Survey of Advanced Nonlinear Control Strategies for UAVs: Integration of Sensors and Hybrid Techniques.

This survey paper explores advanced nonlinear control strategies for Unmanned Aerial Vehicles (UAVs), including systems such as the Twin Rotor MIMO system (TRMS) and quadrotors. UAVs, with their high nonlinearity and significant coupling effects, serve as crucial benchmarks for testing control algorithms. Integration of sophisticated sensors enhances UAV versatility, making traditional linear control techniques less effective. Advanced nonlinear strategies, including sensor-based adaptive controls and AI, are increasingly essential. Recent years have seen the development of diverse sliding surface-based, sensor-driven, and hybrid control strategies for UAVs, offering superior performance over linear methods. This paper reviews the significance of these strategies, emphasizing their role in addressing UAV complexities and outlining future research directions.

Prognostic scores for ursodeoxycholic acid-treated patients predict graft loss and mortality in recurrent primary biliary cholangitis after liver transplantation.

BACKGROUND & AIMS: Recurrent primary biliary cholangitis (rPBC) develops in approximately 30% of patients and negatively impacts graft and overall patient survival after liver transplantation (LT). There is a lack of data regarding the response rate to ursodeoxycholic acid (UDCA) in rPBC. We evaluated a large, international, multi-center cohort to assess the performance of PBC scores in predicting the risk of graft and overall survival after LT in patients with rPBC. METHODS: A total of 332 patients with rPBC after LT were evaluated from 28 centers across Europe, North and South America. The median age at the time of rPBC was 58.0 years [IQR 53.2-62.6], and 298 patients (90%) were female. The biochemical response was measured with serum levels of alkaline phosphatase (ALP) and bilirubin, and Paris-2, GLOBE and UK-PBC scores at 1 year after UDCA initiation. RESULTS: During a median follow-up of 8.7 years [IQR 4.3-12.9] after rPBC diagnosis, 52 patients (16%) had graft loss and 103 (31%) died. After 1 year of UDCA initiation the histological stage at rPBC (hazard ratio [HR] 3.97, 95% CI 1.36-11.55, p = 0.01), use of prednisone (HR 3.18, 95% CI 1.04-9.73, p = 0.04), ALP xULN (HR 1.59, 95% CI 1.26-2.01, p <0.001), Paris-2 criteria (HR 4.14, 95% CI 1.57-10.92, p = 0.004), GLOBE score (HR 2.82, 95% CI 1.71-4.66, p <0.001), and the UK-PBC score (HR 1.06, 95% CI 1.03-1.09, p <0.001) were associated with graft survival in the multivariate analysis. Similar results were observed for overall survival. CONCLUSION: Patients with rPBC and disease activity, as indicated by standard PBC risk scores, have impaired outcomes, supporting efforts to treat recurrent disease in similar ways to pre-transplant PBC. IMPACT AND IMPLICATIONS: One in three people who undergo liver transplantation for primary biliary cholangitis develop recurrent disease in their new liver. Patients with recurrent primary biliary cholangitis and incomplete response to ursodeoxycholic acid, according to conventional prognostic scores, have worse clinical outcomes, with higher risk of graft loss and mortality in similar ways to the disease before liver transplantation. Our results supportsupport efforts to treat recurrent disease in similar ways to pre-transplant primary biliary cholangitis.

Quantitative MRCP and metrics of bile duct disease over time in patients with primary sclerosing cholangitis: A prospective study.

BACKGROUND: Imaging markers of biliary disease in primary sclerosing cholangitis (PSC) have potential for use in clinical and trial disease monitoring. Herein, we evaluate how quantitative magnetic resonance cholangiopancreatography (MRCP) metrics change over time, as per the natural history of disease. METHODS: Individuals with PSC were prospectively scanned using non-contrast MRCP. Quantitative metrics were calculated using MRCP+ post-processing software to assess duct diameters and dilated and strictured regions. Additionally, a hepatopancreatobiliary radiologist (blinded to clinical details, biochemistry and quantitative biliary metrics) reported each scan, including ductal disease assessment according to the modified Amsterdam Cholangiographic Score (MAS). RESULTS: At baseline, 14 quantitative MRCP+ metrics were found to be significantly different in patients with PSC (N = 55) compared to those with primary biliary cholangitis (N = 55), autoimmune hepatitis (N = 57) and healthy controls (N = 18). In PSC specifically, baseline metrics quantifying the number of strictures and the number and length of bile ducts correlated with the MAS, transient elastography and serum ALP values (p < 0.01 for all correlations). Over a median 371-day follow-up (range: 364-462), 29 patients with PSC underwent repeat MRCP, of whom 15 exhibited quantitative changes in MRCP+ metrics. Compared to baseline, quantitative MRCP+ identified an increasing number of strictures over time (p < 0.05). Comparatively, no significant differences in biochemistry, elastography or the MAS were observed between timepoints. Quantitative MRCP+ metrics remained stable in non-PSC liver disease. CONCLUSION: Quantitative MRCP+ identifies changes in ductal disease over time in PSC, despite stability in biochemistry, liver stiffness and radiologist-derived cholangiographic assessment (trial registration: ISRCTN39463479).

A flexible mixed-optimization with H∞ control for coupled twin rotor MIMO system based on the method of inequality (MOI)- An experimental study.

This article introduces a cutting-edge H∞ model-based control method for uncertain Multi Input Multi Output (MIMO) systems, specifically focusing on UAVs, through a flexible mixed-optimization framework using the Method of Inequality (MOI). The proposed approach adaptively addresses crucial challenges such as unmodeled dynamics, noise interference, and parameter variations. Central to the design is a two-step controller development process. The first step involves Nonlinear Dynamic Inversion (NDI) and system decoupling for simplification, while the second step integrates H∞ control with MOI for optimal response tuning. This strategy is distinguished by its adaptability and focus on balancing robust stability and performance, effectively managing the intricate cross-coupling dynamics in UAV systems. The effectiveness of the proposed approach is validated through simulations conducted in MATLAB/Simulink environment. Results demonstrated the efficiency of the proposed robust control approach as evidenced by reduced steady-state error, diminished overshoot, and faster system response times, thus significantly outperforming traditional control methods.

Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain?

BACKGROUND AND AIMS: Normal alkaline phosphatase (ALP) levels in ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC) are associated with better long-term outcome. However, second-line therapies are currently recommended only when ALP levels remain above 1.5 times the upper limit of normal (×ULN) after 12-month UDCA. We assessed whether, in patients considered good responders to UDCA, normal ALP levels were associated with significant survival gains. APPROACH AND RESULTS: We performed a retrospective cohort study of 1047 patients with PBC who attained an adequate response to UDCA according to Paris-2 criteria. Time to liver-related complications, liver transplantation, or death was assessed using adjusted restricted mean survival time (RMST) analysis. The overall incidence rate of events was 17.0 (95% CI: 13.7-21.1) per 1000 out of 4763.2 patient-years. On the whole population, normal serum ALP values (but not normal gamma-glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), or aspartate aminotransferase (AST); or total bilirubin < 0.6 ×ULN) were associated with a significant absolute complication-free survival gain at 10 years (mean 7.6 months, 95% CI: 2.7 - 12.6 mo.; p = 0.003). In subgroup analysis, this association was significant in patients with a liver stiffness measurement ≥ 10 kPa and/or age ≤ 62 years, with a 10-year absolute complication-free survival gain of 52.8 months (95% CI: 45.7-59.9, p < 0.001) when these 2 conditions were met. CONCLUSIONS: PBC patients with an adequate response to UDCA and persistent ALP elevation between 1.1 and 1.5 ×ULN, particularly those with advanced fibrosis and/or who are sufficiently young, remain at risk of poor outcome. Further therapeutic efforts should be considered for these patients.

Critical shortfalls in the management of PBC: Results of a UK-wide, population-based evaluation of care delivery.

Background & Aims: Guidelines for the management of primary biliary cholangitis (PBC) were published by the British Society of Gastroenterology in 2018. In this study, we assessed adherence to these guidelines in the UK National Health Service (NHS). Methods: All NHS acute trusts were invited to contribute data between 1 January 2021 and 31 March 2022, assessing clinical care delivered to patients with PBC in the UK. Results: We obtained data for 8,968 patients with PBC and identified substantial gaps in care across all guideline domains. Ursodeoxycholic acid (UDCA) was used as first-line treatment in 88% of patients (n = 7,864) but was under-dosed in one-third (n = 1,964). Twenty percent of patients who were UDCA-untreated (202/998) and 50% of patients with inadequate UDCA response (1,074/2,102) received second-line treatment. More than one-third of patients were not assessed for fatigue (43%; n = 3,885) or pruritus (38%; n = 3,415) in the previous 2 years. Fifty percent of all patients with evidence of hepatic decompensation were discussed with a liver transplant centre (222/443). Appropriate use of second-line treatment and referral for liver transplantation was significantly better in specialist PBC treatment centres compared with non-specialist centres (p <0.001). Conclusions: Poor adherence to guidelines exists across all domains of PBC care in the NHS. Although specialist PBC treatment centres had greater adherence to guidelines, no single centre met all quality standards. Nationwide improvement in the delivery of PBC-related healthcare is required. Impact and implications: This population-based evaluation of primary biliary cholangitis, spanning four nations of the UK, highlights critical shortfalls in care delivery when measured across all guideline domains. These include the use of liver biopsy in diagnosis; referral practice for second-line treatment and/or liver transplant assessment; and the evaluation of symptoms, extrahepatic manifestations, and complications of cirrhosis. The authors therefore propose implementation of a dedicated primary biliary cholangitis care bundle that aims to minimise heterogeneity in clinical practice and maximise adherence to key guideline standards.

Guidance document: risk assessment of patients with cirrhosis prior to elective non-hepatic surgery.

As a result of the increasing incidence of cirrhosis in the UK, more patients with chronic liver disease are being considered for elective non-hepatic surgery. A historical reluctance to offer surgery to such patients stems from general perceptions of poor postoperative outcomes. While this is true for those with decompensated cirrhosis, selected patients with compensated early-stage cirrhosis can have good outcomes after careful risk assessment. Well-recognised risks include those of general anaesthesia, bleeding, infections, impaired wound healing, acute kidney injury and cardiovascular compromise. Intra-abdominal or cardiothoracic surgery are particularly high-risk interventions. Clinical assessment supplemented by blood tests, imaging, liver stiffness measurement, endoscopy and assessment of portal pressure (derived from the hepatic venous pressure gradient) can facilitate risk stratification. Traditional prognostic scoring systems including the Child-Turcotte-Pugh and Model for End-stage Liver Disease are helpful but may overestimate surgical risk. Specific prognostic scores like Mayo Risk Score, VOCAL-Penn and ADOPT-LC can add precision to risk assessment. Measures to mitigate risk include careful management of varices, nutritional optimisation and where possible addressing any ongoing aetiological drivers such as alcohol consumption. The role of portal decompression such as transjugular intrahepatic portosystemic shunting can be considered in selected high-risk patients, but further prospective study of this approach is required. It is of paramount importance that patients are discussed in a multidisciplinary forum, and that patients are carefully counselled about potential risks and benefits.

UK national trainee survey of hepatology training, research and the future workforce.

Objective: The increasing prevalence of liver disease in the UK means there is a pressing need to expand the hepatology workforce. This survey aims to evaluate current hepatology training provision, and trainee attitudes towards future careers in hepatology. Method: An electronic survey was distributed to higher specialty gastroenterology and hepatology trainees in the UK between March and May 2022. Results: 138 trainees completed the survey covering all training grades and regions of the UK. 73.7% reported receiving adequate hepatology training currently, with 55.6% intending to become future hepatologists. Trainee preference for future hepatology consultant posts in specialist liver centres were almost threefold higher compared with district general hospitals (60.9% vs 22.6%). All trainees, irrespective of training grade reported high confidence in managing decompensated cirrhosis in both inpatient and outpatient settings. Senior trainees (grade ST6 and higher), without advanced training programme (ATP) experience reported significantly lower confidence in managing viral hepatitis, hepatocellular carcinoma and post-transplant patients compared with equivalent trainees with ATP experience. For junior trainees (IMT3-ST5), remaining in their current deanery was the most important factor when considering future hepatology training application. Conclusions: There is a significant need to deliver widely available training on the management of complex liver disease to improve non-ATP trainee confidence. Innovative job planning strategies are required to encourage trainees to pursue careers outside of specialist liver centres. Expansion of hepatology training networks with wider geographical coverage are needed to address the growing need for more hepatologists around the UK.

Identification of a pH-Responsive Peptide-Paclitaxel Conjugate as a Novel Drug with Improved Therapeutic Potential.

A highly sensitive, nontoxic, hydrophilic cell-penetrating peptide (CPP = c[RGDKLAK]) was selected for the construction of an effective peptide-drug conjugate (PDC). A hydrophobic drug paclitaxel (PTX) was successfully conjugated with CPP via ester linkage with succinic acid (SA) as a pH-cleavable linker moiety. The characterization techniques employed in this study indicate the >95% purity of the resulting PDC (CPP-SA-PTX). The in vitro studies show that our proposed PDC exhibits enhanced stability (∼90%) and cytotoxicity (EC50 = 8.32 ± 0.09 nM). Besides the excellent solubility of PDC in water, the PTX effect on positive ß-tubulin-III indicates that the drug releases retained pharmacological properties. Additionally, in vivo, therapeutic-dose treatment reveals the prominent tumor-growth inhibitory effects (2.82-3.24-fold) of PDC in tumor mice models. Subsequently, these observations confirmed that our novel-designed PDC (CPP-SA-PTX) adduct may serve as a promising therapeutic agent to treat glioblastoma.

Cirrhosis and non-hepatic surgery in 2023 - a precision medicine approach.

INTRODUCTION: Patients with liver disease and portal hypertension frequently require surgery carrying high morbidity and mortality. Accurately estimating surgical risk remains challenging despite improved medical and surgical management. AREAS COVERED: This review aims to outline a comprehensive approach to preoperative assessment, appraise methods used to predict surgical risk, and provide an up-to-date overview of outcomes for patients with cirrhosis undergoing non-hepatic surgery. EXPERT OPINION: Robust preoperative, individually tailored, and precise risk assessment can reduce peri- and postoperative complications in patients with cirrhosis. Established prognostic scores aid stratification, providing an estimation of postoperative mortality, albeit with limitations. VOCAL-Penn Risk Score may provide greater precision than established liver severity scores. Amelioration of portal hypertension in advance of surgery may be considered, with prospective data demonstrating hepatic venous pressure gradient as a promising surrogate marker of postoperative outcomes. Morbidity and mortality vary between types of surgery with further studies required in patients with more advanced liver disease. Patient-specific considerations and practicing precision medicine may allow for improved postoperative outcomes.

UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis.

BACKGROUND & AIMS: Thirty-to-forty percent of patients with primary biliary cholangitis inadequately respond to ursodeoxycholic acid. Our aim was to assemble national, real-world data on the effectiveness of obeticholic acid (OCA) as a second-line treatment, alongside non-licensed therapy with fibric acid derivatives (bezafibrate or fenofibrate). METHODS: This was a nationwide observational cohort study conducted from August 2017 until June 2021. RESULTS: We accrued data from 457 patients; 349 treated with OCA and 108 with fibric acid derivatives. At baseline/pre-treatment, individuals in the OCA group manifest higher risk features compared with those taking fibric acid derivatives, evidenced by more elevated alkaline phosphatase values, and a larger proportion of individuals with cirrhosis, abnormal bilirubin, prior non-response to ursodeoxycholic acid, and elastography readings >9.6kPa (P < .05 for all). Overall, 259 patients (OCA) and 80 patients (fibric acid derivatives) completed 12 months of second-line therapy, yielding a dropout rate of 25.7% and 25.9%, respectively. At 12 months, the magnitude of alkaline phosphatase reduction was 29.5% and 56.7% in OCA and fibric acid groups (P < .001). Conversely, 55.9% and 36.4% of patients normalized serum alanine transaminase and bilirubin in the OCA group (P < .001). The proportion with normal alanine transaminase or bilirubin values in the fibric acid group was no different at 12 months compared with baseline. Twelve-month biochemical response rates were 70.6% with OCA and 80% under fibric acid treatment (P = .121). Response rates between treatment groups were no different on propensity-score matching or on sub-analysis of high-risk groups defined at baseline. CONCLUSION: Across the population of patients with primary biliary cholangitis in the United Kingdom, rates of biochemical response and drug discontinuation appear similar under fibric acid and OCA treatment.

Real-time robust generalized dynamic inversion based optimization control for coupled twin rotor MIMO system.

This work is used to design a novel robust optimization control law augmented with Robust Generalized Dynamic Inversion (RGDI) for continuous varying perturbations in the Twin Rotor MIMO System (TRMS). The perturbations like coupling effect, un-known states, gyroscopic disturbance torque, parametric uncertainties and parametric disturbances are considered as unwanted signal which should be optimized by an efficient controller. The variable structured systems like the TRMS (prototype) have great focus due to its high computational cost with a higher order non-linear behavior. The RGDI based controller designed to remove nonlinear dynamics as well as to avoid singularity issue with the augmentation of stability based mathematical operations (lyapunov stability analysis, controllability and observability matrices ) in the presence of considered perturbations during implementation. In this paper, we develop estimation of state deviation calculation between control angles and desired angles known as Euclidean error norm. The next step was to design RGDI based controller [Sliding Mode Control (SMC) and [Formula: see text] optimization] to minimize considered perturbations as well as the computational cost. The sharp (rapid) chattering phenomena in RGDI based SMC reduce the actuators performance that goes towards the failure of actuators. While the RGDI based [Formula: see text] optimization overcome the computational cost and minimizes [Formula: see text] norm that's guaranteeing the robust stability as well as robust performance. The robustness of the optimization control technique validated by taking its worst case via MATLAB-Simulation. A real-time implementation applied to evaluate the worth of novel dynamic approach.

Acute-on-chronic liver failure (ACLF) in 2022: have novel treatment paradigms already arrived?

INTRODUCTION: Acute-on-chronic failure (ACLF) is a recognized syndrome in patients with chronic liver disease and is characterized by acute decompensation, organ failure(s), and a high short-term mortality. ACLF is often triggered by ongoing alcohol consumption, gastrointestinal bleeding and/or infections, and is pathophysiologically characterized by uncontrolled systemic inflammation coupled with paradoxical immunoparesis. Patients with ACLF require prompt and early recognition. Management requires extensive utilization of clinical resources often including escalation to intensive care. AREAS COVERED: Currently, there are no specific targeted treatments for established ACLF, and management revolves around treating underlying precipitants and providing organ support. In this article, we review the epidemiology and pathophysiology of ACLF and summarize recent advances in management strategies of this syndrome, focusing specifically on novel emerging therapies. EXPERT COMMENTARY: ACLF is a challenging condition with rapid clinical course, high short-term mortality and varying clinical phenotypes. Management of ACLF is broadly focused on supportive care often in an intensive care setting with liver transplantation proving to be an increasingly relevant and effective rescue therapy. This disease has clear pathogenesis and epidemiological burden, thus distinguishing it from decompensated cirrhosis; there is clear clinical need for the development of specific and nuanced therapies to treat this condition.

Liver stiffness measurement by vibration-controlled transient elastography improves outcome prediction in primary biliary cholangitis.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) has been shown to predict outcomes of patients with primary biliary cholangitis (PBC) in small-size studies. We aimed to validate the prognostic value of LSM in a large cohort study. METHODS: We performed an international, multicentre, retrospective follow-up study of 3,985 patients with PBC seen at 23 centres in 12 countries. Eligibility criteria included at least 1 reliable LSM by VCTE and a follow-up ≥ 1 year. Independent derivation (n = 2,740) and validation (n = 568) cohorts were built. The primary endpoint was time to poor clinical outcomes defined as liver-related complications, liver transplantation, or death. Hazard ratios (HRs) with CIs were determined using a time-dependent multivariable Cox regression analysis. RESULTS: LSM was independently associated with poor clinical outcomes in the derivation (5,324 LSMs, mean follow-up 5.0 ± 3.1 years) and validation (1,470 LSMs, mean follow-up 5.0 ± 2.8 years) cohorts: adjusted HRs (95% CI) per additional kPa were 1.040 (1.026-1.054) and 1.042 (1.029-1.056), respectively (p <0.0001 for both). Adjusted C-statistics (95% CI) at baseline were 0.83 (0.79-0.87) and 0.92 (0.89-0.95), respectively. Between 5 and 30 kPa, the log-HR increased as a monotonic function of LSM. The predictive value of LSM was stable in time. LSM improved the prognostic ability of biochemical response criteria, fibrosis scores, and prognostic scores. The 8 kPa and 15 kPa cut-offs optimally separated low-, medium-, and high-risk groups. Forty percent of patients were at medium to high risk according to LSM. CONCLUSIONS: LSM by VCTE is a major, independent, validated predictor of PBC outcome. Its value as a surrogate endpoint for clinical benefit in PBC should be considered. LAY SUMMARY: Primary biliary cholangitis (PBC) is a chronic autoimmune disease, wherein the body's immune system mistakenly attacks the bile ducts. PBC progresses gradually, so surrogate markers (markers that predict clinically relevant outcomes like the need for a transplant or death long before the event occurs) are often needed to expedite the drug development and approval process. Herein, we show that liver stiffness measurement is a strong predictor of clinical outcomes and could be a useful surrogate endpoint in PBC trials.

Electrical Stability and Piezoresistive Sensing Performance of High Strain-Range Ultra-Stretchable CNT-Embedded Sensors.

Highly flexible and stretchable sensors are becoming increasingly widespread due to their versatile applicability in human/robot monitoring sensors. Conductive polymeric composites have been regarded as potential candidates for such sensors, and carbon nanotubes (CNTs) are widely used to fabricate such composites. In the present study, CNT-embedded high flexible sensors were fabricated using a facile three-roll milling method, which mitigates the drawbacks of the conventional fabrication methods. CNTs content varied between 0.5 and 4.0 wt.%, and the percolation threshold range was obtained via conductivity/resistivity values of the fabricated sensors. Following this, the electrical stability of the sensors was examined against the various DC and AC signals. Furthermore, the fabricated sensors were stretched up to 500% strain, and their sensitivity against varying strain amplitudes was investigated in terms of the change in resistance and gauge factors. Lastly, the fabricated sensors were applied to human fingers for monitoring finger bending and releasing motions to validate their potential applications. The experimental results indicated that these sensors have a percolation threshold of around 2% CNTs content, and the sensors fabricated with 2 to 4% CNTs content showed measurable resistance changes against the applied strain amplitudes of 50-500%. Among these sensors, the sensor with 2% CNTs content showed the highest sensitivity in the studied strain range, exhibiting a resistance change and gauge factor of about 90% and 1.79 against 50% strain amplitude and about 18,500% and 37.07 against 500% strain amplitude, respectively. All these sensors also showed high sensitivity for finger motion detection, showing a resistance change of between 22 and 69%.

Current Application of Chemometrics Analysis in Authentication of Natural Products: A Review.

BACKGROUND: The efficiency of herbal medicinal products depends on the quantity of active ingredients in them, which can vary considerably in different contents. Hence, the quality control of herbal medicines is a critical concern. OBJECTIVE: This paper aims to provide a succinct review of recent chemometrics applications in solving the uncertainty of the authentication of herbal medicines over the last two decades. METHODS: Studies involving chemometrics applications in conjunction with various analytical methods have been categorized according to the type of research used in the quality evaluation of different samples, including chromatographic (HPLC, GC-MS) and spectroscopic analysis (UVVis, FTIR, NMR, and MS). RESULTS: This review consists of over 90 studies illustrating the relevance of chemometrics methods in the discrimination based on the key bioactive components and phytochemical diversity of several herbs from closely related species. In addition to the prediction of the active components, the distinction between varieties and hybrids was accomplished through quantitative analysis techniques. CONCLUSION: Methods of chemometrics have provided an important and potent tool for the quality control and authentication of various herbs.

Emerging drugs for the treatment of primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare immune-mediated cholestatic disease for which no medical therapy has been shown to slow disease progression. Consequently, liver transplantation is the only lifesaving intervention for patients, and despite being a rare disease, PSC is the lead indication for transplantation across several European countries. The vast majority of patients (>70%) also develop inflammatory bowel disease (IBD) at some point in their lifetime, which imparts added lifetime risks of hepatobiliary malignancy and colorectal cancer. The rare disease nature, variable and often slow rates of disease progression (years rather than months), and lack of robust surrogate biomarkers for early stage yet high risk disease, represent critical challenges in trial design that have long precluded the development of effective medical treatment. However, the horizon for new treatments is encouraging, given innovative clinical trial programmes led by industry, alongside several investigator-initiated studies. Herein, we outline the current platform of interventional trials in PSC, before discussing emerging areas of therapeutic interest.

Overview of Feedstocks for Sustainable Biodiesel Production and Implementation of the Biodiesel Program in Pakistan.

The energy demand of the world is skyrocketing due to the exponential economic growth and population expansion. To meet the energy requirement, the use of fossil fuels is not a good decision, causing environmental pollution such as CO2 emissions. Therefore, the use of renewable energy sources like biofuels can meet the energy crisis especially for countries facing oil shortages such as Pakistan. This review describes the comparative study of biodiesel synthesis for various edible oils, non-edible oils, and wastes such as waste plastic oil, biomass pyrolysis oil, and tyre pyrolysis oil in terms of their oil content and extraction, cetane number, and energy content. The present study also described the importance of biodiesel synthesis via catalytic transesterification and its implementation in Pakistan. Pakistan is importing an extensive quantity of cooking oil that is used in the food processing industries, and as a result, a huge quantity of waste cooking oil (WCO) is generated. The potential waste oils for biodiesel synthesis are chicken fat, dairy scum, WCO, and tallow oil that can be used as potential substrates of biodiesel. The implementation of a biodiesel program as a replacement of conventional diesel will help to minimize the oil imports and uplift the country's economy. Biodiesel production via homogeneous and heterogeneous catalyzed transesterification is more feasible among all transesterification processes due to a lesser energy requirement and low cost. Therefore, biodiesel synthesis and implementation could minimize the imports of diesel by significantly contributing to the overall Gross Domestic Product (GDP). Although, waste oil can meet the energy needs, more available cultivation land should be used for substrate cultivation. In addition, research is still needed to explore innovative solvents and catalysts so that overall biodiesel production cost can be minimized. This would result in successful biodiesel implementation in Pakistan.

ATR-FTIR Spectroscopy, HPLC Chromatography, and Multivariate Analysis for Controlling Bee Pollen Quality in Some Algerian Regions.

Bee pollen collected by honeybees (Apis mellifera) is one of the bee products, and it is as valuable as honey, propolis, royal jelly, or beebread. Its quality varies according to its geographic location or plant sources. This study aimed to apply rapid, simple, and accurate analytical methods such as attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and high-performance liquid chromatography (HPLC) along with chemometrics analysis to construct a model aimed at discriminating between different pollen samples. In total, 33 samples were collected and analyzed using principal component analysis (PCA), hierarchical clustering analysis (HCA), and partial least squares regression (PLS) to assess the differences and similarities between them. The PCA score plot based on both HPLC and ATR-FTIR revealed the same discriminatory pattern, and the samples were divided into four major classes depending on their total content of polyphenols. The results revealed that spectral data obtained from ATR-FTIR acquired in the region (4000-500 cm-1) were further subjected to a standard normal variable (SNV) method that removes scattering effects from spectra. However, PCA, HCA, and PLS showed that the best PLS model was obtained with a regression coefficient (R 2) of 0.9001, root-mean-square estimation error (RMSEE) of 0.0304, and root-mean-squared error cross-validation (RMSEcv) of 0.036. Discrimination between the three species has also been possible by combining the pre-processed ATR-FTIR spectra with PCA and PLS. Additionally, the HPLC chromatograms after pre-treatment (SNV) were subjected to unsupervised analysis (PCA-HCA) and supervised analysis (PLS). The PLS model confers good results by factors (R 2 = 0.98, RMSEE = 8.22, and RMSEcv = 27.86). Prospects for devising bee pollen quality assessment methods include utilizing ATR-FTIR and HPLC in combination with multivariate methods for rapid authentication of the geographic location or plant sources of bee pollen.