C(sp2)-H selenylation of substituted benzo[4,5]imidazo[2,1-b]thiazoles using phenyliodine(iii)bis(trifluoroacetate) as a mediator.

Herein, an expeditious metal-free regioselective C-H selenylation of substituted benzo[4,5]imidazo[2,1-b]thiazole derivatives was devised to synthesize structurally orchestrated selenoethers with good to excellent yields. This PIFA [bis(trifluoroacetoxy)iodobenzene]-mediated protocol operates under mild conditions and offers broad functional group tolerance. In-depth mechanistic investigation supports the involvement of radical pathways. Furthermore, the synthetic utility of this methodology is portrayed through gram-scale synthesis.

Identification of amentoflavone as a potent SARS-CoV-2 Mpro inhibitor: a combination of computational studies and in vitro biological evaluation.

Small-molecule inhibitors of SARS-CoV-2 Mpro that block the active site pocket of the viral main protease have been considered potential therapeutics for the development of drugs against SARS-CoV-2. Here, we report the identification of amentoflavone (a biflavonoid) through docking-based virtual screening of a library comprised of 231 compounds consisting of flavonoids and isoflavonoids. The docking results were further substantiated through extensive analysis of the data obtained from all-atom 150 ns MD simulation. End-state effective free energy calculations using MM-PBSA calculations further suggested that (Ra)-amentoflavone (C3'-C8''-atropisomer) may show a greater binding affinity towards the Mpro than (Sa)-amentoflavone. In vitro cytotoxicity assay established that amentoflavone showed a high CC50 value indicating much lower toxicity. Further, potent inhibition of the Mpro by amentoflavone was established by studying the effect on HEK293T cells treated with SARS-CoV-2 Mpro expressing plasmid.Communicated by Ramaswamy H. Sarma.

Medicinal plant molecules against hepatitis C virus: Current status and future prospect.

Hepatitis C virus (HCV), a global malady, causes acute and chronic hepatitis leading to permanent liver damage, hepatocellular carcinoma, and death. Modern anti-HCV therapies are efficient, but mostly inaccessible for residents of underdeveloped regions. To innovate more effective treatments at affordable cost, medicinal plant-based products need to be explored. The aim of this article is to review plant constituents in the light of putative anti-HCV mechanisms of action, and discuss existing problems, challenges, and future directions for their potential application in therapeutic settings. One hundred sixty literatures were collected by using appropriate search strings via scientific search engines: Google Scholar, PubMed, ScienceDirect, and Scopus. Bibliography was prepared using Mendeley desktop software. We found a substantial number of plants that were reported to inhibit different stages of HCV life cycle. Traditional medicinal plants such as Phyllanthus amarus Schumach. and Thonn., Eclipta alba (L.) Hassk., and Acacia nilotica (L.) Delile exhibited strong anti-HCV activities. Again, several phytochemicals such as epigallocatechin-3-gallate, honokilol, punicalagin, and quercetin have shown broad-spectrum anti-HCV effect. We have presented promising phytochemicals like silymarin, curcumin, glycyrrhizin, and camptothecin for nanoparticle-based hepatocyte-targeted drug delivery. Nevertheless, only a few animal studies have been performed to validate the anti-HCV effect of these plant products. Again, insufficient clinical evaluation of the safety and effectiveness of herbal medications remain a problem. Selected plants products could be developed as novel therapeutics for HCV patients only after scrupulous evaluation of their safety and efficacy in a clinical set-up.

Pediatric Liver Abscess: Outcomes of Protocol-based Management and Predictors of Poor Outcome.

BACKGROUND: Liver abscess (LA) is an important cause of morbidity in children, especially in tropical countries. There is a paucity of data in pediatric LA with no standard guidelines regarding the best modality of treatment and drainage. With a large influx of patients at our center and protocol-based management; we aimed to study clinic-radiologic profile, risk factors, complications and outcomes of children with liver abscess and assessed possible predictors for poor outcomes. MATERIALS AND METHODS: This retrospective observational study was conducted from January 2019 to September 2019 at a tertiary care hospital in India. Records of all children (<12 years of age) with ultrasonographically diagnosed liver abscess were accessed for clinic-radiological and demographic profile, laboratory investigations, treatment, complications and outcomes. Patients were categorized into favorable or unfavorable groups based on predefined criteria and were compared for possible predictors of poor outcomes. Outcomes for the protocol-based management were analyzed. RESULTS: There were 120 cases of pediatric liver abscess with a median age of 5 years at presentation. The commonest clinical features were fever (100%) and pain in the abdomen (89.16%). The majority of liver abscesses were solitary (78.4%) and in the right lobe (73.3%). Malnutrition was present in 27.5%, overcrowding for 76.5% of patients and worm infestation in 2.5% of patients. Age-related leukocytosis ( P = 0.004), neutrophilia ( P = 0.013), elevated Aspartate transaminase ( P = 0.008), elevated alanine transaminase ( P = 0.007) and hypoalbuminemia ( P = 0.014) were significantly more in the unfavorable group. Overall, 29.2% of patients underwent conservative management with antibiotics alone, 25.0% underwent percutaneous needle aspiration (PNA), 49.1% underwent ultrasound-guided percutaneous drain (PCD) insertion and open surgical drainage (OSD) was needed in a single patient. The success rate was 100% for conservative management, 76.6% for PNA, 94.7% for PCD and 100% for OSD with an overall mortality of 2.5%. CONCLUSIONS: Age-related leukocytosis, neutrophilia, elevated aspartate transaminase or alanine transaminase and hypoalbuminemia at presentation are predictors of poor outcomes in pediatric liver abscess. Protocol-based management leads to the appropriate use of PNA and PCD while decreasing mortality and morbidity related to either.

Nonadiabatic transition probabilities for quantum systems in electromagnetic fields: Dephasing and population relaxation due to contact with a bath.

We contrast Dirac's theory of transition probabilities and the theory of nonadiabatic transition probabilities, applied to a perturbed system that is coupled to a bath. In Dirac's analysis, the presence of an excited state |k0⟩ in the time-dependent wave function constitutes a transition. In the nonadiabatic theory, a transition occurs when the wave function develops a term that is not adiabatically connected to the initial state. Landau and Lifshitz separated Dirac's excited-state coefficients into a term that follows the adiabatic theorem of Born and Fock and a nonadiabatic term that represents excitation across an energy gap. If the system remains coherent, the two approaches are equivalent. However, differences between the two approaches arise when coupling to a bath causes dephasing, a situation that was not treated by Dirac. For two-level model systems in static electric fields, we add relaxation terms to the Liouville equation for the time derivative of the density matrix. We contrast the results obtained from the two theories. In the analysis based on Dirac's transition probabilities, the steady state of the system is not an equilibrium state; also, the steady-state population ρkk,s increases with increasing strength of the perturbation and its value depends on the dephasing time T2. In the nonadiabatic theory, the system evolves to the thermal equilibrium with the bath. The difference is not simply due to the choice of basis because the difference remains when the results are transformed to a common basis.

Early Total Versus Gradually Advanced Enteral Nutrition in Stable Very-Low-Birth-Weight Preterm Neonates: A Randomized, Controlled Trial.

OBJECTIVE: To assess whether early total enteral nutrition (80 mL/kg/d) started on day 1 of life in hemodynamically stable preterm very-low-birth-weight (VLBW) neonates with the rapid advancement of feeds (20 mL/kg/d) help in the earlier achievement of full feeds (180 mL/kg/d). METHODS: Early total enteral nutrition (intervention) group feeding was started with 80 mL/kg/d on the first day in all hemodynamically stable neonates admitted with birth weight of 1000-1499 grams, born at 29-33 wk of gestation as determined by first-trimester ultrasonography (USG) or expanded New Ballard Score (NBS) and was advanced by 20 mL/kg/d until maximum feeds of 180 mL/kg/d were achieved; while in control group feeding was started with 30 mL/kg/d on the first day and was advanced by 20 mL/kg/d until maximum feeds were achieved. Primary outcome measure was time taken to achieve full feeds; secondary outcomes were duration of hospital stay, necrotizing enterocolitis (NEC), time to regain birth weight, duration of antibiotics, and death. RESULTS: Sixty VLBW neonates (1000-1499 g) with comparable baseline demographics were randomized within 24 h of admission to two groups. Early total enteral nutrition intervention group (group I, n = 31) achieved the target of full enteral nutrition at median 6 d; IQR: 0 to 7.8 d, a significantly shorter time compared to the controls (n = 29) (median 10 d; IQR: 9 to 11.0 d; p = < 0.05). CONCLUSION: Early total enteral nutrition started from the first day of life results in significantly less time to achieve full feeds in hemodynamically stable preterm and VLBW infants.

Perspectives From a Regional Plastic Surgery Centre on Evidence for the Purported Link Between SGLT2 Inhibitors and Fournier's Gangrene.

Introduction: The recent report issued by the MHRA indicating an association of Sodium glucose linked transporter type 2 (SGLT2) Inhibitors with the contraction of Fournier's Gangrene (FG), has been drawn with insufficient supporting evidence and without an adequately powered study to make any meaningful assertions or recommendations. We aimed to look specifically at the currently available dataset used to link SGLT2 Inhibitors to FG and highlight what conclusions or inferences can meaningfully be made, in particular the power of any study that would be required to make sensible conclusions. Methods: World literature review of SGLT2 Inhibitors and FG was performed. With a subsequent 10-year review of cases of FG seen in a regional burns and plastics centre. Data was collected retrospectively from the coding department at Whiston Hospital for all patients with necrotising fasciitis. An electronic document management system was used to identify patients with FG specifically as well as their diabetes state and medication history. Results: Seventy-eight patients were admitted with FG, of whom 32 had diabetes mellitus (DM). Of those with DM none was taking an SGLT2 Inhibitor, 17 patients were taking metformin, a further nine patients were taking a second line medication and 14 required insulin injections. Discussions: DM is a known major risk factor for FG, which is clearly observed in our patient cohort. The risk of patients with DM developing FG is irrespective of the medication patients are taking. The current articles and reports published have little ground to claim an association between SGLT2 Inhibitors and FG and are missing the crucial message that needs to be conveyed to the public: that DM is a major risk factor for FG and patients suffering with diabetes need to be extra vigilant.

Plant Products as Inhibitors of Coronavirus 3CL Protease.

Background: The ongoing COVID-19 pandemic has created an alarming situation due to extensive loss of human lives and economy, posing enormous threat to global health security. Till date, no antiviral drug or vaccine against SARS-CoV-2 has reached the market, although a number of clinical trials are under way. The viral 3-chymotrypsin-like cysteine protease (3CLpro), playing pivotal roles in coronavirus replication and polyprotein processing, is essential for its life cycle. In fact, 3CLpro is already a proven drug discovery target for SARS- and MERS-CoVs. This underlines the importance of 3CL protease in the design of potent drugs against COVID-19. Methods: We have collected one hundred twenty-seven relevant literatures to prepare the review article. PubMed, Google Scholar and other scientific search engines were used to collect the literature based on keywords, like "SARS-CoVs-3CL protease," "medicinal plant and anti-SARS-CoVs-3CL protease" published during 2003-2020. However, earlier publications related to this topic are also cited for necessary illustration and discussion. Repetitive articles and non-English studies were excluded. Results: From the literature search, we have enlisted medicinal plants reported to inhibit coronavirus 3CL protease. Some of the plants like Isatis tinctoria L. (syn. Isatis indigotica Fort.), Torreya nucifera (L.) Siebold and Zucc., Psoralea corylifolia L., and Rheum palmatum L. have exhibited strong anti-3CLpro activity. We have also discussed about the phytochemicals with encouraging antiviral activity, such as, bavachinin, psoralidin, betulinic acid, curcumin and hinokinin, isolated from traditional medicinal plants. Conclusion: Currently, searching for a plant-derived novel drug with better therapeutic index is highly desirable due to lack of specific treatment for SARS-CoV-2. It is expected that in-depth evaluation of medicinally important plants would reveal new molecules with significant potential to inhibit coronavirus 3CL protease for development into approved antiviral drug against COVID-19 in future.

Quantum transition probabilities due to overlapping electromagnetic pulses: Persistent differences between Dirac's form and nonadiabatic perturbation theory.

The probability of transition to an excited state of a quantum system in a time-dependent electromagnetic field determines the energy uptake from the field. The standard expression for the transition probability has been given by Dirac. Landau and Lifshitz suggested, instead, that the adiabatic effects of a perturbation should be excluded from the transition probability, leaving an expression in terms of the nonadiabatic response. In our previous work, we have found that these two approaches yield different results while a perturbing field is acting on the system. Here, we prove, for the first time, that differences between the two approaches may persist after the perturbing fields have been completely turned off. We have designed a pair of overlapping pulses in order to establish the possibility of lasting differences, in a case with dephasing. Our work goes beyond the analysis presented by Landau and Lifshitz, since they considered only linear response and required that a constant perturbation must remain as t → ∞. First, a "plateau" pulse populates an excited rotational state and produces coherences between the ground and excited states. Then, an infrared pulse acts while the electric field of the first pulse is constant, but after dephasing has occurred. The nonadiabatic perturbation theory permits dephasing, but dephasing of the perturbed part of the wave function cannot occur within Dirac's method. When the frequencies in both pulses are on resonance, the lasting differences in the calculated transition probabilities may exceed 35%. The predicted differences are larger for off-resonant perturbations.

Variance of the energy of a quantum system in a time-dependent perturbation: Determination by nonadiabatic transition probabilities.

For a quantum system in a time-dependent perturbation, we prove that the variance in the energy depends entirely on the nonadiabatic transition probability amplitudes bk(t). Landau and Lifshitz introduced the nonadiabatic coefficients for the excited states of a perturbed quantum system by integrating by parts in Dirac's expressions for the coefficients ck (1)(t) of the excited states to first order in the perturbation. This separates ck (1)(t) for each state into an adiabatic term ak (1)(t) and a nonadiabatic term bk (1)(t). The adiabatic term follows the adiabatic theorem of Born and Fock; it reflects the adjustment of the initial state to the perturbation without transitions. If the response to a time-dependent perturbation is entirely adiabatic, the variance in the energy is zero. The nonadiabatic term bk (1)(t) represents actual excitations away from the initial state. As a key result of the current work, we derive the variance in the energy of the quantum system and all of the higher moments of the energy distribution using the values of |bk(t)|2 for each of the excited states along with the energy differences between the excited states and the ground state. We prove that the same variance (through second order) is obtained in terms of Dirac's excited-state coefficients ck(t). We show that the results from a standard statistical analysis of the variance are consistent with the quantum results if the probability of excitation Pk is set equal to |bk(t)|2, but not if the probability of excitation is set equal to |ck(t)|2. We illustrate the differences between the variances calculated with the two different forms of Pk for vibration-rotation transitions of HCl in the gas phase.

Nonadiabatic transition probabilities in a time-dependent Gaussian pulse or plateau pulse: Toward experimental tests of the differences from Dirac's transition probabilities.

For a quantum system subject to a time-dependent perturbing field, Dirac's analysis gives the probability of transition to an excited state |k⟩ in terms of the norm square of the entire excited-state coefficient ck(t) in the wave function. By integrating by parts in Dirac's equation for ck(t) at first order, Landau and Lifshitz separated ck (1)(t) into an adiabatic term ak (1)(t) that characterizes the gradual adjustment of the ground state to the perturbation without transitions and a nonadiabatic term bk (1)(t) that depends explicitly on the time derivative of the perturbation at times t' ≤ t. Landau and Lifshitz stated that the probability of transition in a pulsed perturbation is given by |bk(t)|2, rather than by |ck(t)|2. We use the term "transition probability" to refer to the probability that a true excited-state component is present in the time-evolved wave function, as opposed to a smooth modification of the initial state. In recent work, we have examined the differences between |bk(t)|2 and |ck(t)|2 when a system is perturbed by a harmonic wave in a Gaussian envelope. We showed that significant differences exist when the frequency of the harmonic wave is off-resonance with the transition frequency. In this paper, we consider Gaussian perturbations and pulses that rise via a half Gaussian shoulder to a level plateau and later return to zero via a down-going half Gaussian. While the perturbation is constant, the transition probability |bk(t)|2 does not change. By contrast, |ck(t)|2 continues to oscillate while the perturbation is constant, and its time averaged value differs from |bk(t)|2. We suggest a general type of experiment to prove that the transition probability is given by |bk(t)|2, not |ck(t)|2. We propose a ratio test that does not require accurate knowledge of transition matrix elements or absolute field intensities.

Lymphangioleiomyomatosis (LAM) presenting as recurrent pneumothorax in an infant with tuberous sclerosis: treated successfully with sirolimus.

Lymphangioleiomyomatosis (LAM) either sporadic or a part of tuberous sclerosis complex is rare in paediatric age group. Here, we report a case of LAM with tuberous sclerosis in an infant. She was referred to our institute at the age of 4 months as a case of recurrent bilateral pneumothorax requiring intercostal tube drainage. Detailed history revealed that patient was symptomatic since 1 month of age in the form of seizures. She had respiratory symptoms for last 15 days. General physical examination revealed whitish macular patches. Brain imaging was suggestive of cortical tubers and subependymal nodules. The echocardiography showed right atrial rhabdomyoma. Chest CT revealed multiple cysts suggesting LAM. On the basis of above findings, a diagnosis of tuberous sclerosis complex with LAM was made. The infant was started on sirolimus and there was significant clinical and radiological improvement over a period of 2 and half years without any side effects.

Acute Hemiplegia in Children: A Prospective Study of Etiology, Clinical Presentation, and Outcome from Western India.

BACKGROUND: Hemiplegia/hemiparesis denotes the weakness of one side of the body. In contrast to adults, hemiparesis in children occurs secondary to a variety of etiological conditions. AIMS: The aim of this study was to assess the clinical, laboratory, and radiological features of children with acquired hemiparesis/hemiplegia of nontraumatic origin and intended to find its underlying etiology in the Indian children. SETTINGS AND DESIGN: This prospective, observational study was carried out at a tertiary care hospital in western India. MATERIALS AND METHODS: Children aged between 3 months and 14 years admitted to the in-patient department of a tertiary care hospital with acquired hemiparesis/hemiplegia were included over 2 years. Children with perinatal insult, preexisting neurological diseases, neurotrauma, hemiplegic migraine, and Todd's paralysis were excluded from the study. Detailed clinical examination, laboratory, and radiological investigations were done, and an attempt was made to find the underlying etiology. These children were also followed up after 1 month of discharge to look at short-term outcomes. All clinical information was recorded in a predesigned performa and was managed with Microsoft Excel spreadsheet. Frequency was presented as number (N) and percentage (%). RESULTS: Fifty-five children (male:female = 1.2:1), predominantly between 1 and 5 years of age were studied. Apart from weakness (92.8%), vomiting (70.9%), fever (58.2%), and seizure (58.2%) were the predominant presenting complaints. One-fifth of them had comorbidities; most commonly congenital heart disease. Cerebral infarction was the most common pathology in neuroimaging. Central nervous system infection (45.5%) was the most common identified etiology followed by vascular events (21.8%). Among those who could be followed up at 1 month, about 65% had some improvement in their power. CONCLUSION: Infections continue to be an important cause of neurodisability in the developing countries.

Quantum transition probabilities during a perturbing pulse: Differences between the nonadiabatic results and Fermi's golden rule forms.

For a perturbed quantum system initially in the ground state, the coefficient ck(t) of excited state k in the time-dependent wave function separates into adiabatic and nonadiabatic terms. The adiabatic term ak(t) accounts for the adjustment of the original ground state to form the new ground state of the instantaneous Hamiltonian H(t), by incorporating excited states of the unperturbed Hamiltonian H0 without transitions; ak(t) follows the adiabatic theorem of Born and Fock. The nonadiabatic term bk(t) describes excitation into another quantum state k; bk(t) is obtained as an integral containing the time derivative of the perturbation. The true transition probability is given by bk(t) 2, as first stated by Landau and Lifshitz. In this work, we contrast bk(t) 2 and ck(t) 2. The latter is the norm-square of the entire excited-state coefficient which is used for the transition probability within Fermi's golden rule. Calculations are performed for a perturbing pulse consisting of a cosine or sine wave in a Gaussian envelope. When the transition frequency ωk0 is on resonance with the frequency ω of the cosine wave, bk(t) 2 and ck(t) 2 rise almost monotonically to the same final value; the two are intertwined, but they are out of phase with each other. Off resonance (when ωk0 ≠ ω), bk(t) 2 and ck(t) 2 differ significantly during the pulse. They oscillate out of phase and reach different maxima but then fall off to equal final values after the pulse has ended, when ak(t) ≡ 0. If ωk0 < ω, bk(t) 2 generally exceeds ck(t) 2, while the opposite is true when ωk0 > ω. While the transition probability is rising, the midpoints between successive maxima and minima fit Gaussian functions of the form a exp[-b(t - d)2]. To our knowledge, this is the first analysis of nonadiabatic transition probabilities during a perturbing pulse.

Expression of Duplex shRNAs through a Lentiviral Vector against Cellular and Viral Genes Inflicts Sustained Inhibition of Hepatitis C Virus Replication.

BACKGROUND: The RNAi-based transient therapeutic approach has been well explored for its potential against the hepatitis V virus (HCV). However, to achieve a sustained virological response, a consistent presence of siRNA is needed and it can be achieved by constitutively expressing shRNAs. In this context, the lentiviral vector has emerged as an attractive tool for shRNA delivery against HCV. METHODS: We monitored HCV inhibition after single and multiple rounds of siRNA treatments against La autoantigen and HCV-NS5B in Huh-7.5 cells infected with the FL-J6/JFH chimeric HCV strain. A bicistronic self-inactivating third-generation lentiviral vector expressing shRNA under U6 and H1 promoters was constructed. To ascertain the long-term HCV inhibition, cells were transduced with lentiviral vectors and HCV inhibition was monitored by RT-PCR and Western blotting at regular intervals. RESULTS: We observed transient antiviral activity after a single round of siRNA treatment, and consecutive rounds of treatments with siRNA demonstrated a sustained HCV inhibition. Delivery of duplex shRNA expressing lentiviral vectors provided constant expression of shRNA leading to synergistic and sustained HCV inhibition. CONCLUSION: A lentiviral vector-based delivery system is a "single-shot" therapeutic strategy. It can express duplex shRNA for long-term synergistic inhibition of HCV and qualify as a promising therapeutic approach for sustained inhibition of HCV replication.