Pd-Catalyzed Cascade Heck/C(sp3)-H Activation for Spirocyclopropyl Oxindoles.

We have demonstrated a Pd(0)-catalyzed Heck/C(sp3)-H activation cascade for the synthesis of spirocyclopropyl oxindoles in high yields from easily accessible ortho-bromoacrylamides. The formation of spirocyclopropyl oxindole is guided by an unconventional four-membered palladacycle through C(sp3)-H activation. The reaction exhibits a wide range of substrate scope and operates efficiently with a mere 0.5 mol % of Pd-catalyst. In addition, the use of microwave conditions facilitates rapid completion of the reaction. Furthermore, this spirocyclopropanation strategy can be coupled with [3 + 2] cycloaddition to produce spiropyrrolidine oxindoles, offering a valuable approach for the preparation of alkaloids such as (±)-horsfiline and (±)-coerulescine.

Intramolecular singlet fission: Quantum dynamical simulations including the effect of the laser field.

In the previous work [Reddy et al., J. Chem. Phys. 151, 044307 (2019)], we have analyzed the dynamics of the intramolecular singlet fission process in a series of prototypical pentacene-based dimers, where the pentacene monomers are covalently bonded to a phenylene linker in ortho, meta, and para positions. The results obtained were qualitatively consistent with the experimental data available, showing an ultrafast population of the multiexcitonic state that mainly takes place via a mediated (superexchange-like) mechanism involving charge transfer and doubly excited states. Our results also highlighted the instrumental role of molecular vibrations in the process as a sizable population of the multiexcitonic state could only be obtained through vibronic coupling. Here, we extend these studies and investigate the effect of the laser field on the dynamics of intramolecular singlet fission by explicitly including the coupling to the laser field in our model. In this manner, and by selectively tuning the laser field to the different low-lying absorption bands of the systems investigated, we analyze the wavelength dependence of the intramolecular singlet fission process. In addition, we have also analyzed how the nature of the initially photoexcited electronic state (either localized or delocalized) affects its dynamics. Altogether, our results provide new insights into the design of intramolecular singlet fission-active molecules.

Performance and robustness analysis of V-Tiger PID controller for automatic voltage regulator.

This paper presents a comprehensive study on the implementation and analysis of PID controllers in an automated voltage regulator (AVR) system. A novel tuning technique, Virtual Time response-based iterative gain evaluation and re-design (V-Tiger), is introduced to iteratively adjust PID gains for optimal control performance. The study begins with the development of a mathematical model for the AVR system and initialization of PID gains using the Pessen Integral Rule. Virtual time-response analysis is then conducted to evaluate system performance, followed by iterative gain adjustments using Particle Swarm Optimization (PSO) within the V-Tiger framework. MATLAB simulations are employed to implement various controllers, including the V-Tiger PID controller, and their performance is compared in terms of transient response, stability, and control signal generation. Robustness analysis is conducted to assess the system's stability under uncertainties, and worst-case gain analysis is performed to quantify robustness. The transient response of the AVR with the proposed PID controller is compared with other heuristic controllers such as the Flower Pollination Algorithm, Teaching-Learning-based Optimization, Pessen Integral Rule, and Zeigler-Nichols methods. By measuring the peak closed-loop gain of the AVR with the controller and adding uncertainty to the AVR's field exciter and amplifier, the robustness of proposed controller is determined. Plotting the performance degradation curves yields robust stability margins and the accompanying maximum uncertainty that the AVR can withstand without compromising its stability or performance. Based on the degradation curves, robust stability margin of the V-Tiger PID controller is estimated at 3.5. The worst-case peak gains are also estimated using the performance degradation curves. Future research directions include exploring novel optimization techniques for further enhancing control performance in various industrial applications.

Revealing magnetic and physical properties of TbFe4.4Al7.6: experiment and theory.

We report on the magnetic, electrical transport, caloric and electronic structure properties of TbFe4.4Al7.6polycrystalline alloy using experiment and theory. The alloy crystallizes in tetragonal structure with I4/mmm space group with lattice parametersa = b= 8.7234(5) Å andc= 5.0387(6) Å. It is ferrimagnetic with a compensation temperature ofTcmp∼151 K, Curie-Weiss temperatureθCW∼172.11 K and an effective magnetic momentµeff= (2.37±0.07)µB/f.u withZ= 2. At low temperatures, kinetic arrest-like first-order phase transition is realized through the thermal hysteresis between field-cooled cooling and field-cooled warming curves ofM(T) and virgin curves ofM(H) andρ(H)which are outside the hysteresis loops with metamagnetic transition. The high magnetic field suppression of multiple transitions and reduced coercive fieldHcoerand remnant magnetizationMremwith increasing temperature are reported.HcoerandMremcease to exist above the compensation temperatureTcmp. A correlation between the isothermal magnetization and resistivity is discussed. Specific heatC(T) analysis reveals a Sommerfeld parameter ofγ= 0.098 J⋅mol-1⋅K-2and a Debye temperature ofθD∼351.2 K. The sample is metallic as inferred from theρ(T)behavior and Sommerfeld parameter. The magnetoresistance of the alloy is low and negative which indicates the suppression of weak spin-fluctuations. This alloy avoids the tricritical point despite first-to-second order phase transition. The electronic and magnetic structure calculations, by making use of full potential linearized augmented plane wave method, suggest metallic ferrimagnetic ground state of TbFe4.4Al7.6with Tb atoms contributing ferromagnetically (5.87µB) and Fe atoms with antiferromagnetic contribution (2.67µB), in close agreement with the experimental observation.

Mitigation of lens opacification by a functional food in a diabetic rodent model.

The current study was designed to test a functional food (FF) mixture containing aldose reductase inhibitors and antiglycation bioactive compounds for suppressing the onset and progression of cataracts in a diabetic rat model. Two-month-old Sprague Dawley rats were grouped as control (C), diabetes untreated (D), and diabetic rats treated with FF at two doses (FF1 = 1.35 g and FF2 = 6.25 g/100g of diet). Diabetes was induced by a single injection of streptozotocin. The FF is a mixture of amla, turmeric, black pepper, cinnamon, ginger, and fenugreek added to the rodent diet. The status of cataracts was monitored weekly by a slit lamp examination for 20 weeks, after which animals were sacrificed to collect eye lenses. Feeding FF1 and FF2 to diabetic rats yielded a significant anti-hyperglycaemic effect and marginally prevented body weight loss. FF delayed cataract progression, and FF2 showed better efficacy than FF1. FF prevented the loss of lens crystallins and their insolubilization in diabetic rats. The antioxidant potential of FF was evident with the lowered protein carbonyls, lipid peroxidation, and prevention of altered antioxidant enzyme activities induced by diabetes. These studies demonstrate the efficacy of plant-derived dietary supplements against the onset and progression of cataracts in a well-established rat model of diabetic eye disease.

Cyperus rotundus L.: Invasive weed plant with insecticidal potential against Aphis craccivora Koch and Planococcus lilacinus (Cockerell).

Cyperus rotundus L. is a widely distributed invasive weed plant with vast traditional medicinal uses. Herein, the methanolic root extract of C. rotundus and its fractions (n-hexane, chloroform, n-butanol, and aqueous) were evaluated for insecticidal activity against nymphs of Aphis craccivora Koch and crawlers of Planococcus lilacinus (Cockerell) to find promising lead (s). In contact topical assay, among extract/fractions, n-hexane fraction exhibited more toxicity against A. craccivora (LD50 = 1.12 µg/insect) and P. lilacinus (LD50 = 0.94 µg/insect). The chemical analysis of n-hexane fraction revealed a volatile composition similar to that of the essential oil (EO) of C. rotundus roots. Hence, EO was extracted using water and deep eutectic solvents (DESs) as cosolvent, which revealed enhancement in EO yield (from 0.28 to 0.46% w/w) on implementing DESs. A total of 35 diverse volatile metabolites were identified in all EO samples, accounting for 85.0 to 91.8% of chemical composition, having cyperotundone, cyperene mustakone, isolongifolen-5-one, boronia butenal as major constituents. The EO obtained with DES-7 [choline chloride: ethylene glycol (1:4)] and DES-6 [choline chloride: lactic acid (1:3)] were found effective against A. craccivora (LD50 = 0.62-0.87 µg/insect) and P. lilacinus (LD50= 0.59-0.67 µg/insect) after 96 h. NMR analysis of EO revealed cyperotundone as a major compound, which was isolated along with cyperene and cyperene epoxide. All the molecules were found effective against P. lilacinus, whereas against A. craccivora cyperotundone, cyperene and cyperene epoxide showed promising toxicity (LD50 = 0.74-0.86 µg/insect). Extract/fractions, EO, and isolated molecules showed a significant reproductive inhibition rate of A. craccivora at higher concentrations. All the tested concentrations of cyperotundone showed significant inhibition of acetylcholinesterase (AChE) and glutathione-S-transferase (GST) in A. craccivora and P. lilacinus. Based upon the present study, C. rotundus can be recommended to control targeted insects in the greenhouse/field conditions after performing bio-efficacy and phytotoxicity studies.

Macrocyclic Sulfur Ligand Stabilized Trans-Palladium Dichloride Complex: Syntheses, Structure, Chlorine Rotation, and Application in α-Olefination of Nitriles by Primary Alcohols.

Herein, we have reported the synthesis of a macrocyclic organosulfur ligand (L1) having a seventeen-membered macrocyclic ring. Subsequently, the corresponding trans-palladium complex (C1) of bulky macrocyclic organosulfur ligand (L1) was synthesized by reacting it with PdCl2 (CH3 CN)2 salt. The newly synthesized ligand and complex were characterized using various analytical and spectroscopic techniques. The complex showed a square planar geometry with trans orientation of two ligands around the palladium center. The complex possesses intramolecular SCH…Cl interactions of 2.648 Šbetween the macrocyclic ligand and palladium dichloride. The potential energy surface (PES) for the rotational process of C1 suggested a barrier of ~23.81 kcal/mol for chlorine rotation. Furthermore, the bulky macrocyclic organosulfur ligand stabilized palladium complex (C1) was used as a catalyst (2.5 mol %) for α-olefination of nitriles by primary alcohols. The α,ß-unsaturated nitrile compounds were found to be the major product of the reaction (57-78 % yield) with broad substrate scope and large functional group tolerance. Notably, the saturated nitrile product was not observed during the reaction. The mechanistic studies suggested the formation of H2 and H2 O as only by-products of the reaction, thereby making the protocol greener and sustainable.

Long-Term Prognosis and Predictors of Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement: A Retrospective Analysis.

BACKGROUND: Aortic valve disease is a common and impactful disorder that imposes significant health burdens and is associated with increased mortality rates. Particularly noteworthy is the emergence of transcatheter aortic valve replacement (TAVR), a minimally invasive procedure that has revolutionized the management of aortic valve disease. However, there remain certain unresolved questions and ongoing research regarding the long-term effectiveness and suitability of TAVR in various patient populations, underscoring the need for further investigation and clinical scrutiny. OBJECTIVE: This retrospective analysis aimed to investigate the long-term outcomes and predictors of mortality in 500 patients who underwent transcatheter aortic valve replacement (TAVR). METHODS: This retrospective analysis included individuals who received transcatheter aortic valve replacement (TAVR) at Sri Venkata Sai (SVS) Medical College, Mahabubnagar, Telangana, India, between January 2020 and July 2023. Demographic characteristics, including age, gender, and comorbidities, were recorded, and long-term outcomes after TAVR were assessed, including the incidence of survival rates and major adverse cardiac events (MACE). Predictors of mortality were also identified using Cox proportional hazards regression analysis. RESULTS: The study group exhibited an average age of 75.6 years (standard deviation (SD): 6.8), with 58% male and 42% female patients. Hypertension (74%), coronary artery disease (CAD) (68%), diabetes mellitus (DM) (42%), and chronic kidney disease (CKD) stage ≥ 3 (36%) were prevalent comorbidities. The median follow-up duration was 5.2 years (interquartile range (IQR): 4.3-6.8 years). The overall long-term survival rate after TAVR was 73.5% (95% confidence interval (CI): 69.8%-77.1%). Additionally, MACE occurred in 21% of patients throughout the follow-up period. The cumulative incidence of MACE at one year, three years, and five years was 6.8% (95% CI: 4.2%-9.5%), 14.2% (95% CI: 10.6%-18.7%), and 21.8% (95% CI: 17.3%-26.7%), respectively. The study found that higher age (hazard ratio (HR): 1.08, 95% CI: 1.04-1.12, p < 0.001), male gender (HR: 1.48, 95% CI: 1.15-1.91, p = 0.002), and the presence of CAD (HR: 1.72, 95% CI: 1.29-2.30, p < 0.001) were linked to an elevated risk of mortality. Additionally, diabetes mellitus (HR: 1.39, 95% CI: 1.05-1.85, p = 0.022) and CKD stage ≥ 3 (HR: 1.96, 95% CI: 1.47-2.61, p < 0.001) emerged as notable predictors of mortality. Conversely, a history of prior coronary artery bypass grafting (CABG) (HR: 0.62, 95% CI: 0.46-0.84, p = 0.003) was associated with a reduced risk of mortality. No significant associations were found between mortality and hypertension (HR: 1.12, 95% CI: 0.88-1.43, p = 0.360) or prior percutaneous coronary intervention (PCI) (HR: 1.21, 95% CI: 0.88-1.67, p = 0.245). CONCLUSION: Age, male gender, CAD, DM, and CKD stage ≥ 3 were significant indicators of mortality risk in TAVR patients. Risk stratification and individualized management are crucial in optimizing long-term outcomes following TAVR procedures.

First report of Cephalerous virescens causing Algal leaf spot of Averrhoa carambola in India.

Averrhoa carambola (Star fruit) is a drought resistant edible fruit belongs to family Oxalidaceae. It is native of Malaysia and further cultivation is extended to China, Southeast Asia, India and Northern South America. Star fruit has juicy texture and used in salads, beverages and traditionally it has been used for ayurvedic medicines in India, Brazil and China (Abduh et al. 2023). In early January 2023, we observed the symptoms of raised, more or less circular, orange to dark brown, velvet textured, scattered algal leaf spots (1-4 mm) on the upper surface of A. carambola leaves at College farm, Agricultural College, Aswaraopet (17.252039 latitude, 81.109573 longitude) (Supplementary Fig 1). The disease was observed in 2 hectare model orchard with incidence of 45% causing leaf defoliation and thereby reducing the yield and quality of fruits. Transverse section cutting of algal spots revealed the algal thalli at subcuticular region and causing necrosis of epidermal cells. Sporangiophores (n=20) raised from algal leaf spot were cylindrical, 4 to 5 celled, 200-450 µm long x 8-20 µm wide, and forming a head cell with suffultory cells and sporangia on the top. Sporangia (n=20) were spherical to elliptical, rusty brown and 17.5-29 µm long × 18-23.6 µm wide and the total number of sporangia produced by each sporangiophores varies from 1 to 6. Setae (n=20) were filamentous with three to six celled, 17.5-50 µm long × 2.5-7.5 µm wide (Supplementary Figure 2). In our collection, mature gametangia were not observed. Morphological characters were studied on 20 diseased leaf samples collected from randomly selected five plants. To isolate pathogen, fresh algal thalli (n=5) were scraped from host tissue, surface sterilized (70% alcohol (30 s), 1% sodium hypochlorite (30 s) and sterile distilled water (3 × 60 s), inoculated to trebouxia liquid media and incubated at 25 ± 2 °C with a 12 hours photoperiod for 72 hours (Vasconcelos et al. 2018). The resultant five algal filaments were subjected to PCR amplification. The primer pair PNS1/NS41 was used in a PCR to amplify a fragment of 18S rRNA (Davis and Kaur 2019). The 18S rRNA gene sequences of the algae were compared using the Basic Local Alignment Search Tool (BLAST; http://www.ncbi.nlm.nih.gov/Blast/Blast.cgi) showed that our partial sequence had 99.5% similarity to C. virescens (KM020142.1). Hence, it was classified as C. virescens and sequences was deposited in NCBI-GenBank with accession numbers (OR053653, OR243777, OR429406, OR429407 and OR243779). For proving pathogenicity, algal filaments obtained from trebouxia liquid media were inoculated to 6 months old healthy A. carambola plant. Pathogenicity test was negative and typical symptoms could not be produced even up to 150 days of inoculation. In previous studies also, due to difficulty with production of zoospores in synthetic media, Koch's postulates of C. virescens as a plant pathogen has not been demonstrated experimentally (Sunpapao et al. 2017; Sanahuja et al. 2018; Kumar et al. 2019). In the second experiment, zoosporangia spore suspension were prepared from small pieces of algal leaf spot tissue processed in a sterile pestle and mortar and filtered through sterile cheesecloth (Sunpapao et al. 2017). A total of five isolates of zoosporangia spore suspension (1 x 102 to 1 x 104/ml of water) was sprayed on healthy, surface sterilized leaves of A. carambola plants (n=5) until runoff with a handheld airpump sprayer and incubated in green house (T: 25 oC, H: 80%). During the experiment leaves were remain attached to plant (5 days old) and plants were 6 months old grown in plastic pots under controlled conditions. Two plants were inoculated with each isolate and three non inoculated control plants were included. Non inoculated controls were sprayed with sterile distilled water. The pathogenicity experiment was repeated. The initial symptoms were produced 60 days after inoculation and complete algal thalli was observed on 90 days after inoculation, control plants were without any symptoms upto 150 days. Reisolated algal thalli from symptomatic plants were morphologically similar to original algal thalli and molecularly identified as C. virescens (accession number OR067193 and OR243810). Red rust caused by C. virescens is a major algal disease in the world and causing severe leaf defoliation in various horticultural crops viz., Mangifera indica (Vasconcelos et al. 2018), Manilkara zapota (Sunpapao et al. 2017), Psidium guajava (Rajbongshi et al. 2022), Ziziphus mauritiana (Shareefa et al. 2022) and Anacardium occidentale (Dooh et al. 2022). The available literature suggest that, this is the first report of algal leaf spot on A. carambola caused by C. virescens in India. This report extends the range of known pathogens associated with A. carambola plant and serves as a basis for development and implementing disease management strategies.

Rapid sub-nanomolar protein determination in serum using electropolymerized molecularly imprinted polymers (E-MIPs).

Rapid detection of biologicals is important for a range of applications such as medical screening and diagnostics. Antibodies are typically employed for biosensing with high sensitivity and selectivity but can take months to prepare. Here, we investigate electropolymerized molecularly imprinted polymers (E-MIPs), which are produced in minutes as alternative-antibody rapid biosensors for the selective recognition of model proteins bovine haemoglobin (BHb) and bovine serum albumin (BSA). We evaluated two disposable screen-printed electrodes (SPE) designated AT-Au and BT-Au based on their different annealing temperatures. E-MIPs for BHb demonstrated an imprinting factor of 146 : 1 at 1 nM and 12 : 1 at 0.1 nM, showing high effectiveness of E-MIPs compared to their control non-imprinted polymers. The BHb imprinted E-MIP, when tested against BSA as a non-target protein, gave a selectivity factor of 6 : 1 for BHb. Sensor sensitivity directly depended on the nature of the SPE, with AT-Au SPE demonstrating limits of detection in the sub-micromolar range typically achieved for MIPs, while BT-Au SPE exhibited sensitivity in the sub-nanomolar range for target protein. We attribute this to differences in electrode surface area between AT-Au and BT-Au SPEs. The E-MIPs were also tested in calf serum as a model biological medium. The BT-Au SPE MIPs detected the presence of target protein in <10 min with an LOD of 50 pM and LOQ of 100 pM, suggesting their suitability for protein determination in serum with minimal sample preparation. Using electrochemical impedance spectroscopy, we determine equilibrium dissociation constants (KD) for E-MIPs using the Hill-Langmuir adsorption model. KD of BHb E-MIP was determined to be 0.86 ± 0.11 nM.

Embryo selection through artificial intelligence versus embryologists: a systematic review.

STUDY QUESTION: What is the present performance of artificial intelligence (AI) decision support during embryo selection compared to the standard embryo selection by embryologists? SUMMARY ANSWER: AI consistently outperformed the clinical teams in all the studies focused on embryo morphology and clinical outcome prediction during embryo selection assessment. WHAT IS KNOWN ALREADY: The ART success rate is ∼30%, with a worrying trend of increasing female age correlating with considerably worse results. As such, there have been ongoing efforts to address this low success rate through the development of new technologies. With the advent of AI, there is potential for machine learning to be applied in such a manner that areas limited by human subjectivity, such as embryo selection, can be enhanced through increased objectivity. Given the potential of AI to improve IVF success rates, it remains crucial to review the performance between AI and embryologists during embryo selection. STUDY DESIGN SIZE DURATION: The search was done across PubMed, EMBASE, Ovid Medline, and IEEE Xplore from 1 June 2005 up to and including 7 January 2022. Included articles were also restricted to those written in English. Search terms utilized across all databases for the study were: ('Artificial intelligence' OR 'Machine Learning' OR 'Deep learning' OR 'Neural network') AND ('IVF' OR 'in vitro fertili*' OR 'assisted reproductive techn*' OR 'embryo'), where the character '*' refers the search engine to include any auto completion of the search term. PARTICIPANTS/MATERIALS SETTING METHODS: A literature search was conducted for literature relating to AI applications to IVF. Primary outcomes of interest were accuracy, sensitivity, and specificity of the embryo morphology grade assessments and the likelihood of clinical outcomes, such as clinical pregnancy after IVF treatments. Risk of bias was assessed using the Modified Down and Black Checklist. MAIN RESULTS AND THE ROLE OF CHANCE: Twenty articles were included in this review. There was no specific embryo assessment day across the studies-Day 1 until Day 5/6 of embryo development was investigated. The types of input for training AI algorithms were images and time-lapse (10/20), clinical information (6/20), and both images and clinical information (4/20). Each AI model demonstrated promise when compared to an embryologist's visual assessment. On average, the models predicted the likelihood of successful clinical pregnancy with greater accuracy than clinical embryologists, signifying greater reliability when compared to human prediction. The AI models performed at a median accuracy of 75.5% (range 59-94%) on predicting embryo morphology grade. The correct prediction (Ground Truth) was defined through the use of embryo images according to post embryologists' assessment following local respective guidelines. Using blind test datasets, the embryologists' accuracy prediction was 65.4% (range 47-75%) with the same ground truth provided by the original local respective assessment. Similarly, AI models had a median accuracy of 77.8% (range 68-90%) in predicting clinical pregnancy through the use of patient clinical treatment information compared to 64% (range 58-76%) when performed by embryologists. When both images/time-lapse and clinical information inputs were combined, the median accuracy by the AI models was higher at 81.5% (range 67-98%), while clinical embryologists had a median accuracy of 51% (range 43-59%). LIMITATIONS REASONS FOR CAUTION: The findings of this review are based on studies that have not been prospectively evaluated in a clinical setting. Additionally, a fair comparison of all the studies were deemed unfeasible owing to the heterogeneity of the studies, development of the AI models, database employed and the study design and quality. WIDER IMPLICATIONS OF THE FINDINGS: AI provides considerable promise to the IVF field and embryo selection. However, there needs to be a shift in developers' perception of the clinical outcome from successful implantation towards ongoing pregnancy or live birth. Additionally, existing models focus on locally generated databases and many lack external validation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Monash Data Future Institute. All authors have no conflicts of interest to declare. REGISTRATION NUMBER: CRD42021256333.

Perioperative Management in Pulmonary Endarterectomy.

Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH), provided lesions are proximal enough in the pulmonary vasculature to be surgically accessible and the patient is well enough to benefit from the operation in the longer term. It is a major cardiothoracic operation, requiring specialized techniques and instruments developed over several decades to access and dissect out the intra-arterial fibrotic material. While in-hospital operative mortality is low (<5%), particularly in high-volume centers, careful perioperative management in the operating theater and intensive care is mandatory to balance ventricular performance, fluid balance, ventilation, and coagulation to avoid or treat complications. Reperfusion pulmonary edema, airway hemorrhage, and right ventricular failure are the most problematic complications, often requiring the use of extracorporeal membrane oxygenation to bridge to recovery. Successful PEA has been shown to improve both morbidity and mortality in large registries, with survival >70% at 10 years. For patients not suitable for PEA or with residual PH after PEA, balloon pulmonary angioplasty and/or PH medical therapy may prove beneficial. Here, we describe the indications for PEA, specific surgical and perioperative strategies, postoperative monitoring and management, and approaches for managing residual PH in the long term.

Dietary zinc inadequacy affects neurotrophic factors and proteostasis in the rat brain.

Zinc (Zn) deficiency has many adverse effects, including growth retardation, loss of appetite, vascular diseases, cognitive and memory impairment, and neurodegenerative diseases. In the current study, we investigated the hypothesis that dietary Zn inadequacy affects neurotrophic factors and proteostasis in the brain. Three-week-old Wistar/Kyoto male rats were fed either a Zn-deficient diet (D; < 1 mg Zn/kg diet; n = 18) or pair-fed with the control diet (C; 48 mg Zn/kg diet; n = 9) for 4 weeks. Subsequently, the rats in the D group were subdivided into two groups (n = 9), in which one group continued to receive a Zn-deficient diet, whereas the other received a Zn-supplemented diet (R; 48 mg Zn/kg diet) for 3 more weeks, after which the rats were sacrificed to collect their brain tissue. Markers of endoplasmic reticulum stress, ubiquitin-proteasome system, autophagy, and apoptosis, along with neurotrophic factors, were investigated by immunoblotting. Proteasomal activity was analyzed by the spectrofluorometric method. The results showed an altered ubiquitin-proteasome system and autophagy components and increased gliosis, endoplasmic reticulum stress, and apoptosis markers in Zn-deficient rats compared with the control group. Zinc repletion for 3 weeks could partially restore these alterations, indicating a necessity for an extended duration of Zn supplementation. In conclusion, a decline in Zn concentrations below a critical threshold may trigger multiple pathways, leading to brain-cell apoptosis.

Gastrointestinal manifestations in symptomatic Coronavirus disease - 19 patients and its relevance in predicting severity and outcome.

INTRODUCTION: Recent developments characterizing the pathophysiological basis of infection in the Coronavirus disease - 19 (COVID-19) have stirred great interest in studying this disease outside the purview of respiratory involvement and especially focusing on the gastrointestinal (GI) system. The present study involving a large cohort of COVID-19-infected patients reports on the characteristics of GI manifestations in patients infected with COVID-19 as well as the predictive role in their association with disease severity and adverse outcomes. METHODS: A retrospective cohort study was carried out in a tertiary care hospital in northern India. Descriptive analysis of GI symptoms was carried out followed by predictive analysis assessing COVID-19 severity and with the primary endpoint of 28-day in-hospital all-cause mortality. RESULTS: Of 3842 hospitalized COVID-19 patients, 2113 (55%) were symptomatic. GI symptoms were present in 163 (7.1%) patients. Common GI symptoms were diarrhea 65 (3.1%), anorexia 61 (2.9%) and vomiting 37 (1.8%). Mild and moderate-to-severe disease was seen in 1725 (81.6%) and 388 (18.4%) patients, respectively. Logistic regression showed greater odds of moderate-to-severe disease in patients with any GI symptoms (odds ratio [OR] 1.849, 95% CI 1.289-2.651 [p = 0.001]) and anorexia in particular (OR 2.797, 95% CI 1.647-4.753 [p = 0.001]); however, on multivariable-analysis, this association lost its significance. A total of 172 patients succumbed to illness. In the Cox proportional hazards model for mortality, patients with any GI symptom (HR 2.184, 95 CI 1.439-3.317 [p < 0.001]) and anorexia (HR 3.556, 95% CI 2.155-5.870 [p < 0.001]) had higher risk. In multi-variable analysis after adjustment to age, sex, oxygen saturation and comorbidities, the presence of any GI symptom was a significant predictor of mortality (hazard ratio adjusted [HRadj] 1.758, 95% CI 1.147-2.694 [p = 0.010]). CONCLUSION: GI symptoms were common among patients infected with COVID-19. The presence of any GI symptom was a significant predictor of the risk of mortality after adjustment to respiratory failure, age, sex and pre-existing comorbidities. The clinical and pathophysiological basis of these associations has been explored.

Optimization of Oral Posaconazole Step Down Therapy in Management of Rhino-Orbital-Cerebral Mucormycosis (ROCM): Outcome of an Institutional Protocol.

All cases of ROCM received antifungal for a prolong period in step down phase. There is no definite guidelines regarding duration. We have formulated and followed an institutional protocol with good results. To determine the outcome of an institutional protocol and required optimum duration of oral posaconazole therapy to cure ROCM in step down phase, 30 ROCM patients were followed up in step down phase. Oral posaconazole tablet was given for minimum 3, 4 & 1/2 and 6 months to stage-II, III & IV cases respectively, with a provision of extension for another 6 weeks in suspected active diseases. Nasal endoscopy, MRI, histopathology /culture of suspected tissue and hematologic investigations were done routinely to identify the residual active disease or recurrences at earliest. Outcome of this protocol proved excellent as all cases of ROCM were cured. Oral posaconazole step down therapy for a duration according to the stages of disease cured 18 cases (60%) of ROCM. Fourteen patients required extended duration of therapy as per provision of our treatment protocol. Only one patient needed re-debridement. The cases with deformities needed extended period of posaconazole therapy. No one needed posaconazole therapy for more than 7and1/2 months.