The need for prosthetic and orthotic rehabilitation inclusion in early pediatric intervention centers in India: A viewpoint.

The article focuses on the need for prosthetic and orthotic services in India to improve the quality of life of children with disabilities through early identification and intervention. Early intervention is the earliest identification and comprehensive service and support for children with developmental delays and disabilities ranging from 0 to 6 years to improve their ability to adapt to society. A practical early intervention delays or prevents future complications and prepares the child for functional adult life. It may positively affect the quality of life of the differently abled and their family members, and they can lead an active personal and social life. Also, such interventions promote the well-being and dignity of the differently abled and their parents, which may result in national economic progress. Prosthetic and orthotic rehabilitation facilities under the leadership of qualified professionals are needed in India's government and private setups.

"Hot and Achy": A Case of an Extensive Spinal Epidural Abscess.

We present a case of a 94-year-old female who presented to the emergency room with a fever and generalized weakness without an initial obvious source of infection. Throughout admission, she continued to be febrile despite broad-spectrum antibiotics. Several days into admission, the patient complained of severe back pain, necessitating magnetic resonance imaging (MRI) of the entire spine. The imaging revealed an extensive epidural fluid collection consistent with a spinal epidural abscess. Fortunately, she did not have any neurological deficits and was treated conservatively with IV antibiotics with improvement. This case highlights this rare presentation and the importance of early diagnosis and management of spinal epidural abscesses.

Study of tear function before and after laser-assisted in-situ keratomileusis.

Purpose: This work assesses the change in tear function after LASIK surgery. Methods: This prospective, observational study was conducted in the Refractive Clinic of a tertiary care rural hospital. Tear dysfunction symptoms and the tear function tests were assessed in 269 eyes of 134 patients, OSDI score was used to document the tear dysfunction symptoms. Tear function was assessed by tear meniscus height, tear film break-up time (TBUT), Lissamine green staining, corneal fluorescein staining, Schirmer test 1 without anesthesia before and at 4-6 weeks and 10-12 weeks after LASIK surgery. Results: Preoperatively OSDI score was 8.54 ± 7.71. It increased to 15.11 ± 9.18 postoperatively at 4-6 weeks after LASIK surgery and 13 ± 9.56 at 10-12 weeks after LASIK surgery Mean TBUT preoperatively was 7.82 ± 3.57 sec which decreased to 5.34 ± 2.56 sec at 4-6 weeks and to 4.53 ± 2.63 sec at 10-12 weeks postoperatively. The number of eyes with clear secretion decreased from 40.5% preoperatively to 23.4% at 4-6 weeks and to 22.3% at 10-12 weeks postoperatively, whereas the granular and cloudy secretions increased significantly in eyes after LASIK surgery. The prevalence of eyes with Lissamine green score >3 (dry eye) increased from 17.1% preoperatively to 27.9% at 4-6 weeks and to 30.5% at 10-12 weeks. Similarly, the number of eyes showing positive fluorescein corneal staining increased from 5.6% preoperatively to 19% postoperatively at 4-6 weeks. Mean Schirmer score was 28.83 ± 6.39 mm preoperatively, 22.47 ± 5.38 mm at 4-6 weeks, and 21.27 ± 4.99 mm at 10-12 weeks after LASIK surgery. Conclusion: The prevalence of dry eye increased after LASIK as was assessed by an increase in the tear dysfunction symptoms using OSDI score and the deranged values of various tear function tests after LASIK surgery.

Recent Advancement in Multicomponent Synthesis of Fused Coumarin Derivatives.

The synthesis of coumarin derivatives has been an essential topic since its discovery in 1820. In bioactive compounds, the coumarin moiety serves as a backbone, as many such bioactive compounds with the coumarin moiety play a significant role in their bioactivities. Given this moiety's relevance, several researchers are developing fused-coumarin derivatives to create new drugs. Mostly the approach done for this purpose was a multicomponent reaction based. Over the years, the multicomponent reaction has gained enormous popularity, and this approach has evolved as a replacement for conventional synthetic methods. Because of all these perspectives, we have reported the various fused-coumarin derivatives synthesized using multicomponent reactions in recent years.

Nickel-Catalyzed Direct Synthesis of N-Substituted Indoles from Amino Alcohols and Alcohols.

A one-pot cascade approach for the synthesis of N-substituted indoles from amino alcohols and alcohols under additive and base-free conditions with the liberation of water as the only stoichiometric byproduct is reported. The commercially available bench-stable Ni(OTf)2 salt in combination with 1,2-bis(dicyclohexylphosphino)ethane (dcype) is very effective for this unprecedented catalytic transformation. A broad range of substrates including aromatic and aliphatic primary alcohols, cyclic and acyclic secondary alcohols, and various substituted 2-aminophenyl ethyl alcohols are employed in the reaction conditions to provide a diverse range of N-alkylated indoles. Mechanistic studies revealed that the reaction proceeds through tandem N-alkylation via hydrogen autotransfer followed by the cyclization of N-alkylated alcohol intermediate.

An Uncommon Correlation of Rheumatoid Arthritis and Lupus Nephritis: A Case Report on the Unusual Progression of Lupus Nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by chronic, widespread inflammation and multisystem organ damage. A serious complication of SLE is damage to the kidneys, which is called lupus nephritis (LN). LN typically manifests after five years post the diagnosis of SLE. However, in this case report, the authors present a 46-year-old female with no previous history of SLE, but rather a history of rheumatoid arthritis (RA) and mixed connective tissue disease (MCTD) with the rapid progression of shortness of breath and lower extremity edema in four months' time. Upon further workup, large amounts of protein were found in the urine, consistent with nephrotic syndrome, and renal biopsy confirmed lupus nephritis. The patient ultimately achieved symptomatic relief with Benlysta® (belimumab), a recombinant human immunoglobulin G1λ (IgG1λ) monoclonal antibody. This report aims to highlight this unique presentation of both SLE and RA and bring awareness to and facilitate the early diagnosis and treatment of LN, thus mitigating permanent kidney damage.

Impact of training on use of inhalational techniques of different inhaler devices: A single institutional cross sectional observation study.

OBJECTIVE: To assess the impact of training on use of inhalational techniques of different inhaler devices in spirometry proved cases of COPD and Bronchial Asthma in a tertiary care centre. METHODS: A total of 128 spirometry proved cases of Asthma and COPD were enrolled. They were equally distributed in four groups comprising of 32 patients each according to their inhalation devices namely pMDI, Rotahaler, Accuhaler and Turbohaler. Patients were asked to demonstrate their inhalation technique and errors were noted according to their inhaler specific checklist. Patients were also interviewed regarding their knowledge about inhalation devices. Training about proper inhalation techniques was given to every participant. Rechecking of inhalation technique was again done at the second visit after 2 wks in the similar manner. Correct and incorrect steps of inhalation technique again evaluated by filling the checklist of the individual device to see post training improvement. RESULT: In our study, out of total cases more than one third of the patients were >60 yrs of age (41.4%) and most of the patients were males (62.5%). During the interview at first visit, almost 92% patients claimed to know how to use the inhalation device correctly but in reality most of the patients (around 96.1%) had committed at least one mistakes in their inhalation technique among all the inhalation steps. Errors were noted in different steps of inhalation including the essential steps among all the four devices. Statistically significant improvement in inhalation techniques including the essential steps were found among all the four devices after educational intervention and demonstration of sequential steps involved in particular inhaler. CONCLUSION: Our study confirmed a significant increase in the percentage of improvement in inhalation technique after proper demonstration and training about the inhalation devices. Inhalation technique including essential steps of inhalation significantly improved in all the four devices used.

Tandem Acceptorless Dehydrogenative Coupling-Decyanation under Nickel Catalysis.

The development of new catalytic processes based on abundantly available starting materials by cheap metals is always a fascinating task and marks an important transition in the chemical industry. Herein, a nickel-catalyzed acceptorless dehydrogenative coupling of alcohols with nitriles followed by decyanation of nitriles to access diversely substituted olefins is reported. This unprecedented C═C bond-forming methodology takes place in a tandem manner with the formation of formamide as a sole byproduct. The significant advantages of this strategy are the low-cost nickel catalyst, good functional group compatibility (ether, thioether, halo, cyano, ester, amino, N/O/S heterocycles; 43 examples), synthetic convenience, and high reaction selectivity and efficiency.

Predictors of success and failure of non-invasive ventilation use in type-2 respiratory failure.

BACKGROUND: Non-invasive ventilation is widely used now a days in patients with hypercapnic respiratory failure. Non-invasive ventilation can be used in Intensive Care Unit setting and wards provided trained staff is there to monitor. METHODS: This was a prospective observational study of 100 adult patients who were admitted with hypercapnic respiratory failure. Demographic information such as Age, Sex were recorded. Clinical parameters like Respiratory Rate, Heart Rate, Oxygen saturation and Arterial Blood Gas variables like pH, PaCO2, HCO3 were measured at the time of admission and at 1st hour, 4 hours and 24 hours after start of non-invasive ventilation. Outcome was recorded as success and failure with Non invasive ventilation. RESULTS: Out of 100 patients, 76 (76%) managed successfully with non-invasive ventilation and 24 patients (24%) needed intubation and invasive mechanical ventilation in this study. Majority of patients (76%) were with clinical diagnosis of Chronic Obstructive Pulmonary Disease. Respiratory Rate and Heart Rate were significantly lower and showed significant improvement at 1st hour, 4 hours and 24 hours in patients who successfully improved with Non invasive ventilation. Oxygen saturation was found to be significantly higher among patients successfully managed with Non invasive ventilation (84.35 ± 8.55 vs 76.87 ± 7.33) as compared to patients who required intubation. pH was found to be significantly higher (7.28 ± 0.06 vs 7.23 ± 0.05) in patients showing good response to Non invasive ventilation and improvement in pH at 1st hour, 4 hours and 24 hours was observed in patients successfully managed with Non invasive ventilation. PaCO2 level was found to be significantly lower and significant improvement in PaCO2 at 1st hour, 4 hours and 24 hours was seen in patients with Non invasive ventilation success. CONCLUSION: Improvement in clinical parameters like respiratory rate, heart rate, Oxygen saturation and improvement in ABG variables like pH, PaCO2 after 1st and 4 hours of start of Non invasive ventilation and maintaining the improvement at 24 hours are predictors of success of non-invasive ventilation in hypercapnic patients.

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19.

Patients with COVID-19 are at high risk for thrombotic arterial and venous occlusions. Lung histopathology often reveals fibrin-based blockages in the small blood vessels of patients who succumb to the disease. Antiphospholipid syndrome is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies targeting phospholipids and phospholipid-binding proteins (aPL antibodies). Case series have recently detected aPL antibodies in patients with COVID-19. Here, we measured eight types of aPL antibodies in serum samples from 172 patients hospitalized with COVID-19. These aPL antibodies included anticardiolipin IgG, IgM, and IgA; anti-ß2 glycoprotein I IgG, IgM, and IgA; and anti-phosphatidylserine/prothrombin (aPS/PT) IgG and IgM. We detected aPS/PT IgG in 24% of serum samples, anticardiolipin IgM in 23% of samples, and aPS/PT IgM in 18% of samples. Antiphospholipid autoantibodies were present in 52% of serum samples using the manufacturer's threshold and in 30% using a more stringent cutoff (≥40 ELISA-specific units). Higher titers of aPL antibodies were associated with neutrophil hyperactivity, including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate. Similar to IgG from patients with antiphospholipid syndrome, IgG fractions isolated from patients with COVID-19 promoted NET release from neutrophils isolated from healthy individuals. Furthermore, injection of IgG purified from COVID-19 patient serum into mice accelerated venous thrombosis in two mouse models. These findings suggest that half of patients hospitalized with COVID-19 become at least transiently positive for aPL antibodies and that these autoantibodies are potentially pathogenic.

Iron-Catalyzed Direct Julia-Type Olefination of Alcohols.

Herein, we report an iron-catalyzed, convenient, and expedient strategy for the synthesis of styrene and naphthalene derivatives with the liberation of dihydrogen. The use of a catalyst derived from an earth-abundant metal provides a sustainable strategy to olefins. This method exhibits wide substrate scope (primary and secondary alcohols) functional group tolerance (amino, nitro, halo, alkoxy, thiomethoxy, and S- and N-heterocyclic compounds) that can be scaled up. The unprecedented synthesis of 1-methyl naphthalenes proceeds via tandem methenylation/double dehydrogenation. Mechanistic study shows that the cleavage of the C-H bond of alcohol is the rate-determining step.

Prothrombotic antiphospholipid antibodies in COVID-19.

Patients with coronavirus disease 19 (COVID-19) are at high risk for thrombotic arterial and venous occlusions. At the same time, lung histopathology often reveals fibrin-based occlusion in the small vessels of patients who succumb to the disease. Antiphospholipid syndrome (APS) is an acquired and potentially life-threatening thrombophilia in which patients develop pathogenic autoantibodies (aPL) targeting phospholipids and phospholipid-binding proteins. Case series have recently detected aPL in patients with COVID-19. Here, we measured eight types of aPL [anticardiolipin IgG/IgM/IgA, anti-beta-2 glycoprotein I IgG/IgM/IgA, and anti- phosphatidylserine/prothrombin (aPS/PT) IgG/IgM] in the sera of 172 patients hospitalized with COVID-19. We detected aPS/PT IgG in 24%, anticardiolipin IgM in 23%, and aPS/PT IgM in 18%. Any aPL was present in 52% of patients using the manufacturer's threshold and in 30% using a more stringent cutoff (≥40 units). Higher levels of aPL were associated with neutrophil hyperactivity (including the release of neutrophil extracellular traps/NETs), higher platelet count, more severe respiratory disease, and lower glomerular filtration rate. Similar to patients with longstanding APS, IgG fractions isolated from patients with COVID-19 promoted NET release from control neutrophils. Furthermore, injection of these COVID-19 IgG fractions into mice accelerated venous thrombosis. Taken together, these studies suggest that a significant percentage of patients with COVID-19 become at least transiently positive for aPL and that these aPL are potentially pathogenic.

Bu4NI-Catalyzed, Radical-Induced Regioselective N-Alkylations and Arylations of Tetrazoles Using Organic Peroxides/Peresters.

Bu4NI-catalyzed regioselective N2-methylation, N2-alkylation, and N2-arylation of tetrazoles have been achieved using tert-butyl hydroperoxide (TBHP) as the methyl source, alkyl diacyl peroxides as the primary alkyl source, alkyl peresters as the secondary and tertiary alkyl sources, and aryl diacyl peroxides as the arylating source. These reactions proceed without pre-functionalization of tetrazole and in the absence of any metal catalysts. Here, peroxides serve the dual role of oxidants as well as alkylating or arylating agents. Based on DFT calculations, it was found that spin density, transition-state barriers (kinetic control), and thermodynamic stability of the products (thermodynamic control) play essential roles in the observed regioselectivity during N-alkylation. This radical-mediated process is amenable to a broad range of substrates and provides products in moderate to good yields.

Nickel(ii)-catalyzed direct olefination of benzyl alcohols with sulfones with the liberation of H2.

A nickel(ii)-catalyzed direct olefination of benzyl alcohols with sulfones to access various terminal and internal olefins with the liberation of hydrogen gas is reported.

Ectonucleotidase tri(di)phosphohydrolase-1 (ENTPD-1) disrupts inflammasome/interleukin 1ß-driven venous thrombosis.

Deep vein thrombosis (DVT), caused by alterations in venous homeostasis is the third most common cause of cardiovascular mortality; however, key molecular determinants in venous thrombosis have not been fully elucidated. Several lines of evidence indicate that DVT occurs at the intersection of dysregulated inflammation and coagulation. The enzyme ectonucleoside tri(di)phosphohydrolase (ENTPD1, also known as CD39) is a vascular ecto-apyrase on the surface of leukocytes and the endothelium that inhibits intravascular inflammation and thrombosis by hydrolysis of phosphodiester bonds from nucleotides released by activated cells. Here, we evaluated the contribution of CD39 to venous thrombosis in a restricted-flow model of murine inferior vena cava stenosis. CD39-deficiency conferred a >2-fold increase in venous thrombogenesis, characterized by increased leukocyte engagement, neutrophil extracellular trap formation, fibrin, and local activation of tissue factor in the thrombotic milieu. This was orchestrated by increased phosphorylation of the p65 subunit of NFκB, activation of the NLRP3 inflammasome, and interleukin-1ß (IL-1ß) release in CD39-deficient mice. Substantiating these findings, an IL-1ß-neutralizing antibody attenuated the thrombosis risk in CD39-deficient mice. These data demonstrate that IL-1ß is a key accelerant of venous thrombo-inflammation, which can be suppressed by CD39. CD39 inhibits in vivo crosstalk between inflammation and coagulation pathways, and is a critical vascular checkpoint in venous thrombosis.

Tuning the Thromboinflammatory Response to Venous Flow Interruption by the Ectonucleotidase CD39.

Objective- Leukocyte flux contributes to thrombus formation in deep veins under pathological conditions, but mechanisms that inhibit venous thrombosis are incompletely understood. Ectonucleotide di(tri)phosphohydrolase 1 ( ENTPD1 or Cd39), an ectoenzyme that catabolizes extracellular adenine nucleotides, is embedded on the surface of endothelial cells and leukocytes. We hypothesized that under venous stasis conditions, CD39 regulates inflammation at the vein:blood interface in a murine model of deep vein thrombosis. Approach and Results- CD39-null mice developed significantly larger venous thrombi under venous stasis, with more leukocyte recruitment compared with wild-type mice. Gene expression profiling of wild-type and Cd39-null mice revealed 76 differentially expressed inflammatory genes that were significantly upregulated in Cd39-deleted mice after venous thrombosis, and validation experiments confirmed high expression of several key inflammatory mediators. P-selectin, known to have proximal involvement in venous inflammatory and thrombotic events, was upregulated in Cd39-null mice. Inferior vena caval ligation resulted in thrombosis and a corresponding increase in both P-selectin and VWF (von Willebrand Factor) levels which were strikingly higher in mice lacking the Cd39 gene. These mice also manifest an increase in circulating platelet-leukocyte heteroaggregates suggesting heterotypic crosstalk between coagulation and inflammatory systems, which is amplified in the absence of CD39. Conclusions- These data suggest that CD39 mitigates the venous thromboinflammatory response to flow interruption.

Substrate-driven chemotactic assembly in an enzyme cascade.

Enzymatic catalysis is essential to cell survival. In many instances, enzymes that participate in reaction cascades have been shown to assemble into metabolons in response to the presence of the substrate for the first enzyme. However, what triggers metabolon formation has remained an open question. Through a combination of theory and experiments, we show that enzymes in a cascade can assemble via chemotaxis. We apply microfluidic and fluorescent spectroscopy techniques to study the coordinated movement of the first four enzymes of the glycolysis cascade: hexokinase, phosphoglucose isomerase, phosphofructokinase and aldolase. We show that each enzyme independently follows its own specific substrate gradient, which in turn is produced by the preceding enzymatic reaction. Furthermore, we find that the chemotactic assembly of enzymes occurs even under cytosolic crowding conditions.

Hydrogen sulfide modulates eukaryotic translation initiation factor 2α (eIF2α) phosphorylation status in the integrated stress-response pathway.

Hydrogen sulfide (H2S) regulates various physiological processes, including neuronal activity, vascular tone, inflammation, and energy metabolism. Moreover, H2S elicits cytoprotective effects against stressors in various cellular models of injury. However, the mechanism of the signaling pathways mediating the cytoprotective functions of H2S is not well understood. We previously uncovered a heme-dependent metabolic switch for transient induction of H2S production in the trans-sulfuration pathway. Here, we demonstrate that increased endogenous H2S production or its exogenous administration modulates major components of the integrated stress response promoting a metabolic state primed for stress response. We show that H2S transiently increases phosphorylation of eukaryotic translation initiation factor 2 (eIF2α) resulting in inhibition of general protein synthesis. The H2S-induced increase in eIF2α phosphorylation was mediated at least in part by inhibition of protein phosphatase-1 (PP1c) via persulfidation at Cys-127. Overexpression of a PP1c cysteine mutant (C127S-PP1c) abrogated the H2S effect on eIF2α phosphorylation. Our data support a model in which H2S exerts its cytoprotective effect on ISR signaling by inducing a transient adaptive reprogramming of global mRNA translation. Although a transient increase in endogenous H2S production provides cytoprotection, its chronic increase such as in cystathionine ß-synthase deficiency may pose a problem.

Heme-dependent Metabolite Switching Regulates H2S Synthesis in Response to Endoplasmic Reticulum (ER) Stress.

Substrate ambiguity and relaxed reaction specificity underlie the diversity of reactions catalyzed by the transsulfuration pathway enzymes, cystathionine ß-synthase (CBS) and γ-cystathionase (CSE). These enzymes either commit sulfur metabolism to cysteine synthesis from homocysteine or utilize cysteine and/or homocysteine for synthesis of H2S, a signaling molecule. We demonstrate that a kinetically controlled heme-dependent metabolite switch in CBS regulates these competing reactions where by cystathionine, the product of CBS, inhibits H2S synthesis by the second enzyme, CSE. Under endoplasmic reticulum stress conditions, induction of CSE and up-regulation of the CBS inhibitor, CO, a product of heme oxygenase-1, flip the operating preference of CSE from cystathionine to cysteine, transiently stimulating H2S production. In contrast, genetic deficiency of CBS leads to chronic stimulation of H2S production. This metabolite switch from cystathionine to cysteine and/or homocysteine renders H2S synthesis by CSE responsive to the known modulators of CBS: S-adenosylmethionine, NO, and CO. Used acutely, it regulates H2S synthesis; used chronically, it might contribute to disease pathology.

Synthetic Nano- and Micromachines in Analytical Chemistry: Sensing, Migration, Capture, Delivery, and Separation.

Synthetic nano- and microscale machines move autonomously in solution or drive fluid flows by converting sources of energy into mechanical work. Their sizes are comparable to analytes (sub-nano- to microscale), and they respond to signals from each other and their surroundings, leading to emergent collective behavior. These machines can potentially enable hitherto difficult analytical applications. In this article, we review the development of different classes of synthetic nano- and micromotors and pumps and indicate their possible applications in real-time in situ chemical sensing, on-demand directional transport, cargo capture and delivery, as well as analyte isolation and separation.