Retinitis pigmentosa in Laurence-Moon-Bardet-Biedl syndrome in India: Electronic medical records driven big data analytics: Report II

Purpose:To describe the clinical presentation and demographic distribution of retinitis pigmentosa (RP) in Laurence–Moon–Bardet–Biedl (LMBB) syndrome patients.Methods: This is a cross-sectional observational hospital-based study wherein 244 patients with RP in LMBB syndrome presenting to our hospital network between March 2012 and October 2020 were included. An electronic medical record database was used for data retrieval.Results: There were 244 patients in total, with a hospital-based prevalence rate of 0.010% or 1000/100,000 population. The mean and median age of patients was 15.22 ± 7.56 and 14 (IQR: 10–18.5) years, respectively, with the majority being in the age group of 11–20 years (133/244 patients; 54.50%). Males were more commonly affected (164 patients; 67.21%), and the majority (182 patients; 74.59%) were students. All 244 patients (100%) complained of defective central vision at presentation. More than one-fourth of the patients had severe visual impairment to blindness at presentation. Prominent retinal feature at presentation was diffuse or widespread retinal pigment epithelial degeneration in all patients.Conclusion: Patients with RP in LMBB syndrome present mainly in the first to second decade of life with severe visual acuity impairment to blindness early in life. It is important to rule out LMBB syndrome in early-onset RP with central visual acuity impairment. On the contrary, all patients diagnosed or suspected with LMBB syndrome systemic features at physician clinic should also be referred for ophthalmic evaluation, low vision assessment, rehabilitation, and vice versa.     

The Photosensitizer Octakis(cholinyl)zinc Phthalocyanine with Ability to Bind to a Model Spike Protein Leads to a Loss of SARS-CoV-2 Infectivity In Vitro When Exposed to Far-Red LED

Photodynamic inactivation of pathogenic microorganisms can be successfully used to eradicate pathogens in localized lesions, infected liquid media, and on various surfaces. This technique utilizes the photosensitizer (PS), light, and molecular oxygen to produce reactive oxygen species that kill pathogens. Here, we used the PS, water soluble octakis(cholinyl)zinc phthalocyanine (Zn-PcChol₈₊), to inactivate an initial 4.75–5.00 IgTCID50/mL titer of SARS-CoV-2, thereby preventing viral infection when tested in Vero E6 cell cultures. Zn-PcChol₈₊ in a minimally studied concentration, 1 µM and LED 3.75 J/cm², completely destroyed the infectivity of SARS-CoV-2. To detect possible PS binding sites on the envelope of SARS-CoV-2, we analyzed electrostatic potential and simulated binding of Zn-PcChol₈₊ to the spike protein of this coronavirus by means of Brownian dynamics software, ProKSim (Protein Kinetics Simulator). Most of the Zn-PcChol₈₊ molecules formed clusters at the upper half of the stalk within a vast area of negative electrostatic potential. Positioning of the PS on the surface of the spike protein at a distance of no more than 10 nm from the viral membrane may be favorable for the oxidative damage. The high sensitivity of SARS-CoV-2 to photodynamic inactivation by Zn-PcChol₈₊ is discussed with respect to the application of this PS to control the spread of COVID-19.     

Artificial intelligence for early diagnosis of lung cancer through incidental nodule detection in low- and middle-income countries-acceleration during the COVID-19 pandemic but here to stay

Although the coronavirus disease of 2019 (COVID-19) pandemic had profound pernicious effects, it revealed deficiencies in health systems, particularly among low- and middle-income countries (LMICs). With increasing uncertainty in healthcare, existing unmet needs such as poor outcomes of lung cancer (LC) patients in LMICs, mainly due to late stages at diagnosis, have been challenging-necessitating a shift in focus for judicious health resource utilization. Leveraging artificial intelligence (AI) for screening large volumes of pulmonary images performed for noncancerous reasons, such as health checks, immigration, tuberculosis screening, or other lung conditions, including but not limited to COVID-19, can facilitate easy and early identification of incidental pulmonary nodules (IPNs), which otherwise could have been missed. AI can review every chest X-ray or computed tomography scan through a trained pair of eyes, thus strengthening the infrastructure and enhancing capabilities of manpower for interpreting images in LMICs for streamlining accurate and early identification of IPNs. AI can be a catalyst for driving LC screening with enhanced efficiency, particularly in primary care settings, for timely referral and adequate management of coincidental IPN. AI can facilitate shift in the stage of LC diagnosis for improving survival, thus fostering optimal health-resource utilization and sustainable healthcare systems resilient to crisis. This article highlights the challenges for organized LC screening in LMICs and describes unique opportunities for leveraging AI. We present pilot initiatives from Asia, Latin America, and Russia illustrating AI-supported IPN identification from routine imaging to facilitate early diagnosis of LC at a potentially curable stage.     

Infectious disease health services for refugees and asylum seekers during a time of crisis: A scoping study of six European Union countries

BackgroundSystematic information on infectious disease services provided to refugees and asylum seekers in the European Union (EU) is sparse. We conducted a scoping study of experts in six EU countries in order to map health system responses related to infectious disease prevention and control among refugees and asylum seekers.MethodsWe conducted 27 semi-structured in-depth interviews with first-line staff and health officials to collect information about existing guidelines and practices at each stage of reception in first-entry (Greece/Italy), transit (Croatia/Slovenia), and destination countries (Austria/Sweden). Thematic coding was used to perform a content analysis of interview material.ResultsGuidance on infectious disease screening and health assessments lack standardisation across and—partly—within countries. Data collection on notifiable infectious diseases is mainly reported to be performed by national public health institutions, but is not stratified by migrant status. Health-related information is not transferred in a standardized way between facilities within a single country. International exchange of medical information between countries along the migration route is irregular. Services were reported to be fragmented, and respondents mentioned no specific coordination bodies beyond health authorities at different levels.ConclusionInfectious disease health services provided to refugees and asylum seekers lack standardisation in health assessments, data collection, transfer of health-related information and (partly) coordination. This may negatively affect health system performance including public health emergency preparedness.     

Novel Dengue Virus NS2B/NS3 Protease Inhibitors

Dengue fever is a severe, widespread, and neglected disease with more than 2 million diagnosed infections per year. The dengue virus NS2B/NS3 protease (PR) represents a prime target for rational drug design. At the moment, there are no clinical PR inhibitors (PIs) available. We have identified diaryl (thio)ethers as candidates for a novel class of PIs. Here, we report the selective and noncompetitive inhibition of the serotype 2 and 3 dengue virus PR in vitro and in cells by benzothiazole derivatives exhibiting 50% inhibitory concentrations (IC₅₀s) in the low-micromolar range. Inhibition of replication of DENV serotypes 1 to 3 was specific, since all substances influenced neither hepatitis C virus (HCV) nor HIV-1 replication. Molecular docking suggests binding at a specific allosteric binding site. In addition to the in vitro assays, a cell-based PR assay was developed to test these substances in a replication-independent way. The new compounds inhibited the DENV PR with IC₅₀s in the low-micromolar or submicromolar range in cells. Furthermore, these novel PIs inhibit viral replication at submicromolar concentrations.     

Transplantation of bovine adrenocortical cells encapsulated in alginate

Current treatment options for adrenal insufficiency are limited to corticosteroid replacement therapies. However, hormone therapy does not replicate circadian rhythms and has unpleasant side effects especially due to the failure to restore normal function of the hypothalamic–pituitary–adrenal (HPA) axis. Adrenal cell transplantation and the restoration of HPA axis function would be a feasible and useful therapeutic strategy for patients with adrenal insufficiency. We created a bioartificial adrenal with 3D cell culture conditions by encapsulation of bovine adrenocortical cells (BACs) in alginate (enBACs). We found that, compared with BACs in monolayer culture, encapsulation in alginate significantly increased the life span of BACs. Encapsulation also improved significantly both the capacity of adrenal cells for stable, long-term basal hormone release as well as the response to pituitary adrenocorticotropic hormone (ACTH) and hypothalamic luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6]LHRH. The enBACs were transplanted into adrenalectomized, immunodeficient, and immunocompetent rats. Animals received enBACs intraperitoneally, under the kidney capsule (free cells or cells encapsulated in alginate slabs) or s.c. enclosed in oxygenating and immunoisolating βAir devices. Graft function was confirmed by the presence of cortisol in the plasma of rats. Both types of grafted encapsulated cells, explanted after 21–25 d, preserved their morphology and functional response to ACTH stimulation. In conclusion, transplantation of a bioartificial adrenal with xenogeneic cells may be a treatment option for patients with adrenocortical insufficiency and other stress-related disorders. Furthermore, this model provides a microenvironment that ensures 3D cell–cell interactions as a unique tool to investigate new insights into cell biology, differentiation, tissue organization, and homeostasis.Adrenal insufficiency is the failure of adrenocortical cells to produce adequate amounts of glucocorticoids and/or mineralocorticoids. These steroid hormones play a central role in the body’s homeostasis of energy, salt, and fluid; thus, adrenal insufficiency is a potentially life-threatening condition. The most relevant causes of adrenal insufficiency are autoimmune disorders (up to 80%); infectious diseases; hereditary factors; traumatic, metabolic, or neoplastic conditions; or surgical bilateral adrenalectomy, sometimes due to a compulsory therapeutic strategy in the treatment of adrenal tumors or congenital adrenal hyperplasia (CAH).CAH due to 21-hydroxylase deficiency is the most common form of inherited adrenal insufficiency, presenting with clinical symptoms of neuroendocrine perturbations, virilization, and metabolic diseases in later life. Patients may suffer from hypotensive crises, hypoglycemia, acne, and infertility (1, 2). Current options of treatment consisting of replacement therapy with glucocorticoids, mineralocorticoids, and/or androgens can reverse the symptoms only partially, exhibit the unpleasant side effects of inappropriate glucocorticoid substitution, and leave the patients without the diurnal rhythm of glucocorticoid release. Furthermore, adrenomedullary functions, including catecholamine and neuropeptide secretion, also are disrupted (2), which correlates with cardiovascular risks, hypoglycemia, and physical disability in these patients (1, 3).Adrenal gland transplantation could and would be a desirable therapeutic alternative for these patients if it was available and practical (4). Transplanted organs restore and maintain normal hormonal levels, adequately respond to functional demands, and regulate steroid production in response to endogenous and exogenous stimulation, including the circadian rhythm of hormone secretion. However, the application of this strategy is currently extremely limited due to the lack of human donor organs, the surgical difficulties of adrenal transplantation, and the required chronic immunosuppression.For the correction of adrenocortical insufficiency, transplantation of whole adrenal glands might not be mandatory and the transplantation of isolated adrenal cells may be sufficient. An additional advantage of transplantation using isolated cells is the availability of various immunoisolating materials and methods for immune protection of such transplants. Application of these materials not only allows avoidance of chronic immunosuppression but also allows the transplantation of xenogeneic cells (5, 6).Sodium alginate is one of the clinically approved immunoisolating biopolymers; it has already been widely used in a variety of biomedical applications (5–10). Alginates have several unique structural and chemical parameters, appropriate not only for immune isolation but also for the creation of 3D cellular scaffolds that allow artificial organs to function long term in vitro and in vivo (7, 8, 11). The potential of xenogeneic adrenocortical cells to replace adrenal gland function has already been tested in animal models but requires acquisition of immunodeficiency (12, 13). Alginate encapsulation may protect xenogeneic adrenocortical cells from destruction by immunological processes (6). Alternatively, similar to pancreatic islets (9, 14), adrenocortical cells can be transplanted within special oxygenating and immunoisolating devices, thus reducing the risk of an immunological host versus graft response.Creating a long-lasting, immune-isolated, and functional bioartificial adrenal was the main aim of this research. The objectives of our work included testing of primary bovine adrenocortical cells (BACs) as a potential source of cells, defining optimal conditions, and long-term monitoring. Because adrenocortical cells also express receptors for luteinizing hormone-releasing hormone (LHRH), the effect of the LHRH agonist [D-Trp6]LHRH on adrenocortical steroidogenesis in encapsulated BACs (enBACs) was tested. We characterized bioartificial adrenals in vivo and investigated their functionality and efficacy after implantation into bilaterally adrenalectomized rats.     

Clinical outcomes of levosimendan versus dobutamine in patients with acute decompensated heart failure with reduced ejection fraction and impaired renal function

To assess the clinical outcomes of levosimendan and dobutamine in patients with acute decompensated heart failure with reduced ejection fraction and impaired renal function in Indian scenario. Cardiac, renal, electrolytes and hepatic parameters as well as the clinical outcomes were assessed. Levosimendan and dobutamine improved ejection fraction significantly. Levosimendan in comparison to dobutamine, increased cardiac output (0.76 vs. ?0.38 at 48 h, 1.15 vs. ?0.31 day 7, -2.02 vs. ?1.51 day 30), cardiac index (0.89 vs.-0.13 at 48 h, 1.16 vs. ?0.07 at day 7 and 1.05 vs. ?0.25 at day 30) and eGFR (?1.4 vs. ?0.75 at day 30) significantly. Levosimendan reduced ICU stay (p = 0.038) significantly whereas dobutamine decreased the hospital stay duration (p = 0.015). There was no major difference in re-hospitalization and mortality between groups. Ventricular tachyarrhythmia was the main adverse event noted in Levosimendan arm. Levosimendan showed improved cardiac as well as renal outcomes within a month when compared to dobutamine and it is the first study to determine the renal parameters of Levosimendan in an Indian setting.     

Musashi 2 (MSI2) expression as an independent prognostic biomarker in non-small cell lung cancer (NSCLC)

BackgroundMusashi-2 (MSI2) is a member of RNA-binding protein family that regulates mRNA translation of numerous intracellular targets and influences maintenance of stem cell identity. This study assessed MSI2 as a potential clinical biomarker in non-small cell lung cancer (NSCLC).MethodsThe current study included 40 patients with NSCLC, of whom one presented with stage 1, 14 presented with stage II, 15 presented with stage III, and 10 patients had stage IV. All patients received standard of care treatments. All patient samples were obtained before treatment started. We used immunohistochemical (IHC) approach to measure MSI2 protein expression in matching specimens of normal lung versus tumor tissues, and primary versus metastatic tumors, followed by correlative analysis in relation to clinical outcomes. In parallel, clinical correlative analysis of MSI2 mRNA expression was performed in silico using publicly available datasets (TCGA/ICGC and KM plots).ResultsMSI2 protein expression in patient samples was significantly elevated in NSCLC primary tumors versus normal lung tissue (P=0.03). MSI2 elevated expression positively correlated with a decreased progression free survival (PFS) (P=0.026) combined for all stages and with overall survival (OS) at stage IV (P=0.013). Elevated MSI2 expression on RNA level was confirmed in primary tumor versus normal tissue samples in TCGA dataset (P<0.0001), and positively correlated with decreased OS (P=0.02). No correlation was observed between MSI2 expression and age, sex, smoking, and treatment type.ConclusionsElevated MSI2 expression in primary NSCLC tumors is associated with poor prognosis and can be used as a novel potential prognostic biomarker in NSCLC patients. Future studies in an extended patient cohort are warranted.