had no comorbidities. Sepsis with multi-organ dysfunction syndrome was the most common cause of death. HOW TO CITE THIS ARTICLE: Aggarwal R, Bhatia R, Kulshrestha K, Soni KD, Viswanath R, Singh AK, et al. Clinicoepidemiological Features and Mortality Analysis of Deceased Patients with COVID-19 in a Tertiary Care Center. Indian J Crit Care Med 2021; 25(6):622-628.

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Oceanic transform faults are seismically and tectonically active plate boundaries1 that leave scars-known as fracture zones-on oceanic plates that can cross entire ocean basins2. Current descriptions of plate tectonics assume transform faults to be conservative two-dimensional strike-slip boundaries1,3, at which lithosphere is neither created nor destroyed and along which the lithosphere cools and deepens as a function of the age of the plate4. However, a recent compilation of high-resolution multibeam bathymetric data from 41 oceanic transform faults and their associated fracture zones that covers all possible spreading rates shows that this assumption is incorrect. Here we show that the seafloor along transform faults is systemically deeper (by up to 1.6 kilometres) than their associated fracture zones, in contrast to expectations based on plate-cooling arguments. Accretion at intersections between oceanic ridges and transform faults seems to be strongly asymmetric: the outside corners of the intersections show shallower relief and more extensive magmatism, whereas the inside corners have deep nodal basins and seem to be magmatically starved. Three-dimensional viscoplastic numerical models show that plastic-shear failure within the deformation zone around the transform fault results in the plate boundary experiencing increasingly oblique shear at increasing depths below the seafloor. This results in extension around the inside corner, which thins the crust and lithosphere at the transform fault and is linked to deepening of the seafloor along the transform fault. Bathymetric data suggest that the thinned transform-fault crust is augmented by a second stage of magmatism as the transform fault intersects the opposing ridge axis. This makes accretion at transform-fault systems a two-stage process, fundamentally different from accretion elsewhere along mid-ocean ridges.

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On its way to the surface, the Siberian Traps magma created a complex sub-volcanic plumbing system. This resulted in a large-scale sill emplacement within the Tunguska Basin and subsequent release of sediment-derived volatiles during contact metamorphism. The distribution of sills and the released sediment-stored gas volume is, however, poorly constrained. In this paper, results from a study of nearly 300 deep boreholes intersecting sills are presented. The results show that sills with thicknesses above 100 m are abundant throughout the upper part of the sedimentary succession. A high proportion of the sills was emplaced within the Cambrian evaporites with average thicknesses in the 115-130 m range and a maximum thickness of 428 m. Thermal modelling of the cooling of the sills shows that the contact metamorphic aureoles are capable of generating 52-80 tonnes of CO2 m-2 with contributions from both marine and terrestrial carbon. When up-scaling these borehole results, an area of 12-19 000 km2 is required to generate 1000 Gt CO2 This represents only 0.7-1.2% of the total area in the Tunguska Basin affected by sills, emphasizing the importance of metamorphic gas generation in the Siberian Traps. These results strengthen the hypothesis of a sub-volcanic trigger and driver for the environmental perturbations during the End-Permian crisis.This article is part of a discussion meeting issue 'Hyperthermals: rapid and extreme global warming in our geological past'.

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The end-Triassic is characterized by one of the largest mass extinctions in the Phanerozoic, coinciding with major carbon cycle perturbations and global warming. It has been suggested that the environmental crisis is linked to widespread sill intrusions during magmatism associated with the Central Atlantic Magmatic Province (CAMP). Sub-volcanic sills are abundant in two of the largest onshore sedimentary basins in Brazil, the Amazonas and Solimões basins, where they comprise up to 20% of the stratigraphy. These basins contain extensive deposits of carbonate and evaporite, in addition to organic-rich shales and major hydrocarbon reservoirs. Here we show that large scale volatile generation followed sill emplacement in these lithologies. Thermal modeling demonstrates that contact metamorphism in the two basins could have generated 88,000 Gt CO2. In order to constrain the timing of gas generation, zircon from two sills has been dated by the U-Pb CA-ID-TIMS method, resulting in 206Pb/238U dates of 201.477 ± 0.062 Ma and 201.470 ± 0.089 Ma. Our findings demonstrate synchronicity between the intrusive phase and the end-Triassic mass extinction, and provide a quantified degassing scenario for one of the most dramatic time periods in the history of Earth.