Publications by authors named "Manish Jain"

261 Publications

Intrinsically photosensitive retinal ganglion cells may disrupt the effects of visual cycle suppression in central serous chorioretinopathy.

Authors:
Manish Jain

Arq Bras Oftalmol 2022 1;85(4):437-438. Epub 2022 Aug 1.

Department of Ophthalmology, Veer Chandra Singh Garhwali, Government Institute of Medical Sciences & Research, Srinagar 246174, Uttarakhand, India.

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http://dx.doi.org/10.5935/0004-2749.2022-0125DOI Listing
August 2022

5-HT SNPs Alter the Pharmacological Signaling of Potentially Therapeutic Psychedelics.

ACS Chem Neurosci 2022 Jul 27. Epub 2022 Jul 27.

Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7365, United States.

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptor (5-HT2AR) signaling is essential for the actions of classical psychedelic drugs. In this study, we examined whether sequence variations in the 5-HT2AR gene affect the signaling of four commonly used psychedelic drugs. We examined the pharmacology of seven non-synonymous single-nucleotide polymorphisms (SNPs), which give rise to Ser12Asn, Thr25Asn, Asp48Asn, Ile197Val, Ala230Thr, Ala447Val, and His452Tyr variant 5-HT2A serotonin receptors. We found that these non-synonymous SNPs exert statistically significant, although modest, effects on the efficacy and potency of four therapeutically relevant psychedelics. Significantly, the pharmacological effects of the SNP drug actions at 5-HT2AR are drug specific.
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http://dx.doi.org/10.1021/acschemneuro.1c00815DOI Listing
July 2022

Alterations in Smell During Pregnancy: Myth or Fact?

Indian J Otolaryngol Head Neck Surg 2022 Jun 30;74(2):146-149. Epub 2020 Oct 30.

Public Health Dentistry, SMBT IDS&RC, Nasik, Maharashtra India.

To compare the olfactory functions of pregnant and non pregnant females draining the tribal tertiary care centre. Odor identification (OI), odor discrimination (OD) and odor threshold (OT) in subjects and control group with no previous Sino-nasal symptoms or pathology were included in the study. Mean scores of all the parameters were calculated in both the groups. Group A being of 60 pregnant females in 1st trimester and Group B constituted 60 non pregnant females as control group. Both the groups were matched for Age and Normal Mucociliary clearance range. Modified Indian Smell Identification Kit was used to assess all parameters. Before doing objective olfactory assessment all the study participants were given questionnaire for subjective assessment of olfaction in which we found significant impairment in drinking beverage and fragrance perception of flowers in pregnant females compared to non pregnant females. We also found there was no significant difference in mean scores of various olfactory parameters in multigravida and non pregnant females. The mean OI score in both groups was 9.54 ± 1.87 and 8.70 ± 1.62 respectively. Mean OD score of the two groups was 8.80 ± 2.61 and 9.80 ± 2.61 respectively and the mean OT score of both the groups was 6.99 ± 4.63 and 4.13 ± 2.48 respectively.
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http://dx.doi.org/10.1007/s12070-020-02243-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9256883PMC
June 2022

Design, Synthesis, and Characterization of [F]mG2P026 as a High-Contrast PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

J Med Chem 2022 Jul 8;65(14):9939-9954. Epub 2022 Jul 8.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, Massachusetts 02129, United States.

An array of triazolopyridines based on JNJ-46356479 () were synthesized as potential positron emission tomography radiotracers for metabotropic glutamate receptor 2 (mGluR2). The selected candidates featured enhanced positive allosteric modulator (PAM) activity (20-fold max.) and mGluR2 agonist activity (25-fold max.) compared to compound in the cAMP GloSensor assays. Radiolabeling of compounds and (mG2P026) was achieved via Cu-mediated radiofluorination with satisfactory radiochemical yield, >5% (non-decay-corrected); high molar activity, >180 GBq/μmol; and excellent radiochemical purity, >98%. Preliminary characterization of [F] and [F] in rats confirmed their excellent brain permeability and binding kinetics. Further evaluation of [F] in a non-human primate confirmed its superior brain heterogeneity in mapping mGluR2 and higher affinity than [F]. Pretreatment with different classes of PAMs in rats and a primate led to similarly enhanced brain uptake of [F]. As a selective ligand, [F] has the potential to be developed for translational studies.
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http://dx.doi.org/10.1021/acs.jmedchem.2c00593DOI Listing
July 2022

Efficacy and Safety of Fluticasone Furoate and Oxymetazoline Nasal Spray: A Novel First Fixed Dose Combination for the Management of Allergic Rhinitis with Nasal Congestion.

J Asthma Allergy 2022 10;15:783-792. Epub 2022 Jun 10.

Department of Clinical Research and Regulatory Affairs, Cadila Healthcare Limited, Ahmedabad, India.

Objective: To compare the efficacy and safety of a fixed dose combination of Fluticasone Furoate and Oxymetazoline Hydrochloride Nasal Spray 27.5/50 mcg (FDC) with Fluticasone Furoate Nasal Spray 27.5 mcg (Fluticasone) in the management of allergic rhinitis.

Patients And Methods: A prospective, randomized, double-blind, two-arm, active-controlled, parallel, multicenter, comparative clinical study was conducted in patients with allergic rhinitis aged 18 years and above having moderate-to-severe nasal congestion.

Results: A total of 250 patients were randomized (1:1) to receive either the FDC or Fluticasone alone in a dose of two sprays in each nostril once daily at night. There was a significantly (<0.001) greater reduction in night-time Total Nasal Symptom Score with the FDC as compared to Fluticasone at all the time points starting from as early as day 3 and sustained till the end of treatment (Day 28) (Day 3: -3.1 vs -2.2; Day 7: -4.0 vs -3.4; Day 14: -5.7 vs -5.0; Day 28: -7.0 vs -6.4). A significantly greater number of patients (<0.05) had complete relief in Nasal Congestion with the FDC (44.7%) as compared to Fluticasone (26.8%). Both the study medications were well tolerated by all the patients. The proportion of patients showing worsening of symptoms (rebound congestion/rhinitis medicamentosa) after stoppage of medication was similar in both groups (>0.05).

Conclusion: The FDC was superior to Fluticasone alone in relieving the nasal congestion and reduction of Total Nasal Symptom Score in allergic rhinitis patients with moderate-to-severe nasal congestion when administered once daily in the evening. Oxymetazoline when used along with the nasal steroid in a once daily dose does not cause rebound congestion and rhinitis medicamentosa even after long-term continuous use of 28 days.
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http://dx.doi.org/10.2147/JAA.S357288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9196668PMC
June 2022

Infectious causes of acute encephalitis syndrome hospitalizations in Central India, 2018-20.

J Clin Virol 2022 Aug 28;153:105194. Epub 2022 May 28.

Kakatiya Medical College, Warangal, Telangana, India.

Background: We enhanced surveillance of hospitalizations of all ages for acute encephalitis syndrome (AES) along with infectious aetiologies, including the Japanese encephalitis virus (JEV).

Methods: From October 2018 to September 2020, we screened neurological patients for AES in all age groups in Maharashtra and Telangana States. AES cases were enrolled at study hospitals along with other referrals and sampled with cerebrospinal fluid, acute and convalescent sera. We tested specimens for non-viral aetiologies viz. leptospirosis, typhoid, scrub typhus, malaria and acute bacterial meningitis, along with viruses - JEV, Dengue virus (DENV), Chikungunya virus (CHIKV), Chandipura virus (CHPV) and Herpes simplex virus (HSV).

Results: Among 4977 neurological hospitalizations at three study site hospitals over two years period, 857 (17.2%) were AES. However, only 287 (33.5%) AES cases were eligible. Among 278 (96.9%) enrolled AES cases, infectious aetiologies were identified in 115 (41.4%) cases, including non-viral in 17 (6.1%) cases - leptospirosis (8), scrub-typhus (3) and typhoid (6); and viral in 98 (35.3%) cases - JEV (58, 20.9%), HSV (22, 7.9%), DENV (15, 5.4%) and CHPV (3, 1.1%). JEV confirmation was significantly higher in enrolled cases than referred cases (10.2%) (p < 0.05). However, the contribution of JEV in AES cases was similar in both children and adults. JE was reported year-round and from adjacent non-endemic districts.

Conclusions: The Japanese encephalitis virus continues to be the leading cause of acute encephalitis syndrome in central India despite vaccination among children. Surveillance needs to be strengthened along with advanced diagnostic testing for assessing the impact of vaccination.
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http://dx.doi.org/10.1016/j.jcv.2022.105194DOI Listing
August 2022

Cathepsin B-Cleavable Polymeric Photosensitizer Prodrug for Selective Photodynamic Therapy: In Vitro Studies.

Pharmaceuticals (Basel) 2022 Apr 30;15(5). Epub 2022 Apr 30.

Department EMC, Faculty of Sciences and Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.

Cathepsin B is a lysosomal cysteine protease that plays an important role in cancer, atherosclerosis, and other inflammatory diseases. The suppression of cathepsin B can inhibit tumor growth. The overexpression of cathepsin B can be used for the imaging and photodynamic therapy (PDT) of cancer. PDT targeting of cathepsin B may have a significant potential for selective destruction of cells with high cathepsin B activity. We synthesized a cathepsin B-cleavable polymeric photosensitizer prodrug (CTSB-PPP) that releases pheophorbide a (Pha), an efficient photosensitizer upon activation with cathepsin B. We determined the concentration dependant uptake in vitro, the safety, and subsequent PDT-induced toxicity of CTSB-PPP, and ROS production. CTSB-PPP was cleaved in bone marrow cells (BMCs), which express a high cathepsin B level. We showed that the intracellular fluorescence of Pha increased with increasing doses (3-48 µM) and exerted significant dark toxicity above 12 µM, as assessed by MTT assay. However, 6 µM showed no toxicity on cell viability and ex vivo vascular function. Time-dependent studies revealed that cellular accumulation of CTSB-PPP (6 µM) peaked at 60 min of treatment. PDT (light dose: 0-100 J/cm, fluence rate: 100 mW/cm) was applied after CTSB-PPP treatment (6 µM for 60 min) using a special frontal light diffuser coupled to a diode laser (671 nm). PDT resulted in a light dose-dependent reduction in the viability of BMCs and was associated with an increased intracellular ROS generation. Fluorescence and ROS generation was significantly reduced when the BMCs were pre-treated with E64-d, a cysteine protease inhibitor. In conclusion, we provide evidence that CTSB-PPP showed no dark toxicity at low concentrations. This probe could be utilized as a potential imaging agent to identify cells or tissues with cathepsin B activity. CTSB-PPP-based PDT results in effective cytotoxicity and thus, holds great promise as a therapeutic agent for achieving the selective destruction of cells with high cathepsin B activity.
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http://dx.doi.org/10.3390/ph15050564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9146285PMC
April 2022

Tunable lattice thermal conductivity of twisted bilayer MoS.

Phys Chem Chem Phys 2022 Jun 8;24(22):13860-13868. Epub 2022 Jun 8.

Centre for Condensed Matter Theory, Department of Physics, Indian Institute of Science, Bangalore-560012, India.

We have studied the thermal conductivity () of layered MoS, a typical member of the transition metal dichalcogenide (TMDC) materials, using fully atomistic molecular dynamics simulations and Boltzmann transport equation (BTE) based first principles methods. We investigate the tuning of the thermal conductivity with the twist angle between two layers and found a decreasing trend of with the increase in the lattice constant of the moiré superlattice. The thermal conductivity at twist angle = 21.78° is found to be 72.03 W m K and for an angle of 2.87°, it reaches 54.48 W m K, leading to a 32% reduction in the thermal conductivity. We use first principles calculations based on the BTE for phonons to give a microscopic origin of the decrease in thermal conductivity through anharmonic phonon scattering events and also reaffirm the MD simulation results for the monolayer and bilayer.
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http://dx.doi.org/10.1039/d2cp01304eDOI Listing
June 2022

Myeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis.

Circ Res 2022 Apr 11;130(9):1289-1305. Epub 2022 Apr 11.

Division of Hematology/Oncology, Department of Internal Medicine, University of Iowa.

Background: The glycolytic enzyme PKM2 (pyruvate kinase muscle 2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined. We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis.

Methods: We generated myeloid cell-specific PKM2 mice on Ldlr (low-density lipoprotein receptor)-deficient background (PKM2Ldlr). Controls were littermate PKM2Ldlr mice. Susceptibility to atherosclerosis was evaluated in whole aortae and cross sections of the aortic sinus in male and female mice fed a high-fat Western diet for 14 weeks, starting at 8 weeks.

Results: PKM2 was upregulated in macrophages of Ldlr mice fed a high-fat Western diet compared with chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2 mice associated with decreased MCP-1 (monocyte chemoattractant protein 1) levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2 mice fed the Western diet exhibited reduced expression of proinflammatory genes, including MCP-1, IL (interleukin)-1β, and IL-12. Myeloid cell-specific PKM2 mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP (LDLR-related protein)-1 in macrophages in vitro and atherosclerotic lesions in vivo. Silencing LRP-1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr mice.

Conclusions: Genetic deletion of PKM2 in myeloid cells or limiting its nuclear translocation reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.
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http://dx.doi.org/10.1161/CIRCRESAHA.121.320704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050913PMC
April 2022

Breakdown of semiclassical description of thermoelectricity in near-magic angle twisted bilayer graphene.

Nat Commun 2022 Mar 21;13(1):1522. Epub 2022 Mar 21.

Department of Physics, Indian Institute of Science, Bangalore, 560012, India.

The planar assembly of twisted bilayer graphene (tBLG) hosts multitude of interaction-driven phases when the relative rotation is close to the magic angle (θ = 1.1). This includes correlation-induced ground states that reveal spontaneous symmetry breaking at low temperature, as well as possibility of non-Fermi liquid (NFL) excitations. However, experimentally, manifestation of NFL effects in transport properties of twisted bilayer graphene remains ambiguous. Here we report simultaneous measurements of electrical resistivity (ρ) and thermoelectric power (S) in tBLG for several twist angles between θ ~ 1.0 - 1.7. We observe an emergent violation of the semiclassical Mott relation in the form of excess S close to half-filling for θ ~ 1.6 that vanishes for θ ≳ 2. The excess S (≈2 μV/K at low temperatures T ~ 10 K at θ ≈ 1.6) persists upto ≈40 K, and is accompanied by metallic T-linear ρ with transport scattering rate (τ) of near-Planckian magnitude τ ~ kT/ℏ. Closer to θ, the excess S was also observed for fractional band filling (ν ≈ 0.5). The combination of non-trivial electrical transport and violation of Mott relation provides compelling evidence of NFL physics intrinsic to tBLG.
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http://dx.doi.org/10.1038/s41467-022-29198-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8938509PMC
March 2022

ABO-Incompatible Kidney Transplantation in India: A Single-Center Experience of First Hundred Cases.

Indian J Nephrol 2022 Jan-Feb;32(1):42-46. Epub 2021 Sep 21.

Department of Nephrology, Medanta - The Medicity, Sector 38, Gurugram, Haryana, India.

Aim: ABO-incompatible (ABOi) kidney transplantation overcomes immunological barrier of blood group incompatibility. There have been very few published experiences of ABOi kidney transplantation from India. We present our single-center experience of the first hundred ABOi kidney transplants.

Material And Methods: This is a single-center retrospective study of consecutive first hundred ABOi kidney transplant with at least 6 months of follow-up.

Results: During the study period (2011-2020), a total of 121 ABOi kidney transplants were performed. Of these, first hundred patients were analyzed. Median follow-up duration was 33 (10-101) months. Mean recipient and donor age were 41.5 ± 13 and 47.68 ± 11.25 years, respectively. Mean HLA mismatch was 4 ± 1.5. Median baseline anti-blood group antibody titer was 128 (2-1024). Most common recipient blood group was O. Patient and death censored graft survival was 93% and 94%, respectively, at median follow-up of 33 months. Biopsy-proven acute rejection (BPAR) rate was 17% with acute antibody-mediated rejection being 3%. Rate of infection was 37%, most common being urinary tract infection.

Conclusion: ABOi kidney transplant patients had acceptable patient and graft survival as well as BPAR rates. With current preconditioning protocol, infection rate was high.
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http://dx.doi.org/10.4103/ijn.IJN_465_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8916160PMC
September 2021

Immortal plain gut sutures: A case report.

Am J Ophthalmol Case Rep 2022 Jun 1;26:101461. Epub 2022 Mar 1.

Mid Atlantic Retina, The Retina Service of Wills Eye Hospital, Philadelphia, PA, USA.

Purpose: We report the case of a 79-year-old male who presented with irritation and foreign body sensation due to the subconjunctival plain gut sutures that did not dissolve three years after undergoing pars plana vitrectomy (PPV) for macular hole repair.

Observation: A 79-year-old male presented with foreign body sensation and irritation in his left eye. On slit lamp examination, the source of the foreign body sensation was two apparently intact plain gut sutures were visible under the conjunctiva, nasal and temporal to the cornea. These plain gut sutures were placed at the conclusion of PPV surgery three years prior to presentation. After discussion, the patient elected suture removal, and two thin, translucent suture fragments were removed. Histopathologic evaluation revealed eosinophilic dense collagenous material with frayed edges, compatible with gut suture, associated with rare macrophages and scant fibrous tissue.

Conclusion And Importance: The sclerotomies created for PPV occasionally need to be sutured at the conclusion of surgery to ensure wound closure, to retain tamponade, or to reduce endophthalmitis risk. Plain gut sutures have been shown to cause less scleral inflammation and to improve patient comfort compared to Vicryl sutures. However, in this case the plain gut sutures had not dissolved three years after PPV and had caused discomfort for patient and needed to be removed.
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http://dx.doi.org/10.1016/j.ajoc.2022.101461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8899224PMC
June 2022

Platelet transfusion therapy in the management of dengue patients: Role of fundus examination.

Transfus Clin Biol 2022 Feb 12. Epub 2022 Feb 12.

Department of Microbiology, VCSG Government Institute of Medical Science and Research, Srinagar, Uttarakhand, India.

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http://dx.doi.org/10.1016/j.tracli.2022.02.002DOI Listing
February 2022

Role of Integrins in Modulating Smooth Muscle Cell Plasticity and Vascular Remodeling: From Expression to Therapeutic Implications.

Cells 2022 02 13;11(4). Epub 2022 Feb 13.

Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, IA 52242, USA.

Smooth muscle cells (SMCs), present in the media layer of blood vessels, are crucial in maintaining vascular homeostasis. Upon vascular injury, SMCs show a high degree of plasticity, undergo a change from a "contractile" to a "synthetic" phenotype, and play an essential role in the pathophysiology of diseases including atherosclerosis and restenosis. Integrins are cell surface receptors, which are involved in cell-to-cell binding and cell-to-extracellular-matrix interactions. By binding to extracellular matrix components, integrins trigger intracellular signaling and regulate several of the SMC function, including proliferation, migration, and phenotypic switching. Although pharmacological approaches, including antibodies and synthetic peptides, have been effectively utilized to target integrins to limit atherosclerosis and restenosis, none has been commercialized yet. A clear understanding of how integrins modulate SMC biology is essential to facilitate the development of integrin-based interventions to combat atherosclerosis and restenosis. Herein, we highlight the importance of integrins in modulating functional properties of SMCs and their implications for vascular pathology.
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http://dx.doi.org/10.3390/cells11040646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8870356PMC
February 2022

Synthesis and Characterization of 5-(2-Fluoro-4-[C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2-pyrano[2,3-]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

J Med Chem 2022 02 28;65(3):2593-2609. Epub 2022 Jan 28.

Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, 3rd Avenue, Charlestown, Massachusetts 02129, United States.

Metabotropic glutamate receptor 2 (mGluR2) is a therapeutic target for several neuropsychiatric disorders. An mGluR2 function in etiology could be unveiled by positron emission tomography (PET). In this regard, 5-(2-fluoro-4-[C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2-pyrano[2,3-]pyridine-7-carboxamide ([C], [C]mG2N001), a potent negative allosteric modulator (NAM), was developed to support this endeavor. [C] was synthesized via the -[C]methylation of phenol with a high molar activity of 212 ± 76 GBq/μmol ( = 5) and excellent radiochemical purity (>99%). PET imaging of [C] in rats demonstrated its superior brain heterogeneity and reduced accumulation with pretreatment of mGluR2 NAMs, VU6001966 () and MNI-137 (), the extent of which revealed a time-dependent drug effect of the blocking agents. In a nonhuman primate, [C] selectively accumulated in mGluR2-rich regions and resulted in high-contrast brain images. Therefore, [C] is a potential candidate for translational PET imaging of the mGluR2 function.
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http://dx.doi.org/10.1021/acs.jmedchem.1c02004DOI Listing
February 2022

Anxiolytics and psychotropic medications in central serous chorioretinopathy: Caveats and concerns.

Authors:
Manish Jain

Indian J Ophthalmol 2022 02;70(2):700-701

Department of Ophthalmology, VCSG Government Institute of Medical Science and Research, Srinagar, Uttarakhand, India.

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http://dx.doi.org/10.4103/ijo.IJO_2917_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9023940PMC
February 2022

Risk factors and outcomes of COVID associated mucormycosis in kidney transplant recipients.

Transpl Infect Dis 2022 Apr 31;24(2):e13777. Epub 2022 Jan 31.

Director, Department of Nephrology and Renal Transplant Medicine, Medanta-The Medicity, Gurugram, Haryana, India.

Background: Invasive mucormycosis (IM) is a life-threatening fungal infection occurring mostly in solid organ transplant (SOT) recipients, patients with hematological malignancies, and diabetes. A sudden spurt of mucormycosis has been reported in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic in India; however, there is little data about coronavirus disease 2019 (COVID-19) associated mucormycosis (CAM) in kidney transplant recipients (KTRs).

Methods: We describe the clinical presentations, risk factors, treatment and outcomes of 11 mucormycosis cases in KTRs post-COVID-19 infection from February 2020 to June 2021 at a single center in India.

Results: Mucormycosis was seen in 11/102 (10.7%) KTRs during the pandemic. Six patients had mild disease and rest five had moderate disease. Seven patients had pre-existing diabetes mellitus and four developed new onset hyperglycemia after receiving steroids for COVID-19 infection. All had poorly controlled sugars at the time of presentation. Most common presentation was rhino-orbital-cerebral mucormycosis (ROCM) in 10/11 (89%) patients and one has pulmonary mucormycosis. All patients received combination of amphotericin B and surgical debridement/excision of affected tissue followed by posaconazole prophylaxis. Nine patients recovered, however two patients succumbed to their illness after median of 14 (7-21) days from diagnosis. One patient developed acute T-cell-mediated rejection during the course of recovery. At last follow up, the mean serum creatinine was 2.05 mg/dl as compared to 1.4 mg/dl at presentation.

Conclusions: IM is a common fungal infection in transplant recipients in India after COVID-19. Early diagnosis and prompt treatment with combination of surgical debridement and liposomal amphotericin B are key to better outcomes in CAM. Judicious use of steroids and control of hyperglycemia is key to avoid flaring up of the fungal infection.
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http://dx.doi.org/10.1111/tid.13777DOI Listing
April 2022

Impact of COVID-19-associated Mucormycosis in Kidney Transplant Recipients: A Multicenter Cohort Study.

Transplant Direct 2022 Jan 13;8(1):e1255. Epub 2021 Dec 13.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD.

Background: COVID-19-associated mucormycosis (CAM) is a recently emerging entity. There is a lack of reports of CAM in organ transplant recipients.

Methods: We conducted a multicenter (n = 18) retrospective research in India during November 2020 to July 2021. The purpose of this study was to explore the clinical spectrum, outcome and risk factors for mortality of CAM in kidney transplant recipients (KTRs).

Results: The incidence of CAM was 4.4% (61/1382 COVID-19-positive KTRs) with 26.2% mortality. The median age of the cohort was 45 (38-54) y. Twenty (32%) were not hospitalized and 14 (22.9%) were on room air during COVID-19. The proportion of postdischarge CAM was 59.1%, while concurrent CAM was reported in 40.9%. The presentation of CAM was 91.8% rhino-orbital-cerebral mucormycosis and 8.2% pulmonary with 19.6% and 100% mortality, respectively. In the univariable analysis, older age, obesity, difficulty of breathing, high-flow oxygen requirement, and delay in starting therapy were significantly associated with mortality. In the multivariable logistic regression analysis, patients requiring high-flow oxygen therapy [odds ratio (95% confidence interval) = 9.3 (1.6-51); = 0.01] and obesity [odds ratio (95% confidence interval) = 5.2 (1-28); = 0.05] was associated with mortality. The median follow-up of the study was 60 (35-60) d.

Conclusions: We describe the largest case series of CAM in KTRs. Morality in pulmonary CAM is extremely high. Severe COVID-19 pose extra risk for the development of CAM and associated mortality. Our report will help in better understanding the conundrum and management of CAM.
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http://dx.doi.org/10.1097/TXD.0000000000001255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8670583PMC
January 2022

Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.

Nature 2022 01 15;601(7893):452-459. Epub 2021 Dec 15.

Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA.

Structure-based virtual ligand screening is emerging as a key paradigm for early drug discovery owing to the availability of high-resolution target structures and ultra-large libraries of virtual compounds. However, to keep pace with the rapid growth of virtual libraries, such as readily available for synthesis (REAL) combinatorial libraries, new approaches to compound screening are needed. Here we introduce a modular synthon-based approach-V-SYNTHES-to perform hierarchical structure-based screening of a REAL Space library of more than 11 billion compounds. V-SYNTHES first identifies the best scaffold-synthon combinations as seeds suitable for further growth, and then iteratively elaborates these seeds to select complete molecules with the best docking scores. This hierarchical combinatorial approach enables the rapid detection of the best-scoring compounds in the gigascale chemical space while performing docking of only a small fraction (<0.1%) of the library compounds. Chemical synthesis and experimental testing of novel cannabinoid antagonists predicted by V-SYNTHES demonstrated a 33% hit rate, including 14 submicromolar ligands, substantially improving over a standard virtual screening of the Enamine REAL diversity subset, which required approximately 100 times more computational resources. Synthesis of selected analogues of the best hits further improved potencies and affinities (best inhibitory constant (K) = 0.9 nM) and CB/CB selectivity (50-200-fold). V-SYNTHES was also tested on a kinase target, ROCK1, further supporting its use for lead discovery. The approach is easily scalable for the rapid growth of combinatorial libraries and potentially adaptable to any docking algorithm.
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http://dx.doi.org/10.1038/s41586-021-04220-9DOI Listing
January 2022

Plasticity of Metal-Organic Framework Glasses.

J Am Chem Soc 2021 Dec 2;143(49):20717-20724. Epub 2021 Dec 2.

Empa-Swiss Federal Laboratories for Materials Science and Technology, Feuerwerkerstrasse 39, 3602 Thun, Switzerland.

Metal-organic framework (MOF) glasses provide new perspectives on many material properties due to their unique chemical and structural nature. Their mechanical properties are of particular interest because glasses are inherently brittle, which limits their applications as structural materials. Here we perform strain-rate-dependent uniaxial micropillar compression experiments on ZIF-62, ZIF-UC-5, and TIF-4, a series of MOF glasses with different substituting linker molecules, and find that these glasses show substantial plasticity, at least on the micrometer scale. At a quasi-static strain rate of 0.001 s, the micropillars yielded at approximately 0.32 GPa and subsequently deformed plastically up to 35% strain, irrespective of the type of substituting linker. With increasing strain rate, the yield strength of ZIF-62 evolved with the strain-rate sensitivity = 0.024 to reach a yield strength of 0.44 GPa at a strain rate of 510 s. On the basis of this relatively low strain-rate sensitivity and the absence of serrated flow, we conclude that structural densification is the predominant mechanism that accommodates such extensive plasticity.
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http://dx.doi.org/10.1021/jacs.1c08368DOI Listing
December 2021

Microbial fermentation of Fossence™, a short-chain fructo-oligosaccharide, under simulated human proximal colonic condition and assessment of its prebiotic effects-a pilot study.

FEMS Microbiol Lett 2021 12;368(21-24)

Tata Chemicals Limited-Innovation Centre, Survey No 315, Hissa No 1-14, Ambedveth (V), Paud road, Mulshi, Pune 412111, Maharashtra, India.

A short-chain fructo-oligosaccharide (sc-FOS) was tested in a simulator of the human gut microbial ecosystem (SHIME) in vitro model to quantify its prebiotic effects according to Prebiotic Index (PI) and Measure of prebiotic effect (MPE) equations. FossenceTM, (sc-FOS, 0.5%) was fermented in a simulated human proximal colonic condition, using a fecal inoculum from a healthy individual. We analysed the pH reduction, substrate utilization, lactate and short-chain fatty acid (SCFA) production and microbial community modulation. Microbial fermentation of sc-FOS strongly reduced the media pH indicating the production of lactate and SCFA with accumulation of lactate and enhanced levels of acetate (34.38 ± 0.38 mM), propionate (20.93 ± 0.56 mM) and butyrate (4.93 ± 0.03 mM) compared to 18.46 ± 0.20 mM, 6.24 ± 0.10 mM and 3.3 ± 0.06 mM in the blank, respectively. Total SCFA production in test media was 61.91 ± 0.87 mM compared to 33.65 ± 0.36 mM in blank and the contribution of free-sugars present in sc-FOS to SCFAs was negligible. Modulation of the microbial community was analysed through 16S rRNA sequencing and we found that sc-FOS greatly stimulated the beneficial bacteria such as Bifidobacteria and Lactobacillus. We report the PI and MPE values for FossenceTM, as 14.9 and 0.01 respectively at the end of 24 h, which is an indicator of a strong prebiotic effect.
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http://dx.doi.org/10.1093/femsle/fnab147DOI Listing
December 2021

Immunogenicity of Fractional Dose Inactivated Poliovirus Vaccine in India.

J Pediatric Infect Dis Soc 2022 Feb;11(2):60-68

World Health Organization, Geneva, Switzerland.

Introduction: Following the withdrawal of Sabin type 2 from trivalent oral poliovirus vaccine (tOPV) in 2016, the introduction of ≥1 dose of inactivated poliovirus vaccine (IPV) in routine immunization was recommended, either as 1 full dose (0.5mL, intramuscular) or 2 fractional doses of IPV (fIPV-0.1mL, intradermal). India opted for fIPV. We conducted a comparative assessment of IPV and fIPV.

Methods: This was a 4-arm, open-label, multicenter, randomized controlled trial. Infants were enrolled and vaccines administered according to the study design, and the blood was drawn at age 6, 14, and 18 weeks for neutralization testing against all 3 poliovirus types.

Results: Study enrolled 799 infants. The seroconversion against type 2 poliovirus with 2 fIPV doses was 85.8% (95% confidence interval [CI]: 80.1%-90.0%) when administered at age 6 and 14 weeks, 77.0% (95% CI: 70.5-82.5) when given at age 10 and 14 weeks, compared to 67.9% (95% CI: 60.4-74.6) following 1 full-dose IPV at age 14 weeks.

Conclusion: The study demonstrated the superiority of 2 fIPV doses over 1 full-dose IPV in India. Doses of fIPV given at 6 and 14 weeks were more immunogenic than those given at 10 and 14 weeks. Clinical Trial Registry of India (CTRI). Clinical trial registration number was CTRI/2017/02/007793.
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http://dx.doi.org/10.1093/jpids/piab091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8865014PMC
February 2022

Managing comorbidities in Covid-19 patients: A drug utilization study in a COVID-dedicated hospital in Northern India.

J Family Med Prim Care 2021 Sep 30;10(9):3387-3394. Epub 2021 Sep 30.

Department of Pharmacology, Mahatma Gandhi Medical College and Associated Group of Hospitals, Jaipur, Rajasthan, India.

Introduction: In the prevailing COVID-19 pandemic, the Indian healthcare system has worked hard towards restricting the adverse outcomes to the least possible figures. The present study aims to share the experience of a COVID-dedicated tertiary care government hospital in Northern India of managing COVID-19 patients with comorbidities.

Methodology: A retrospective, observational study was conducted in a COVID-dedicated tertiary health care government hospital in Northern India. Details on sociodemographic data, hospital admission data, and drug utilization pattern of all laboratory-confirmed COVID-19 patients of all age groups, either gender, having comorbidity (s), and admitted between April and September, 2020 were noted and evaluated.

Results: Among the total study participants (N = 406), 2868 drugs were prescribed. Out of these, 2336 were used for the management of symptoms of COVID-19 and 532 were used for the management of coexistent comorbidity (s). For COVID-19 symptoms, the most commonly prescribed class of drugs were antimicrobials (853, 36.52%), followed by nonsteroidal antiinflammatory drugs (374, 16.01%), proton pump inhibitors (299, 12.80%), antihistamines (232, 9.93%), immunosuppressant drugs (103, 4.41%), and others. For comorbidities most commonly prescribed were antihypertensive (310, 58.60%) drugs, followed by antidiabetic drugs (166, 31.38%), bronchodilators (34, 6.43%), thyroid hormones (11, 2.08%), immunosuppressant drugs (7, 1.32%).

Conclusion: The most frequently prescribed antihypertensives were calcium channel blockers (CCBs) and least prescribed was beta blocker+CCB. Among the antidiabetic drugs, most frequently prescribed was insulin and least prescribed was DPP-4 inhibitors and Biguanide+DPP-4 inhibitor both.
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http://dx.doi.org/10.4103/jfmpc.jfmpc_724_21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8565135PMC
September 2021

Grafalon® vs. Thymoglobulin® as an Induction Agent in Renal Transplantation - A Retrospective Study.

Indian J Nephrol 2021 Jul-Aug;31(4):336-340. Epub 2020 Nov 11.

Department of Nephrology, Medanta Institute of Kidney and Urology, Medanta - The Medicity, Sector 38, Gurugram, Haryana, India.

Introduction: Antihuman thymocyte immunoglobulin, used as an induction agent in renal transplantation, is of two types - thymoglobulin and grafalon (formerly ATG-Fresenius). In this study, we compared outcomes with these two agents.

Methods: This was a single-center retrospective study of patients transplanted from January 2017 to October 2019, who received either grafalon or thymoglobulin induction. Grafalon or thymoglobulin was given at 6 and 3 mg/kg, respectively, followed by standard triple immunosuppression of tacrolimus, MMF, and prednisolone.

Results: Median follow up was 22 (3-36) months. Thymoglobulin was given to 255 patients, whereas 78 patients received grafalon. Baseline demographics were similar between the two groups although significantly more patients in the grafalon group received ABO incompatible transplant (15% vs. 4.3%; = 0.002). Patient survival was similar between the two groups (99% in grafalon vs. 98.8% in thymoglobulin; = 1.0). Death censored graft survival was also similar (99% in grafalon vs. 100% in thymoglobulin; = 0.23). Biopsy proven acute rejection (BPAR) was significantly higher in the grafalon group (12.8% vs. 5.1%, = 0.04). The significance persisted after multivariable regression analysis ( = 0.02). Other outcomes such as infection rate and estimated glomerular filtration rate on last follow up were comparable between the two groups.

Conclusions: Grafalon (6 mg/kg dose) when used as an induction agent was associated with significantly higher rate of BPARs as compared to thymoglobulin (3 mg/kg dose) although with comparable short-term patient and death censored graft survival, graft function, and infection rates.
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http://dx.doi.org/10.4103/ijn.IJN_205_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443089PMC
November 2020

Childhood encephalitis hospitalizations associated with virus agents in medium-endemic states in India.

J Clin Virol 2021 11 14;144:104970. Epub 2021 Sep 14.

ICMR - National Institute of Virology, Pune, Maharashtra, India; Kakatiya Medical College, Warangal, Telangana, India; Government Medical College, Nagpur, Maharashtra, India; Mahatma Gandhi Institute of Medical Sciences, Sewagram, Wardha, Maharashtra, India.

Background: Japanese encephalitis (JE) is the leading cause of childhood acute encephalitis syndrome (AES) in India. We enhanced the AES surveillance in sentinel hospitals to determine trends and virus etiologies in central India.

Methods: The neurological hospitalizations among children ≤15 years were tracked by using the AES case definition implemented by the national program. Acute and convalescent sera along with cerebrospinal fluid (CSF) specimens were collected and tested at the strengthened site hospital laboratories for anti-JE, anti-Dengue and anti-Chikungunya virus by IgM ELISA; along with Chandipura virus RT-PCR. Herpes simplex and enterovirus testing was undertaken at the reference laboratory.

Results: Among 1619 pediatric neurological hospitalizations reported during 2015-16, AES case definition was fulfilled in 332 (20.5%) cases. After excluding 52 non-AES cases, 280 AES cases resident from study districts were considered eligible for study. The treating physicians diagnosed non-viral causes in 90 cases, therefore 190 (67.9%) of 280 AES cases were suspected with viral etiologies. We enrolled 140 (73.7%) of 190 eligible AES cases. Viral etiologies were confirmed in 31 (22.1%) of 140 enrolled AES cases. JE (n = 22) was the leading cause. Additional non-JE viral agents included Chikungunya (5), Dengue (2) and Chandipura (2). However, only 21 (9.4%) of 222 additional AES cases referred from peripheral hospitals were confirmed as JE.

Conclusions: Japanese encephalitis virus continues to be the leading cause of childhood acute encephalitis syndrome in central India despite vaccination program. Surveillance needs to be intensified for assessing the true disease burden of Japanese encephalitis following vaccination program implementation.
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http://dx.doi.org/10.1016/j.jcv.2021.104970DOI Listing
November 2021

PKM2 promotes neutrophil activation and cerebral thromboinflammation: therapeutic implications for ischemic stroke.

Blood 2022 02;139(8):1234-1245

Department of Internal Medicine, Division of Hematology/Oncology, University of Iowa, Iowa City, IA.

There is a critical need for cerebro-protective interventions to improve the suboptimal outcomes of patients with ischemic stroke who have been treated with reperfusion strategies. We found that nuclear pyruvate kinase muscle 2 (PKM2), a modulator of systemic inflammation, was upregulated in neutrophils after the onset of ischemic stroke in both humans and mice. Therefore, we determined the role of PKM2 in stroke pathogenesis by using murine models with preexisting comorbidities. We generated novel myeloid cell-specific PKM2-/- mice on wild-type (PKM2fl/flLysMCre+) and hyperlipidemic background (PKM2fl/flLysMCre+Apoe-/-). Controls were littermate PKM2fl/flLysMCre- or PKM2fl/flLysMCre-Apoe-/- mice. Genetic deletion of PKM2 in myeloid cells limited inflammatory response in peripheral neutrophils and reduced neutrophil extracellular traps after cerebral ischemia and reperfusion, suggesting that PKM2 promotes neutrophil hyperactivation in the setting of stroke. In the filament and autologous clot and recombinant tissue plasminogen activator stroke models, irrespective of sex, deletion of PKM2 in myeloid cells in either wild-type or hyperlipidemic mice reduced infarcts and enhanced long-term sensorimotor recovery. Laser speckle imaging revealed improved regional cerebral blood flow in myeloid cell-specific PKM2-deficient mice that was concomitant with reduced post-ischemic cerebral thrombo-inflammation (intracerebral fibrinogen, platelet [CD41+] deposition, neutrophil infiltration, and inflammatory cytokines). Mechanistically, PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. To enhance the translational significance, we inhibited PKM2 nuclear translocation using a small molecule and found significantly reduced neutrophil hyperactivation and improved short-term and long-term functional outcomes after stroke. Collectively, these findings identify PKM2 as a novel therapeutic target to improve brain salvage and recovery after reperfusion.
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http://dx.doi.org/10.1182/blood.2021012322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8874361PMC
February 2022

Interrelationship of Indoor Particulate Matter and Respiratory Dust Depositions of Women in the Residence of Dhanbad City, India.

Environ Sci Pollut Res Int 2022 Jan 19;29(3):4668-4689. Epub 2021 Aug 19.

Department of Environmental Science and Engineering, Indian Institute of Technology (Indian School of Mines), Dhanbad, Jharkhand, 826004, India.

Women spend relatively more time in indoor environments in developing countries. Exposure to various indoor air pollutants leads them to higher health risks according to household air quality in which they reside. Particulate matter (PM) exposure with their exposure duration inside the household plays a significant role in women's respiratory problems. This study measured size-segregated particulate matter concentrations in 63 residences at different locations. Respiratory dust depositions (RDDs) for 118 women in their different respiratory regions like head airway (HD), tracheobronchial (TB), and alveolar (AL) regions for the three PM size fractions (PM, PM, and PM) were investigated. For different positions like light exercise and the sitting condition, RDDs values found for AL region were 0.091 μgmin (SD: 0.067, 0.012-0.408) and 0.028 μgmin (SD: 0.021, 0.003-0.126) for PM, 0.325 μgmin (SD: 0.254, 0.053-1.521) and 0.183 μgmin (SD: 0.143, 0.031-0.857) for PM, 0.257 μgmin (SD: 0.197, 0.043-1.04) and 0.057 μgmin (SD: 0.044, 0.009-0.233) respectively for PM to females. RDDs values in the AL region significantly increase as PM (11%), PM (68%), and PM (21%), confirming that for women, the AL region is the most prominent affected zone by fine particles (PM).
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http://dx.doi.org/10.1007/s11356-021-15584-wDOI Listing
January 2022

Increasing adherence to plotting e-partograph: a quality improvement project in a rural maternity hospital in India.

BMJ Open Qual 2021 07;10(Suppl 1)

Obstetrics & Gynecology, Mahatma Gandhi Institute of Medical Sciences, Sevagram, Maharashtra, India.

Abnormal prolonged labour and its effects are important contributors to maternal and perinatal mortality and morbidity worldwide. E-partograph is a modern tool for real-time computerised recording of labour data which improves maternal and neonatal outcome. The aim was to improve the rates of e-partograph plotting in all eligible women in the labour room from existing 30% to achieve 90% in 6 months through a quality improvement (QI) process.A team of nurses, obstetricians, postgraduates and a data entry operator did a root cause analysis to identify the possible reasons for the drop in e-partograph plotting to 30%. The team used process flow mapping and fish bone analysis. Various change ideas were tested through sequential Plan-Do-Study-Act (PDSA) cycles to address the issues identified.The interventions included training labour room staff, identification of eligible women and providing an additional computer and internet facility for plotting and assigning responsibility of plotting e-partographs. We implemented these interventions in five PDSA cycles and observed outcomes by using control charts. A set of process, output and outcome indicators were used to track if the changes made were leading to improvement.The rate of e-partograph plotting increased from 30% to 93% over the study period of 6 months from August 2018 to January 2019. The result has been sustained since the last PDSA cycle. The maternal outcome included a decrease in obstructed and prolonged labour with its associated complications from 6.2% to 2.4%. The neonatal outcomes included a decrease in admissions in the neonatal intensive care unit for birth asphyxia from 8% to 3.4%. It can thus be concluded that a QI approach can help in improving adherence to e-partography plotting resulting in improved maternal health services in a rural maternity hospital in India.
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http://dx.doi.org/10.1136/bmjoq-2021-001404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336132PMC
July 2021

Institution of an antibiotic stewardship programme for rationalising antibiotic usage: a quality improvement project in the NICU of a public teaching hospital in rural central India.

BMJ Open Qual 2021 07;10(Suppl 1)

Neonatology, The University of Tennessee Health Science Center, Memphis, Tennessee, USA.

Antibiotic misuse is the most common cause of antimicrobial resistance-a globally declared emergency. This necessitates the introduction of rational antibiotic usage management policy. The paediatrics department of a public teaching hospital with around 500 neonatal intensive care unit (NICU) admissions annually revealed 75% of NICU admission exposure to any antibiotics. The aim was to institute antibiotic stewardship programme (ASP) to optimise antibiotic usage from existing 75% to 40% in a 6-month period through a quality improvement (QI) project.A root cause analysis using fishbone diagram was performed to identify the possible reasons for the high antibiotic usage. Six Plan-Do-Study-Act cycles were conducted to implement the protocols for usage of antibiotics for well-defined indications; active laboratory engagement to decrease the turnaround time for blood culture results; a hard stop to all antibiotic orders after 72 hours; streamlining of antibiotic usage; strengthening universal aseptic practices; and confidence building of staff. The outcomes monitored were antibiotic exposure rates, average number of antibiotic days in all NICU admissions, sepsis rates and mortality.Institution of ASP had significantly reduced antibiotic exposure in NICU admissions, that is, from 75% in March to 41% in August 2018. Median (IQR) antibiotic days per infant in NICU went down from 3 to 0 (0-6). The per cent of NICU admission with culture-positive sepsis and all-cause mortality rate in NICU declined from 18% to 11.56% and 25% to 16%, respectively, over these 6 months.Thus, ASP for rationalising antibiotic usage was successfully instituted in NICU of a rural medical college in central India through QI, without any adverse effect on sepsis and mortality.
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http://dx.doi.org/10.1136/bmjoq-2021-001456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8336129PMC
July 2021

Bacille Calmette-Guérin: An ophthalmic perspective.

Surv Ophthalmol 2022 Mar-Apr;67(2):307-320. Epub 2021 Jul 31.

Director of Uveitis & Ocular Pathology Department, Sankara Nethralaya, Chennai, TN, India.

Vaccines such as bacille Calmette-Guérin (BCG) are known for their heterologous effects mediated through a number of mechanisms, including trained immunity constituted by monocyte-macrophage based innate immunity. Other events such as direct hematogenous spread and induction of autoimmunity are also described. There has been a resurgent interest in harnessing some of the benefits of trained immunity in the management of COVID-19, even as several specific vaccines have been approved. We summarize the current knowledge of ocular effects of BCG. Potential effect of granulomatous inflammation on angiotensin converting enzyme activity and accentuation of cytokine storm that may result in undesirable ocular and systemic effects are also discussed.
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http://dx.doi.org/10.1016/j.survophthal.2021.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325561PMC
February 2022
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