Accessibility audit of a health care institute in India: Are people with disabilities being provided their rights?

Background: Poor accessibility of health care facilities is a major barrier for differently abled people when seeking health care. Yet, accessibility is rarely audited. This study reports findings from the first assessment of the accessibility in a health care institution of national importance. This study also assumes importance from various laws and legislation that assure equality and rights for people with disabilities (PWDs). Keeping the objectives in mind, this study was performed with an aim to study the situational analysis of the health institution of national importance for assessing the compliance of hospital premises for being disabled friendly, to find any lacunae, and to suggest remedial measures based on the study finding. The aim was to conduct a content and quality review of research into the hospital experiences of PWD and to identify gaps. Methods: This was a hospital-based cross sectional study done in a period of 30 days. The gap analysis was performed with validated checklist provided by Central Public Works Department, Government of India (CPWD). Results: Out of total 126 pointers, 45 pointers were found to be totally compliant, 30 pointers were found to be partially compliant, and remaining 51 pointers were found to be not applicable to the hospitals. Conclusion: This assessment of the accessibility of health care facilities showed that that it is feasible to undertake these audits on a large scale, and these audits should be repeated in other settings. It highlights important gaps in accessibility, increasing the risk of the violation of the right to health of PWDs.

Co-Delivery of Aceclofenac and Methotrexate Nanoparticles Presents an Effective Treatment for Rheumatoid Arthritis.

Background: Rheumatoid arthritis (RA) is a common acute inflammatory autoimmune connective tissue arthropathy. The genetic studies, tissue analyses, experimental animal models, and clinical investigations have confirmed that stromal tissue damage and pathology driven by RA mounts the chronic inflammation and dysregulated immune events. Methods: We developed methotrexate (MTX)-loaded lipid-polymer hybrid nanoparticles (MTX-LPHNPs) and aceclofenac (ACE)-loaded nanostructured lipid carriers (ACE-NLCs) for the efficient co-delivery of MTX and ACE via intravenous and transdermal routes, respectively. Bio-assays were performed using ex-vivo skin permeation and transport, macrophage model of inflammation (MMI) (LPS-stimulated THP-1 macrophages), Wistar rats with experimental RA (induction of arthritis with Complete Freund's adjuvant; CFA and BCG), and programmed death of RA affected cells. In addition, gene transcription profiling and serum estimation of inflammatory, signaling, and cell death markers were performed on the blood samples collected from patients with RA. Results: Higher permeation of ACE-NLCs/CE across skin layers confirming the greater "therapeutic index" of ACE. The systemic delivery of MTX-loaded LPHNPs via the parenteral (intravenous) route is shown to modulate the RA-induced inflammation and other immune events. The regulated immunological and signaling pathway(s) influence the immunological axis to program the death of inflamed cells in the MMI and the animals with the experimental RA. Our data suggested the CD40-mediated and Akt1 controlled cell death along with the inhibited autophagy in vitro. Moreover, the ex vivo gene transcription profiling in drug-treated PBMCs and serum analysis of immune/signalling markers confirmed the therapeutic role co-delivery of drug nanoparticles to treat RA. The animals with experimental RA receiving drug treatment were shown to regain the structure of paw bones and joints similar to the control and were comparable with the market formulations. Conclusion: Our findings confirmed the use of co-delivery of drug nanoformulations as the "combination drug regimen" to treat RA.

Novel Discoveries and Clinical Advancements for Treating Onychomycosis: A Mechanistic Insight.

Onychomycosis continues to be the most challenging disease condition for pharmaceutical scientists to develop an effective drug delivery system. Treatment challenges lie in incomplete cure and high relapse rate. Present compilation provides cumulative information on pathophysiology, diagnostic techniques, and conventional treatment strategies to manage onychomycosis. Novel technologies developed for successful delivery of antifungal molecules are also discussed in brief. Multidirectional information offered by this article also unlocks the panoramic view of leading patented technologies and clinical trials. The obtained clinical landscape recommends the use of advanced technology driven approaches, as a promising way-out for treatment of onychomycosis. Collectively, present review warrants the application of novel technologies for the successful management of onychomycosis. This review will assist readers to envision a better understanding about the technologies available for combating onychomycosis. We also trust that these contributions address and certainly will encourage the design and development of nanocarriers-based delivery vehicles for effective management of onychomycosis.

Corrigendum: Nanostructured lipid carrier-mediated transdermal delivery of aceclofenac hydrogel present an effective therapeutic approach for inflammatory diseases.

[This corrects the article DOI: 10.3389/fphar.2021.713616.].

ML-Based Texture and Wavelet Features Extraction Technique to Predict Gastric Mesothelioma Cancer.

Microsatellites are small, repetitive sequences found all across the human genome. Microsatellite instability is the phenomenon of variations in the length of microsatellites induced by the insertion or deletion of repeat units in tumor tissue (MSI). MSI-type stomach malignancy has distinct genetic phenotypes and clinic pathological characteristics, and the stability of microsatellites influences whether or not patients with gastric mesothelioma react to immunotherapy. As a result, determining MSI status prior to surgery is critical for developing treatment options for individuals with gastric cancer. Traditional MSI detection approaches need immunological histochemistry and genetic analysis, which adds to the expense and makes it difficult to apply to every patient in clinical practice. In this study, to predict the MSI status of gastric cancer patients, researchers used image feature extraction technology and a machine learning algorithm to evaluate high-resolution histopathology pictures of patients. 279 cases of raw data were obtained from the TCGA database, 442 samples were obtained after preprocessing and upsampling, and 445 quantitative image features, including first-order statistics of impressions, texture features, and wavelet features, were extracted from the histopathological images of each sample. To filter the characteristics and provide a prediction label (risk score) for MSI status of gastric cancer, Lasso regression was utilized. The predictive label's classification performance was evaluated using a logistic classification model, which was then coupled with the clinical data of each patient to create a customized nomogram for MSI status prediction using multivariate analysis.

Application of lean management after audit of Medical Records Department in a COVID19 dedicated center during the COVID pandemic.

Background: The Medical Record (MR) contains the information which is needed to plan, provide, and evaluate the care given to the individual. It also serves as a pivotal tool for communicating information to all the health personnel who manage the patient, and it contributes to the continuity of patient care. There is an unmet need of identifying and correcting the issues faced with MR and Medical Records Departments (MRDs) so that higher efficiency can be achieved. This study was conducted to study the deficiencies and discrepancies found in MRD files during COVID management and to correlate the deficiencies with the facilities available and the workflow. Later Lean Management (LM) was applied to ensure compliance and efficiency in the system. Methods: An observational study was done on the audit of COVID 19 patient files and facilities in the care centres. Process mapping was done. The data for LM were collected by brainstorming, observation, interview, and workflow review of several processes, values, number of wastes, and suggestions were documented the MRD staff. Results: Area available was 400 m2 which is adequate against the norm of 350 m2. The existing staff of 30 was adequate as per norms. Deficiencies were observed in physical examination, history, radiology, and laboratory reports. The findings showed that the MRD units had 13 current processes, 26 wastes, and 10 values were identified. In addition, they were offered a total of 25 comments on eliminating the waste. Conclusion: Staff and equipment were adequate. Recommendations include regular staff training and usage of electronic medical records, focus on deficiency check by specific MRD staff on regular basis monitored by the administration and supported by the medical audit committee. The study also recommends that suggestions applied after LM should be implemented in letter and spirit and a repeat study of LM is advisable after regular intervals to maintain the quality standards and to maintain or further improve the efficiency.

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

A Rare Case of Isolated Intraventricular Primary Central Nervous System Lymphoma in an 85-Year-Old Man.

Primary CNS lymphoma (PCNSL) is rare malignant B cell lymphoid tumor of brain which predominantly occurs in supratentorial region in periventricular location. Majority of PCNSL are of DLBCL type and idiopathic in etiology. Here we are reporting a case of primary CNS lymphoma, DLBCL involving extremely uncommon intraventricular location. Central neurocytoma, subependymal giant cell astrocytoma, choroid plexus tumors and meningiomas are the common diagnosis at this site. Aim of reporting this case is to bring awareness of unusual intraventricular location of primary CNS lymphoma which should be kept in mind before considering gross total excision of lesion.

Nanostructured Lipid Carrier-Mediated Transdermal Delivery of Aceclofenac Hydrogel Present an Effective Therapeutic Approach for Inflammatory Diseases.

Aceclofenac (ACE), a cyclooxygenase-2 inhibitor, is the derivative of the diclofenac group that has been in use for the symptomatic treatment of systemic inflammatory autoimmune disease, rheumatoid arthritis (RA). Partial solubility, high lipophilic nature, and stability challenge its use in developing topical formulations. Hence, we developed and characterized nanostructured lipid carrier (NLC)-based ACE (ACE-NLC) hydrogel for an efficient transdermal delivery. NLC microemulsion was prepared using different lipids by various methods and was characterized with respect to particle size, zeta potential, surface morphology, and drug encapsulation efficiency. The optimized NLC formulation was incorporated into Carbopol® 940 gel, and this arrangement was characterized and compared with the existing marketed gel (Mkt-gel) formulation to assess in vitro drug release, rheology, texture profile, in vivo skin retention and permeation, and stability. Furthermore, prepared and characterized ACE-loaded NLC formulation was evaluated for skin integrity and fitted in a dermatokinetic model. The results of this study confirmed the spherical shape; smooth morphology and nanometric size attested by Zetasizer and scanning and transmission electron microcopy; and stability of the ACE-NLC formulation. The ACE-NLC-gel formulation showed good rheological and texture characteristics, and better skin distribution in the epidermis and dermis. Moreover, ACE-NLC permeated deeper in the skin layers and kept the skin integrity intact. Overall, NLC-based gel formulation of ACE might be a promising nanoscale lipid carrier for topical application when compared with the conventional Mkt-gel formulation.

Attaining a British consensus statement on managing idiopathic congenital talipes equinovarus (CTEV) through a Delphi process: a study protocol.

INTRODUCTION: Idiopathic congenital talipes equinovarus (CTEV) is the most common congenital limb deformity. Non-operative intervention using the Ponseti method has shown to be superior to soft tissue release and has become the gold standard for first-line treatment. However, numerous deviations from the Ponseti protocol are still reported following incomplete correction or deformity relapse. Significant variation in treatment protocols and management is evident in the literature. Reducing geographical treatment variation has been identified as one of The James Lind Alliance priorities in children's orthopaedics. For this reason, the British Society of Children's Orthopaedic Surgery (BSCOS) commissioned a consensus document to form a benchmark for practitioners and ensure consistent high quality care for children with CTEV. METHODS AND ANALYSIS: The consensus will follow an established Delphi approach aiming at gaining an agreement on the items to be included in the consensus statement for the management of primary idiopathic CTEV up to walking age. The process will include the following steps: (1) establishing a steering group, (2) steering group meetings, (3) a two-round Delphi survey aimed at BSCOS members, (4) final consensus meeting and (5) dissemination of the consensus statement. Degree of agreement for each item will be predetermined. Descriptive statistics will be used for analysis of the Delphi survey results. ETHICS AND DISSEMINATION: No patient involvement is required for this project. Informed consent will be assumed from participants taking part in the Delphi survey. Study findings will be published in an open access journal and presented at relevant national and international conferences. Charities and associations will be engaged to promote awareness of the consensus statement.

Radial EBUS-Guided Cryobiopsy of Peripheral Lung Lesions With Flexible Bronchoscopy Without Using Guide-Sheath.

BACKGROUND: A guide-sheath (GS) is conventionally used as a conduit for biopsy forceps under the guidance of radial endobronchial ultrasound (REBUS) for sampling the peripheral pulmonary lesions (PPLs). As compared with forceps, the cryoprobe has the advantage of obtaining larger samples. There is a paucity of literature on the use of cryobiopsy for PPL. We evaluated the diagnostic yield and safety of the REBUS-guided cryobiopsy (REBUS-CB) without using GS for the diagnosis of PPL. METHODS: We retrospectively analyzed the database of 126 patients with PPL between November 2015 and December 2019. The REBUS-CB was performed using a flexible bronchoscopy without GS. Multidisciplinary consensus diagnostic yield was determined and procedural complications were recorded. RESULTS: The histopathologic diagnosis by REBUS-CB, which is the primary objective of the study was obtained in 99 (78.6%) of total 126 cases. Yield was significantly higher in central lesions as compared to adjacent lesions visualized by the REBUS probe (81.4% versus 53.8%, P=0.021) but not significantly different between large (≥30 mm) and small (<30 mm) lesions (81.6% versus 71.8%, P=0.214). The average largest diameter of biopsy specimens was 6.9 mm (range 1-12, SD 2.132). We witnessed moderate bleeding in 7 (5.6%) and post procedure hypoxic respiratory failure in 4 (3.2%) cases which could be managed without escalation of care. CONCLUSION: The REBUS-CB from peripheral lung lesions are feasible even without using GS and significantly large samples can be obtained.

Efficient in vitro and in vivo docetaxel delivery mediated by pH-sensitive LPHNPs for effective breast cancer therapy.

The present study was designed to develop pH-sensitive lipid polymer hybrid nanoparticles (pHS-LPHNPs) for specific cytosolic-delivery of docetaxel (DTX). The pHS-LPHNPs-DTX formulation was prepared by self-assembled nano-precipitation technique and characterized for zeta potential, particle size, entrapment efficiency, polydispersity index (PDI), and in vitro drug release. In vitro cytotoxicity of pHS-LPHNPs-DTX was assessed on breast cancer cells (MDA-MB-231 and MCF-7) and compared with DTX-loaded conventional LPHNPs and bare DTX. In vitro cellular uptake in MDA-MB-231 cell lines showed better uptake of pHS-LPHNPs. Further, a significant reduction in the IC50 of pHS-LPHNPs-DTX against both breast cancer cells was observed. Flow cytometry results showed greater apoptosis in case of pHS-LPHNPs-DTX treated MDA-MB-231 cells. Breast cancer was experimentally induced in BALB/c female mice, and the in vivo efficacy of the developed pHS-LPHNPs formulation was assessed with respect to the pharmacokinetics, biodistribution in the vital organs (liver, kidney, heart, lungs, and spleen), percentage tumor burden, and survival of breast cancer-bearing animals. In vivo studies showed improved pharmacokinetic and target-specificity with minimum DTX circulation in the deep-seated organs in the case of pHS-LPHNPs-DTX compared to the LPHNPs-DTX and free DTX. Mice treated with pHS-LPHNPs-DTX exhibited a significantly lesser tumor burden than other treatment groups. Also, reduced distribution of DTX in the serum was evident for pHS-LPHNPs-DTX treated mice compared to the LPHNPs-DTX and free DTX. In essence, pHS-LPHNPs mediated delivery of DTX presents a viable platform for developing therapeutic-interventions against breast-cancer.

Safety and diagnostic yield of transbronchial lung cryobiopsy by flexible bronchoscopy using laryngeal mask airway in diffuse and localized peripheral lung diseases: A single-center retrospective analysis of 326 cases.

BACKGROUND: Intubation with either an endotracheal tube or a rigid bronchoscope is generally preferred to provide airway protection as well as to manage unpredictable complications during transbronchial lung cryobiopsy (TBLC). The laryngeal mask airway has been described as a safe and convenient tool for airway control during bronchoscopy. AIMS AND OBJECTIVES: In this study, we evaluated the safety and outcome of using a laryngeal mask airway (LMA) as a conduit for performing TBLC by flexible video bronchoscopy (FB). METHODS: We retrospectively analyzed the database of the patients who underwent TBLC between November 2015 and September 2019. The procedure was performed using FB through LMA under general anesthesia. Prophylactic occlusion balloon was routinely used starting January 2017 onwards. Radial endobronchial ultrasound (R-EBUS) guidance was used for TBLC in the localized lung lesions when deemed necessary. Multidisciplinary consensus diagnostic yield was determined and periprocedural complications were recorded. RESULTS: A total of 326 patients were analysed. The overall diagnostic yield was 81.60% (266/326) which included a positive yield of 82.98% (161/194) in patients with diffuse lung disease and 79.54% (105/132) in patients with localized disease. Serious bleeding complication occurred in 3 (0.92%) cases. Pneumothorax was encountered in 8 (2.45%) cases. A total of 9 (2.76%) cases had at least 1 major complication. CONCLUSION: This study demonstrates that the use of LMA during TBLC by flexible bronchoscopy allows for a convenient port of entry, adequate airway support and effective endoscopic management of intrabronchial haemorrhage especially with the use of occlusion balloon.

Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability.

Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.

Chemoselective probe for detailed analysis of ketones and aldehydes produced by gut microbiota in human samples.

New strategies are required for the discovery of unknown bioactive molecules produced by gut microbiota in the human host. Herein, we utilize a chemoselective probe immobilized to magnetic beads for analysis of carbonyls in human fecal samples. We identified 112 metabolites due to femtomole analysis and an increased mass spectrometric sensitivity by up to six orders of magnitude.

Low reporting of violence against health-care workers in India in spite of high prevalence.

BACKGROUND: Violence against health-care workers has become a great issue in health-care organizations. This study was conceptualized with the aim to know the prevalence of violence and to identify gap between rate of reporting of an incident of violence at a tertiary care hospital in India. METHODS: The study was descriptive and cross-sectional; a validated questionnaire was used as a tool. Reported incidents of violence against workers were collected. P value <0.05 was considered statistically significant in the analysis. A Z test for proportion at 95% confidence interval was applied to analyze the level of difference between prevalence, rate of reporting, and their level of awareness. RESULTS: Of 394 respondents, 136(34.5%) workers had experienced workplace violence in the last 12 months. It was found that total 32 incidents of workplace violence were reported to the concerned authority. The reporting rate of violence is significantly low (23.5%), in spite of high prevalence (34.5%). Level of awareness regarding the reporting mechanism and regulations for the safeguard of health-care workers against workplace violence is only 24.6 %. CONCLUSION: This study concluded that the prevalence of violence among health-care workers is quite high, but the reporting rate is significantly low. The low rate of reporting is because of lack of awareness about the reporting mechanism of workplace violence. It is recommended that sensitizing workshops should be conducted to increase the level of awareness, which will result in reduction in the prevalence of violence and building a safe and secured workplace for health-care providers.

Chemoselective Probe Containing a Unique Bioorthogonal Cleavage Site for Investigation of Gut Microbiota Metabolism.

While metabolites derived from gut microbiota metabolism have been linked to disease development in the human host, the chemical tools required for their detailed analysis and the discovery of biomarkers are limited. A unique and multifunctional chemical probe for mass spectrometric analysis, which contains p-nitrocinnamyloxycarbonyl as a new bioorthogonal cleavage site has been designed and synthesized. Coupled to magnetic beads, this chemical probe allows for straightforward extraction of metabolites from human samples and release under mild conditions. This isolation from the sample matrix results in significantly reduced ion suppression, an increased mass spectrometric sensitivity, and facilitates the detection of metabolites in femtomole quantities. The chemoselective probe was applied to the analysis of human fecal samples, resulting in the discovery of four metabolites previously unreported in this sample type and confirmation of the presence of medically relevant gut microbiota-derived metabolites.

New enzymatic and mass spectrometric methodology for the selective investigation of gut microbiota-derived metabolites.

Gut microbiota significantly impact human physiology through metabolic interaction. Selective investigation of the co-metabolism of bacteria and their human host is a challenging task and methods for their analysis are limited. One class of metabolites associated with this co-metabolism are O-sulfated compounds. Herein, we describe the development of a new enzymatic assay for the selective mass spectrometric investigation of this phase II modification class. Analysis of human urine and fecal samples resulted in the detection of 206 sulfated metabolites, which is three times more than reported in the Human Metabolome Database. We confirmed the chemical structure of 36 sulfated metabolites including unknown and commonly reported microbiota-derived sulfated metabolites using synthesized internal standards and mass spectrometric fragmentation experiments. Our findings demonstrate that enzymatic sample pre-treatment combined with state-of-the-art metabolomics analysis represents a new and efficient strategy for the discovery of unknown microbiota-derived metabolites in human samples. Our described approach can be adapted for the targeted investigation of other metabolite classes as well as the discovery of biomarkers for diseases affected by microbiota.