CHARACTERISTICS AND OUTCOMES OF HOSPITALISED PATIENTS WITH HEART FAILURE AND SARCOIDOSIS: A PROPENISTY-MATCHED ANALYSIS OF THE NATIONWIDE READMISSIONS DATABASE 2010-2019.

BACKGROUND: Sarcoidosis is associated with a poor prognosis. There is a lack of data examining the outcomes and readmission rates of sarcoidosis patients with heart failure (SwHF) and without heart failure (SwoHF). We aimed to compare the impact of non-ischemic heart failure on outcomes and readmissions in these two groups. METHODS: The US Nationwide Readmission Database was queried from 2010-2019 for SwHF and SwoHF patients identified using the International Classification of Diseases, Ninth and Tenth Editions. Those with ischemic heart disease were excluded, and both cohorts were propensity matched for age, gender, and Charlson Comorbidity Index (CCI). Clinical characteristics, length of stay, adjusted healthcare-associated costs, 90-day readmission and mortality were analyzed. RESULTS: We identified 97,961 hospitalized patients (median age 63 years, 37.9% male) with a diagnosis of sarcoidosis (35.9% SwHF vs. 64.1% SwoHF). On index admission, heart failure patients had higher prevalences of atrioventricular block (3.3% vs. 1.4%, p<0.0001), ventricular tachycardia (6.5% vs. 1.3%, p<0.0001), ventricular fibrillation (0.4% vs. 0.1%, p<0.0001) and atrial fibrillation (22.1% vs. 7.5%, p<0.0001). SwHF patients were more likely to be readmitted (hazard ratio 1.28, p<0.0001), had higher length of hospital stay (5 vs. 4 days, p<0.0001), adjusted healthcare-associated costs ($9,667.0 vs. $9,087.1, p<0.0001) and mortality rates on readmission (5.1% vs. 3.8%, p<0.0001). Predictors of mortality included heart failure, increasing age, male sex, higher CCI and liver disease. CONCLUSION: SwHF is associated with higher rates of arrhythmia at index admission, as well as greater hospital cost, readmission and mortality rates compared to those without heart failure.

Comparing outcomes of an 'early' versus 'late' diagnosis of cardiac sarcoidosis following a baseline presentation of high-grade atrioventricular block.

BACKGROUND: There is a paucity of evidence on impact of a delay in Cardiac Sarcoidosis (CS) diagnosis after high-grade atrioventricular-block (AVB) and this study aims to fill this void. METHODS: Consecutive CS patients (n = 77) with high grade AVB referred to one specialist hospital in London between February 2007 to February 2023 were retrospectively reviewed. The median time from AVB to diagnosing CS (112 days) was used to define the Early (n = 38) and Late (n = 39) cohorts. The primary endpoint was a composite of all-cause mortality, cardiac transplantation, ventricular arrhythmic events or heart failure hospitalisation. Secondary endpoints included difference in maintenance prednisolone dose, need for cardiac device upgrade and device complications. RESULTS: The mean age of the cohort was 54.4 (±10.6) years of whom 64 % were male and 81 % Caucasian. After a mean follow up of 54.9 (±45.3) months, the primary endpoint was reached by more patients from the Late cohort (16/39 vs. 6/38, p = 0.02; multivariable HR 6.9; 95 %CI 1.5-32.2, p = 0.01). Early Group were more likely to have received an Implantable Cardioverter Defibrillator or Cardiac Resynchronisation Therapy-defibrillator as index device after AVB (19/38 vs. 6/39; p < 0.01) and had fewer device upgrades (19/38 vs. 30/39, p = 0.01) and a trend towards fewer device complications (1 vs. 5, p = 0.20). The maintenance dose of prednisolone was significantly higher in Late Group [20.7(±9.7) mg vs. 15.3(±7.9) mg, p = 0.02]. CONCLUSION: A late diagnosis of CS was associated with more adverse events, a greater probability of needing a device upgrade and required higher maintenance steroid dose.

Clinical Investigation of Large Volume Subcutaneous Delivery up to 25 mL for Lean and Non-Lean Subjects.

PURPOSE: To evaluate the clinical feasibility and tolerability of large volume subcutaneous delivery at different injection depths for lean and non-lean subjects. METHODS: A single-center, randomized, subject-blinded, crossover study in 62 healthy subjects was conducted to evaluate delivery of a 10-cP solution containing hyaluronic acid. Subjects were separated into lean and non-lean cohort by SC thickness. A syringe pump was used to study the effect of different volumes (5, 12, 25 mL) of a viscous placebo solution and needle lengths (6, 9 and 12 mm) delivered at 0.5 mL/min. RESULTS: Across all treatments, injection sites were observed to have negligible leakage, ~34 kPa of back pressure, and VAS of mild pain with higher pain from needle insertion than during injection. While mild to moderate erythema was the most frequently reported ISR and edema was most prominent for 25 mL injections, all ISRs were resolved within 4 hours post injection. Subjects were unbothered by ISRs across all treatments and rated them as low distress scores (average 1.0-1.5 out of 6). CONCLUSION: SC injection of 25 mL is feasible and tolerable using a low-pain formulation for abdomen injection irrespective of subcutaneous thickness and injection depths at a delivery rate of 0.5 mL/min.

Role of serial 18F-fludeoxyglucose positron emission tomography in determining the therapeutic efficacy of immunosuppression and clinical outcome in patients with cardiac sarcoidosis.

BACKGROUND: Myocardial inflammation and perfusion defects detected by 18F-fludeoxyglucose (FDG) and Rubidium-82 positron emission tomography (PET) may be associated with ventricular arrhythmias (VAs) in cardiac sarcoidosis (CS). The role of serial quantitative PET in determining the effect of treatment on myocardial inflammation and clinical outcomes is yet to be defined. METHODS: Newly diagnosed CS patients with active myocardial inflammation (maximum standardised uptake value (SUVmax) ≥ 2.5) were treated with immunosuppression, then underwent repeat FDG-PET, Rubidium-82, and echocardiographic imaging 6-12 months later. Serial changes in SUVmax, SUVmean, inflammatory extent, perfusion defect (PD) extent, metabolism/perfusion mismatch extent, global cardiac metabolic activity, and left ventricular ejection fraction (LVEF) were assessed. The primary endpoint was a composite of all-cause mortality, serious VA and heart-failure (HF) hospitalisation. Event data were recorded from the date of the second FDG-PET. RESULTS: The study population consisted of 113 patients (66% male, age: 55 ± 11 years, LVEF: 54 ± 13%). SUVmax reduced from 4.5 (interquartile range: 3.3-7.1) to 2.7 (2.2-3.6). Overall, 94 (83%) patients saw serial reduction in SUVmax, with 42 (37%) demonstrating complete response (SUVmax <2.5). Following a median of 46 (25-57) months, 28 (25%) patients reached the endpoint (8 deaths, 17 VAs, and 3 HF hospitalisations). PD extent (Hazard ratio 1.03, 95% confidence interval: 1.01-1.05; p = 0.035) was a significant predictor of outcome following treatment, even after accounting for LVEF and change in SUVmean. The risk of adverse events was the greatest in those with a pre-treatment or post-treatment PD extent of >10%. CONCLUSION: In our cohort with active CS, following a treatment-induced reduction in myocardial inflammation, PD extent was the main predictor of adverse events.

Racial disparities among patients with cardiac sarcoidosis and arrhythmias in the United States: A propensity matched-analysis from the national inpatient sample database 2016-2020.

BACKGROUND: Cardiac sarcoidosis (CS) is frequently associated with conduction abnormalities and arrhythmias. In this study, we aim to evaluate racial disparities in the frequency of arrhythmias, and associated co-morbidities, among patients with CS. METHODS: White and African American (AA) patients diagnosed with CS were identified and compared from the 2016-2020 National Inpatient Sample (NIS) database whilst adjusting for confounders via logistic regression models. RESULTS: A total of 7,935 patients with CS were included in the study. The propensity-matched sample comprised of 5,570 patients, of whom 2,785 were White and 2,785 were AA. AA patients had a longer mean length of hospital stay (LOS) (7.84 vs. 6.94, p<0.01), a higher mean Charlson Comorbidity Index (CCI) score (3.10 vs. 2.84, p<0.01), and significantly higher incidences of cardiogenic shock [(9.2% vs 6.3%, p<0.01), aOR 1.45 (95% CI 1.17-1.78), p<0.01] and acute kidney injury (AKI) [(34.3% vs. 26.9%, p<0.01), aOR 1.41 (95% CI 1.24-1.61), p<0.01]. From an arrhythmia perspective, AA CS patients were shown to have a lower frequency of: (1) ventricular tachycardia (32.5% vs. 37.9%, p<0.01), (2) ventricular fibrillation (5.4% vs.7.2%, p<0.01), (3) first-degree AV block (1.8% vs. 4.1%, p<0.01), (4) complete AV block (6.3% vs. 14.2%, p<0.01), and (5) atrial fibrillation (31.8% vs. 34.8%, p=0.016) when compared to Whites with CS. Mortality remained higher for AAs (3.8% vs. 2.7%, p=0.024). CONCLUSION: Our study demonstrates a higher incidence of cardiac arrhythmias among White patients but a higher incidence of cardiogenic shock, AKI, mean LOS, and mortality among AA patients with cardiac sarcoidosis.

Grossing to reporting of Wilms tumor with emphasis on proper sampling in treatment-naive and postchemotherapy specimens and their clinicopathological correlation with outcome.

Context: Emphasis on grossing to reporting for the assessment of histopathological parameters predicting outcomes in Wilms tumor. Aims: To analyze various clinicopathological parameters that effect outcomes in treatment naïve and post chemotherapy Wilms tumor specimens. Settings and Design: This was a retrospective observational study. Subjects and Methods: All patients diagnosed with Wilms tumor between 2012 and 2018 at our institute will be included with their clinical findings, laboratory reports, and radiological findings. The patients will be categorized into two groups based on treatment protocol (Society of Pediatric Oncology (SIOP) or the National Wilms Tumor Study Group/Children's Oncology Group (COG) guidelines) used. Details of Grossing and reporting protocols used for the in pre treatment and post treatment specimens will be analyzed. Follow-up till December 2020 will be analyzed. Statistical Analysis Used: Chi-square and Fisher's exact tests were used for statistical analysis. Results: A total of 36 patients with the diagnosis of Wilms tumor were included in the present study. The mean age of presentation was 3.9 ± 0.7 years, and males were more common than females. Most of them presented as abdominal mass and few with isolated hematuria. Twenty-six (72%) patients were treated under SIOP protocol with preoperative neoadjuvant chemotherapy. Ten patients underwent upfront surgery as per COG protocol. In SIOP group patients, the mean tumor size was 9.3cm. Forty percent (n = 10) we mixed histological type followed by blastemal type constituting (32%, n = 8). Regressive and epithelial histological types constituted 16% (n = 4) and 12% (n = 3), respectively. In the SIOP group 72% (n = 19) had no anaplasia and 28% (n = 7) had anaplasia. Fifty seven percent (n = 15) cases were Stage I, followed by 26.9% n = 7) and 11.5% (n = 3) being Stage II and Stage III, respectively. Ten patients underwent upfront surgery as per COG protocol. The mean tumor size among this group was 8 cm ranging from 7 cm to 11 cm. Eight (80%) cases had favorable histology and two cases showed focal anaplasia. Heterologous differentiation is seen in 3 (70%). Out of the 10 cases, one case was Stage I, six were Stage 2, one was Stage III, and two were clinical Stage IV. None of the cases showed either vessel or lymph node metastasis. All the patients received adjuvant chemotherapy postsurgery and were followed up till December 2020 for (at least 3 years). Of 25 patients in the SIOP group, 18 (72%) had complete remission with no radiological evidence of residual disease. Of the 10 patients in the COG group, 6 (70%) had complete remission. Conclusions: Histopathological evaluation of Wilms tumor is a critical aspect in the management of Wilms tumor, as tumor characteristics are different in the tumors treated under SIOP and COG protocols, which will ultimately affect the prognostic risk stratification. This necessitates the knowledge of the important grossing and reporting of these tumors under the two protocols.

Does Unidirectional Polyglycolide Caprolactone Barbed Suture Have Improved Outcomes Over Non-barbed Suture When Applied for Intra-oral Incision Closure?

Purpose: The choice of wound closure material may influence the clinical outcomes of intra-oral incision closure. Studies evaluating the application of barbed suture in the oral cavity are scarce. Hence, the present study was carried out with the aim to monitor and compare the efficacy and ease of handling of monofilament polyglycolide caprolactone (PGCL) unidirectional barbed and non-barbed sutures used for intra-oral incision closure in patients undergoing transalveolar extraction of impacted mandibular third molar and mandible fracture open reduction internal fixation. Methods: A prospective randomized open label study was carried out among subjects requiring intra-oral incision closure following mandibular third molar extraction and isolated mandible fracture fixation. The difficulty index of the impacted third molars was evaluated pre-operatively. Subjects were randomized to receive either 3-0 monofilament PGCL unidirectional barbed or non-barbed sutures. Incision closure time and ease of suture handling were recorded intra-operatively. Post-operatively, patients were monitored for incision healing using the Hollander wound evaluation scale (HWES) and intensity of pain using visual analog scale (VAS) on post-operative days 1, 3 and 7. Data analysis involved descriptive statistics, Chi-square, unpaired t test and multivariate analysis using the IBM SPSS-PC software (v.25.0). Results: A total of 60 subjects completed the study protocol, who were randomized into two groups (n1 = n2 = 30), comparable in terms of age, gender and treatment (TAE = 51; ORIF = 9) received. The incision healing outcomes were significantly better (p = 0.016) with barbed suture using HWES on day 7. The mean closure time using barbed suture (142.50 ± 34.803 secs) was significantly (p = 0.001) shorter than that with non-barbed suture (204.56 ± 52.94 secs). The mean VAS for the barbed suture (0.97 ± 1.89) was less (p = 0.015, 95% CI) than the non-barbed suture (2.50 ± 2.91) on day 3. The suture handling ease was comparable between the two groups. Conclusion: Monofilament unidirectional PGCL barbed suture has merits over the non-barbed suture with regards to superior post-operative incision healing, reduced incision closure time (43%), lower post-operative pain and comparable ease of suture handling. Hence, knotless PGCL suture is a promising alternative for intra-oral surgical incision closure in oral and maxillofacial surgery.

Characterisation and management of expected and unexpected urgent findings from positron emission tomography with 18F-fluorodeoxyglucose integrated with computed tomography in cardiovascular disease.

BACKGROUND: Cardiac 18F-fluorodeoxyglucose (FDG)-PET-CT plays an important role in the assessment of cardiovascular diseases. Effective management of urgent scan findings facilitates optimal patient care. METHODS: We characterised the management of urgent, expected and unexpected findings in patients referred for cardiac [18F]fluorodeoxyglucose integrated with computed tomography (FDG-PET-CT) at the Royal Brompton Hospital (United Kingdom). Urgent findings are escalated by the reporting physicians/radiologists raising RadAlert notifications to the referring clinician. We characterised the indications and time to management (TTM) between the RadAlert and the resulting management. As controls, we characterised the TTM of 33 urgent findings identified before the RadAlert system was implemented. RESULTS: Of the 1497 consecutive FDG-PET-CT scans screened (April 2021 to February 2023), 93 RadAlerts were suitable for analysis (TTM 7 days [interquartile range: 2-14]). Expected urgent findings included active cardiac sarcoidosis (56%; TTM 8 days [5-18]), heart transplant rejection (12%; 6 ± 4 days), infective endocarditis (9%; 2 days [1-12]), cardiac device infections (5%; 1 day [0-2]), acute myocarditis (2%; 5 and 14 days) and epicardial mass (1%; 1 day). TTM did not differ significantly between indications (P = 0.06). RadAlert cases had significantly shorter TTM than controls without RadAlert, P = 0.001. After the RadAlerts, 81% of patients had clinical reviews, and 55% had escalation of medical/surgical therapies. Unexpected findings (total N = 45; median TTM 6 days [1-10]) included malignancies (N = 3), infections (N = 2), pneumothorax (N = 1), benign diagnosis (N = 30), unclear diagnosis (N = 5) and 4 findings disappeared on repeat imaging. CONCLUSIONS: Cardiac FDG-PET-CT identifies expected and unexpected findings in a range of cardiovascular diseases. Serious, unexpected findings are rare and can be effectively escalated by the RadAlert system.

Spatio-temporal epidemiology and associated indicators of COVID-19 (wave-I and II) in India.

The spatio-temporal distribution of COVID-19 across India's states and union territories is not uniform, and the reasons for the heterogeneous spread are unclear. Identifying the space-time trends and underlying indicators influencing COVID-19 epidemiology at micro-administrative units (districts) will help guide public health strategies. The district-wise daily COVID-19 data of cases and deaths from February 2020 to August 2021 (COVID-19 waves-I and II) for the entire country were downloaded and curated from public databases. The COVID-19 data normalized with the projected population (2020) and used for space-time trend analysis shows the states/districts in southern India are the worst hit. Coastal districts and districts adjoining large urban regions of Mumbai, Chennai, Bengaluru, Goa, and New Delhi experienced > 50,001 cases per million population. Negative binomial regression analysis with 21 independent variables (identified through multicollinearity analysis, with VIF < 10) covering demography, socio-economic status, environment, and health was carried out for wave-I, wave-II, and total (wave-I and wave-II) cases and deaths. It shows wealth index, derived from household amenities datasets, has a high positive risk ratio (RR) with COVID-19 cases (RR: 3.577; 95% CI: 2.062-6.205) and deaths (RR: 2.477; 95% CI: 1.361-4.506) across the districts. Furthermore, socio-economic factors such as literacy rate, health services, other workers' rate, alcohol use in men, tobacco use in women, overweight/obese women, and rainfall have a positive RR and are significantly associated with COVID-19 cases/deaths at the district level. These positively associated variables are highly interconnected in COVID-19 hotspot districts. Among these, the wealth index, literacy rate, and health services, the key indices of socio-economic development within a state, are some of the significant indicators associated with COVID-19 epidemiology in India. The identification of district-level space-time trends and indicators associated with COVID-19 would help policymakers devise strategies and guidelines during public health emergencies.

Sarcoidosis Associated Pulmonary Hypertension.

In patients with sarcoidosis, the development of pulmonary hypertension is associated with significant morbidity and mortality. The global prevalence of sarcoidosis-associated pulmonary hypertension (SAPH) reportedly ranges between 2.9% and 20% of sarcoidosis patients. Multiple factors may contribute to the development of SAPH, including advanced parenchymal lung disease, severe systolic and/or diastolic left ventricular dysfunction, veno-occlusive or thromboembolic disease, as well as extrinsic factors such as pulmonary vascular compression from enlarged lymph nodes, anemia, and liver disease. Early diagnosis of SAPH is important but rarely achieved primarily due to insufficiently accurate screening strategies, which rely entirely on non-invasive tests and clinical assessment. The definitive diagnosis of SAPH requires right heart catheterization (RHC), with transthoracic echocardiography as the recommended gatekeeper to RHC according to current guidelines. A 6-min walk test (6MWT) had the greatest prognostic value in SAPH patients based on recent registry outcomes, while advanced lung disease determined using a reduced DLCO (<35% predicted) was associated with reduced transplant-free survival in pre-capillary SAPH. Clinical management involves the identification and treatment of the underlying mechanism. Pulmonary vasodilators are useful in several scenarios, especially when a pulmonary vascular phenotype predominates. End-stage SAPH may warrant consideration for lung transplantation, which remains a high-risk option. Multi-centered randomized controlled trials are required to develop existing therapies further and improve the prognosis of SAPH patients.

Cooperative STAT3-NFkB signaling modulates mitochondrial dysfunction and metabolic profiling in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) continues to pose a significant health challenge and is often diagnosed at advanced stages. Metabolic reprogramming is a hallmark of many cancer types, including HCC and it involves alterations in various metabolic or nutrient-sensing pathways within liver cells to facilitate the rapid growth and progression of tumours. However, the role of STAT3-NFκB in metabolic reprogramming is still not clear. APPROACH AND RESULTS: Diethylnitrosamine (DEN) administered animals showed decreased body weight and elevated level of serum enzymes. Also, Transmission electron microscopy (TEM) analysis revealed ultrastructural alterations. Increased phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated nuclear factor kappa B (p-NFκß), dynamin related protein 1 (Drp-1) and alpha-fetoprotein (AFP) expression enhance the carcinogenicity as revealed in immunohistochemistry (IHC). The enzyme-linked immunosorbent assay (ELISA) concentration of IL-6 was found to be elevated in time dependent manner both in blood serum and liver tissue. Moreover, immunoblot analysis showed increased level of p-STAT3, p-NFκß and IL-6 stimulated the upregulation of mitophagy proteins such as Drp-1, Phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK-1). Meanwhile, downregulation of Poly [ADP-ribose] polymerase 1 (PARP-1) and cleaved caspase 3 suppresses apoptosis and enhanced expression of AFP supports tumorigenesis. The mRNA level of STAT3 and Drp-1 was also found to be significantly increased. Furthermore, we performed high-field 800 MHz Nuclear Magnetic Resonance (NMR) based tissue and serum metabolomics analysis to identify metabolic signatures associated with the progression of liver cancer. The metabolomics findings revealed aberrant metabolic alterations in liver tissue and serum of 75th and 105th days of intervention groups in comparison to control, 15th and 45th days of intervention groups. Tissue metabolomics analysis revealed the accumulation of succinate in the liver tissue samples, whereas, serum metabolomics analysis revealed significantly decreased circulatory levels of ketone bodies (such as 3-hydroxybutyrate, acetate, acetone, etc.) and membrane metabolites suggesting activated ketolysis in advanced stages of liver cancer. CONCLUSION: STAT3-NFκß signaling axis has a significant role in mitochondrial dysfunction and metabolic alterations in the development of HCC.

Current veterinary regulations and way ahead.

This article aims to perform a comparative systematic review of regulations in veterinary medicine between the years 2016 to 2023. It explores the complex web of veterinary medicine regulations in various agencies and the nations, including USA (United States of America), EU (European Union), UK (United Kingdom), Japan, Australia, and India. Current article provides the comparative study on the veterinary regulations of different countries, including acts, directives, and drug approval processes. Such as, the specific legislation is needed to address zoonotic diseases. The strategic and regulated stockpiling of the veterinary drugs especially in chronic veterinary disease outbreak. It is essential to develop the dedicated Veterinary Pharmacopoeia for the regulated standardization of the raw materials as well as the formulations. Veterinary medical device is a field which is highly unregulated. There is a need to have regulations for the same. It is important to have dedicated veterinary pharmacovigilance centers which help in improving quality of medications to the livestock farms. After comparing the regulations of different countries. We observed that there is the absence of the zoonotic diseases and pharma stockpiling in every country. There is also an absence of the dedicated veterinary pharmacopoeia in every country. USA and Australia have the veterinary medical device regulation which is not there in other countries. Around the globe only Australia has the dedicated pharmacovigilance center. Including these recommendations into regulatory framework enhances the quality and safety of veterinary medicine. The current article adds a valuable resource for policymakers, veterinarians, and stakeholders in the field of animal health care.

Innovative Genoceuticals in Human Gene Therapy Solutions: Challenges and Safe Clinical Trials of Orphan Gene Therapy Products.

The success of gene therapy attempts is controversial and inconclusive. Currently, it is popular among the public, the scientific community, and manufacturers of Gene Therapy Medical Products. In the absence of any remedy or treatment options available for untreatable inborn metabolic orphan or genetic diseases, cancer, or brain diseases, gene therapy treatment by genoceuticals and T-cells for gene editing and recovery remains the preferred choice as the last hope. A new concept of "Genoceutical Gene Therapy" by using orphan 'nucleic acid-based therapy' aims to introduce scientific principles of treating acquired tissue damage and rare diseases. These Orphan Genoceuticals provide new scope for the 'genodrug' development and evaluation of genoceuticals and gene products for ideal 'gene therapy' use in humans with marketing authorization application (MAA). This perspective study focuses on the quality control, safety, and efficacy requirements of using 'nucleic acid-based and human cell-based new gene therapy' genoceutical products to set scientific advice on genoceutical-based 'orphan genodrug' design for clinical trials as per Western and European guidelines. The ethical Western FDA and European EMA guidelines suggest stringent legal and technical requirements on genoceutical medical products or orphan genodrug use for other countries to frame their own guidelines. The introduction section proposes lessknown 'orphan drug-like' properties of modified RNA/DNA, human cell origin gene therapy medical products, and their transgene products. The clinical trial section explores the genoceutical sources, FDA/EMA approvals for genoceutical efficacy criteria with challenges, and ethical guidelines relating to gene therapy of specific rare metabolic, cancer and neurological diseases. The safety evaluation of approved genoceuticals or orphan drugs is highlighted with basic principles and 'genovigilance' requirements (to observe any adverse effects, side effects, developed signs/symptoms) to establish their therapeutic use. Current European Union and Food and Drug Administration guidelines continuously administer fast-track regulatory legal framework from time to time, and they monitor the success of gene therapy medical product efficacy and safety. Moreover, new ethical guidelines on 'orphan drug-like genoceuticals' are updated for biodistribution of the vector, genokinetics studies of the transgene product, requirements for efficacy studies in industries for market authorization, and clinical safety endpoints with their specific concerns in clinical trials or public use.

Mixed Pluronic/lecithin micelles formulation for oral bioavailability of candesartan cilexetil drug: in vitro characterization and in vivo pharmacokinetic investigations.

OBJECTIVE: This study aimed to develop a mixed polymeric micelle formulation incorporating candesartan cilexetil (CAND) drug to enhance its oral bioavailability for the better treatment of hypertension. METHODS: A Box-Behnken design was utilized to optimize the CAND-incorporated mixed polymeric micelles formulation (CAND-PFLC) consisting of Pluronics (P123 and F68) and lecithin (LC). The optimized CAND-PFLC micelles formulation was characterized for size, shape, zeta potential, polydispersity index (PDI), and entrapment efficiency (%EE). An in vitro release study, ex vivo permeability investigation, and an in vivo pharmacokinetic analysis were carried out to evaluate the performance of the formulation. RESULTS: The optimized CAND-PFLC micelles formulation demonstrated a spherical shape, a particle size of 44 ± 2.03 nm, a zeta potential of -7.07 ± 1.39 mV, a PDI of 0.326 ± 0.06, and an entrapment efficiency of 87 ± 3.12%. The formulation exhibited excellent compatibility, better stability, and a noncrystalline nature. An in vitro release study revealed a faster drug release of 7.98% at gastric pH in 2 hrs and 94.45% at intestinal pH within 24 hrs. The ex vivo investigation demonstrated a significantly enhanced permeability of CAND, with 94.86% in the micelle formulation compared to 9.03% of the pure drug. In vivo pharmacokinetic analysis showed a 4.11-fold increase in oral bioavailability of CAND compared to the marketed formulation. CONCLUSION: The CAND-PFLC mixed micelle formulation demonstrated improved performance compared to pure CAND, indicating its potential as a promising oral drug delivery system for the effective treatment of hypertension.

Scleral collagen cross linkage in progressive myopia.

High myopia is often associated with local ectasia and scleral thinning. The progression of myopia depends upon scleral biochemical and biomechanical properties. Scleral thinning is associated with decreased collagen fiber diameter, defective collagen fibrillogenesis, and collagen cross-linking. Reversing these abnormalities may make the sclera tougher and might serve as a treatment option for myopic progression. Collagen cross-linking is a natural process in the cornea and sclera, which makes the structure stiff. Exogenous collagen cross-linkage is artificially induced with the help of external mediators by using light and dark methods. In this systematic review, we discussed existing literature available on the internet on current evidence-based applications of scleral collagen cross-linking (SXL) by using different interventions. In addition, we compared them in tabular form in terms of their technique, mechanisms, cytotoxicity, and the stage of transition from preclinical to clinical development. Furthermore, we discussed the in-vivo technique to evaluate the post-SXL scleral biomechanical property and outcome in the human eye.

Optimization of Lurasidone HCl-Loaded PLGA Nanoparticles for Intramuscular Delivery: Enhanced Bioavailability, Reduced Dosing Frequency, Pharmacokinetics, and Therapeutic Outcomes.

This study aimed to develop a nanoparticle drug delivery system using poly (lactic-co-glycolic acid) (PLGA) for enhancing the therapeutic efficacy of lurasidone hydrochloride (LH) in treatment of schizophrenia through intramuscular injection. LH-loaded PLGA nanoparticles (LH-PNPs) were prepared using the nanoprecipitation technique and their physicochemical characteristics were assessed. Particle size (PS), zeta potential, morphology, % encapsulation efficiency, % drug loading, drug content, and solid-state properties were analyzed. Stability, in vitro release, and in vivo pharmacokinetic studies were conducted to evaluate the therapeutic efficacy of the developed LH-PNPs. The optimized batch of LH-PNPs exhibited a narrow and uniform PS distribution before and after lyophilization, with sizes of 112.7 ± 1.8 nm and 115.0 ± 1.3 nm, respectively, and a low polydispersity index. The PNPs showed high drug entrapment efficiency, drug loading, and drug content uniformity. Solid-state characterization indicated good stability and compatibility, with a nonamorphous state. The drug release profile demonstrated sustained release behavior. Intramuscular administration of LH-PNPs in rats resulted in a significantly prolonged mean residence time compared with the drug suspension. These findings highlight that intramuscular delivery of the LH-PNP formulation is a promising approach for enhancing the therapeutic efficacy of LH in treatment of schizophrenia.

Ethyl Isothiocyanate as a Novel Antifungal Agent Against Candida albicans.

In the recent years, occurrence of candidiasis has increased drastically which leads to significant mortality and morbidity mainly in immune compromised patients. Glucosinolate (GLS) derivatives are reported to have antifungal activities. Ethyl isothiocyanate (EITC) and its antifungal activity and mechanism of action is still unclear against Candida albicans. The present work was designed to get a mechanistic insight in to the anti-Candida efficacy of EITC through in vitro and in vivo studies. EITC inhibited C. albicans planktonic growth at 0.5 mg/ml and virulence factors like yeast to hyphal form morphogenesis (0.0312 mg/ml), adhesion to polystyrene surface (0.0312 mg/ml) and biofilm formation (developing biofilm at 2 mg/ml and mature biofilm at 0.5 mg/ml) effectively. EITC blocked ergosterol biosynthesis and arrested C. albicans cells at S-phase. EITC caused ROS-dependent cellular death and nuclear or DNA fragmentation. EITC at 0.0312 mg/ml concentration regulated the expression of genes involved in the signal transduction pathway and inhibited yeast to hyphal form morphogenesis by upregulating TUP1, MIG1, and NRG1 by 3.10, 5.84 and 2.64-fold, respectively and downregulating PDE2 and CEK1 genes by 15.38 and 2.10-fold, respectively. EITC has showed haemolytic activity at 0.5 mg/ml concentration. In vivo study in silk worm model showed that EITC has toxicity to C. albicans at 0.5 mg/ml concentration. Thus, from present study we conclude that EITC has antifungal activity and to reduce its MIC and toxicity, combination study with other antifungal drugs need to be done. EITC and its combinations might be used as alternative therapeutics for the prevention and treatment of C. albicans infections.

Ti3C2Tx nanosheet@Cu/Fe-MOF separators for high-performance lithium-sulfur batteries: an experimental and density functional theory study.

Lithium-sulfur (Li-S) batteries have attracted much attention due to their superior theoretical specific capacity and high theoretical energy density. However, rapid capacity fading originating from the shuttle effect, insulating the S cathode and the dendrite formation on the Li anode restrict the practical applications of Li-S batteries. Herein, we suggest novel coatings on glass fiber separators to satisfy all high-performance Li-S battery requirements. A conductive Ti3C2Tx (MXene) nanosheet/Fe-MOF or Ti3C2Tx (MXene) nanosheet/Cu-MOF layer was coated on a glass fiber separator to act as a polysulfide trapping layer. The MXene layer with high conductivity and polar surface functional groups could confine polysulfides and accelerate the redox conversions. The porous MOF layer acts as a Li ion sieve, thereby leading to the interception of polysulfides and mitigation of Li dendrite growth. The cells with the Cu-MOF/MXenes and Fe-MOF/MXene separators display superior capacities of 1100 and 1131 mA h g-1 after 300 cycles, respectively, whereas the cell with a pure glass fiber separator delivers a very low capacity of 309 mA h g-1 after 300 cycles. With Fe-MOF/MXene and Cu-MOF/MXene configurations, the discharge capacity, coulombic efficiency, cycling stability, and electrochemical conversion reactions are significantly improved. Our ab initio calculations demonstrate that the MXene layer dissociates lithium polysulfides into adsorbed S and mobile Li ions, which explains the experimental findings.