Safety of robotic cholecystectomy as index training procedure: the UK experience.

AIMS: To evaluate the safety profile of robotic cholecystectomy performed within the United Kingdom (UK) Robotic Hepatopancreatobiliary (HPB) training programme. METHODS: A retrospective evaluation of prospectively collected data from eleven centres participating in the UK Robotic HPB training programme was conducted. All adult patients undergoing robotic cholecystectomy for symptomatic gallstone disease or gallbladder polyp were considered. Bile duct injury, conversion to open procedure, conversion to subtotal cholecystectomy, length of hospital stay, 30-day re-admission, and post-operative complications were the evaluated outcome parameters. RESULTS: A total of 600 patients were included. The median age was 53 (IQR 65-41) years and the majority (72.7%; 436/600) were female. The main indications for robotic cholecystectomy were biliary colic (55.5%, 333/600), cholecystitis (18.8%, 113/600), gallbladder polyps (7.7%, 46/600), and pancreatitis (6.2%, 37/600). The median length of stay was 0 (IQR 0-1) days. Of the included patients, 88.5% (531/600) were discharged on the day of procedure with 30-day re-admission rate of 5.5% (33/600). There were no bile duct injuries and the rate of conversion to open was 0.8% (5/600) with subtotal cholecystectomy rate of 0.8% (5/600). CONCLUSION: The current study confirms that robotic cholecystectomy can be safely implemented to routine practice with a low risk of bile duct injury, low bile leak rate, low conversion to open surgery, and low need for subtotal cholecystectomy.

Pyoderma Gangrenosum: A Case Highlighting the Importance of Timely Diagnosis.

Pyoderma Gangrenosum (PG) is a distinctive dermatologic condition characterized by recurrent inflammatory ulcers, often manifesting with violaceous borders and undermined edges. We describe a 40-year-old male who presented with acute on chronic necrotic ulcer of the left index finger following foreign body penetration. Despite multiple emergency department visits and treatments for presumed recurrent cellulitis, including various debridements, his condition persisted without symptomatic relief. A high index of clinical suspicion, due to recurrent presentations and potential pathergy, prompted an excision biopsy which confirmed Pyoderma Gangrenosum (PG). Regrettably, due to delays in appropriate management, the patient chose amputation because of intolerable pain, highlighting the critical importance of timely diagnosis for optimal patient outcomes.

In-vitro and in-vivo antidiabetic activity of aerial parts of Aitchisonia rosea supported by phytochemical and GC-MS analysis.

Medicinal plants contain a wide variety of bioactive phytoconstituents which can serve as new therapeutic agents for several diseases. This study examines the antidiabetic potential of Aitchisonia rosea in alloxan-induced diabetic rats and identifies its bioactive phytoconstituents using GC-MS. In vitro, antidiabetic potential was established using the α-amylase inhibition assay. In vivo, antidiabetic potential was investigated by employing the oral glucose tolerance test (OGTT). GC-MS analysis was used to identify the bioactive phytoconstituents. The in vitro and in vivo tests showed that the aqueous extract of A. rosea possesses better antidiabetic potential. The α-amylase inhibition assay highlighted an IC50 value of 134.87µg/ml. In an oral glucose tolerance test, rats given an aqueous A. rosea extract significantly lowered their blood sugar levels significant reduction in the blood glucose concentration was observed in the oral glucose tolerance test in rats treated with the aqueous A. rosea extract. GC-MS investigation revealed many phytoconstituents, with serverogenin acetate and cycloheptasiloxane tetradecamethyl being important antidiabetic agents. This study found anti-diabetic properties in A. rosea extract. The phytochemical and GC-MS investigation also found serverogenin acetate and cycloheptasiloxane tetradecamethyl, which could be used to develop new antidiabetic drugs.

Investigating the effect of curing temperature on the corrosion resistance of epoxy-based composite coatings for aluminium alloy 7075 in artificial seawater.

Araldite LY5052 epoxy resin and Aradur HY5052 hardener were used in a ratio of 100 : 38 to produce composite coatings containing 0.05 proportion of functionalized SiO2. Coating samples were cured at curing temperatures of 60, 80, 100, 120, and 140 °C. The results of Fourier Transform Infrared Spectroscopy (FTIR) verified that silica particles were successfully functionalized with methyltrimethoxysilane (MTMS)/3-aminopropyl-triethoxysilane (APTES). The epoxide and Si-O bond peaks in the EHS100 coating were present due to the effective incorporation of functionalized silica (FSiO2) particles in the polymeric matrix (epoxy resin). The surface morphology of the bare aluminium alloy AA7075 and EHS100 coating was investigated by Field Emission Scanning Electron Microscopy (FE-SEM). Additionally, corrosion analysis was conducted at room temperature using an electrolytic solution of artificial seawater, prepared according to ASTM standard D1141-98. Charge transfer resistance (Rct) was shown to increase by 86.43, 92.15, 94.76, 90.65, and 83.96% for EHS60, EHS80, EHS100, EHS120, and EHS140 in comparison to bare AA7075 substrate using electrochemical impedance spectroscopy (EIS) examination. Furthermore, potentiodynamic polarization (PDP) measurements were carried out to determine the corrosion rates, which demonstrated a drop of 55.98, 98.96, 99.37, 98.33, and 50.39% for EHS60, EHS80, EHS100, EHS120, and EHS140, as compared to the bare AA7075 sample. The highest charge transfer resistance (29.77 kΩ) and lowest corrosion rate (0.00078 mm per year) were recorded for EHS100, which reveals that the EHS100 coating has the best anti-corrosion performance and provides the maximum corrosion protection for the aluminium alloy AA7075 substrate.

A direct examination of microbial specialized metabolites associated with ocean sediments from Baffin Bay and the Gulf of Maine.

Specialized metabolites produced by microorganisms found in ocean sediments display a wide range of clinically relevant bioactivities, including antimicrobial, anticancer, antiviral, and anti-inflammatory. Due to limitations in our ability to culture many benthic microorganisms under laboratory conditions, their potential to produce bioactive compounds remains underexplored. However, the advent of modern mass spectrometry technologies and data analysis methods for chemical structure prediction has aided in the discovery of such metabolites from complex mixtures. In this study, ocean sediments were collected from Baffin Bay (Canadian Arctic) and the Gulf of Maine for untargeted metabolomics using mass spectrometry. A direct examination of prepared organic extracts identified 1468 spectra, of which ∼45% could be annotated using in silico analysis methods. A comparable number of spectral features were detected in sediments collected from both locations, but 16S rRNA gene sequencing revealed a significantly more diverse bacterial community in samples from Baffin Bay. Based on spectral abundance, 12 specialized metabolites known to be associated with bacteria were selected for discussion. The application of metabolomics directly on marine sediments provides an avenue for culture-independent detection of metabolites produced under natural settings. The strategy can help prioritize samples for novel bioactive metabolite discovery using traditional workflows.

Biomass-Printed Hybrid Solar Evaporator Derived from Bio-polluted Invasive Species, a Potential Step toward Carbon Neutrality.

Biomass-based photothermal conversion is of great importance for solar energy utilization toward carbon neutrality. Herein, a hybrid solar evaporator is innovatively designed via UV-induced printing of pyrolyzed Kudzu biochar on hydrophilic cotton fabric (KB@CF) to integrate all parameters in a single evaporator, such as solar evaporation, salt collection, waste heat recovery for thermoelectricity, sieving oil emulsions, and water disinfection from microorganisms. The UV-induced printed fabric demonstrates stronger material adhesion as compared to the conventional dip-dry technique. The hybrid solar evaporator gives an enhanced evaporation rate (2.32 kg/m2 h), and the complementary waste heat recovery system generates maximum open-circuit voltage (Vout ∼ 143.9 mV) and solar to vapor conversion efficiency (92%), excluding heat losses under one sun illumination. More importantly, 99.98% of photothermal-induced bacterial killing efficiency was achieved within 20 min under 1 kW m-2 using the hyperthermia effect of Kudzu biochar. Furthermore, numerical heat-transfer simulations were performed successfully to analyze the enhanced interfacial heat accumulation (75.3 °C) and heat flux distribution of the thermoelectric generators under one sun. We firmly believe that the safe use of bio-polluted invasive species in hybrid solar-driven evaporation systems eases the environmental pressure toward carbon neutrality.

No difference in treatment outcome between patients with nodal versus extranodal diffuse large B-cell lymphoma.

Background and Aim: Diffuse large B-cell lymphoma (DLBCL) has been classified using various parameters, including the site of origin. Studies have reported conflicting outcomes when DLBLC patients were stratified according to the site of origin. This study aimed to investigate the response rate and survival outcomes in nodal versus extranodal DLBCL and compare the results to a region-matched study covering the 1988 - 2005 period. Methods: A single-center retrospective cohort study was conducted on all patients diagnosed with DLBCL and treated in a tertiary care hospital in Pakistan during 2014 - 2019. We calculated the mean and median for continuous variables and frequency and percentages for all categorical variables. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier survival curves. A Cox proportional hazards model was used to determine the hazard ratio (HR) for OS. Results: Of the 118 patients, 49 patients (41.5%) had nodal disease and 69 patients (58.5%) were diagnosed with extranodal DLBCL. The majority of patients in the nodal and extranodal cohorts presented with Stages III and IV disease (73.4% and 62.3%, respectively). A complete response to (immuno) chemotherapy was achieved in 71.4% of nodal DLBCL patients and 65.2% of extranodal DLBCL patients. The 5-year PFS and median PFS in the entire cohort were 0.8% and 17 m, respectively. The PFS and median PFS in the nodal and extranodal DLBCL cohort were 0% and 1.4%, respectively, and 15 m and 19 m, respectively. The 5-year OS and median OS in the entire cohort were 16.1% and 19 m, respectively. The OS and median OS in the nodal and extranodal DLBCL cohort were 8.2% and 21.7%, respectively, and 19 m and 21 m, respectively. Multivariable linear regression revealed that the ABC phenotype (nodal, HR = 1.37, 95% CI = 1.37 - 3.20; extranodal, HR = 1.65, 95% CI = 1.46 - 3.17; GBC as reference) and double and triple hit DLBCL (nodal, HR = 1.29, 95% CI = 1.19 - 2.81; extranodal, HR = 1.87, 95% CI = 1.28 - 2.43; and non-expressors as reference) are independent negative predictors of OS. Conclusions: DLBCL incidence in the Karachi region has remained comparable but patient composition in the extranodal DLBCL cohort has shifted to predominantly advanced stage. Nodal and extranodal DLBCL were associated with similar PFS and OS profiles and first- and second-line treatment responses. Cell of origin and antigen expression status was independent negative predictors of OS, disfavoring the ABC phenotype and lesions with c-MYC and BCL2 and/or BCL6 overexpression. Relevance for Patients: DLBCL is an aggressive type of non-Hodgkin's lymphoma, however; patients respond well to standard systemic chemotherapy. Extranodal type of DLBCL patients tend to have more residual disease after first-line systemic chemotherapy, but physicians should keep in mind that the subsequent line treatment mitigates its negative impact on survival.

Ensuring environmental inclusion in developing countries: the role of macroeconomic policies.

In every society, there exist disadvantaged groups who have failed constantly to take part in the development of the economy and reap the benefits of economic growth as well. Along with economic and social factors, environmental factors are also accountable in making inclusion a challenge for the marginalized group. Contaminated drinking water, inappropriate sanitation systems, and pollution are the factors that affect health and wellbeing of the poor class by affecting their productivity. Thus, the lack of a clean environment leads the poor section towards further poverty and income inequality. Since the 2030 Agenda for Sustainable Development emphasizes three components to achieve sustainable development, namely economic, social, and environmental, this study inspects the role of macroeconomic policies in ensuring an inclusive clean environment in developing countries. Moreover, it considers the composite effect of fiscal policy and monetary policy on environmental inclusion by including interactive terms. This investigation uses FE-2SLS on a panel of 51 developing countries for the period of 1995-2019 to analyse the impact of macroeconomic policies on environmental inclusion. The study provides empirical evidence that fiscal and monetary policy has the potential to ensure an inclusive clean environment in developing countries. The findings imply that the macroeconomic policy actions depend on each other. Furthermore, governments in developing regions are required to cut nondeveloping expenditures and use expansionary monetary policy to promote green growth.

Spatio-temporal change detection of land use and land cover in Malakand Division Khyber Pakhtunkhwa, Pakistan, using remote sensing and geographic information system.

The land use land cover (LULC) change due to the rapidly growing population is a common feature of the urban area. The rapidly growing population in Malakand Division is a greater threat to the LULC of the area due to its negative impact on environment and ecology. This research aims to detect the variations in LULC from 1991 to 2017 in the Malakand Division, Khyber Pakhtunkhwa (KP) province of Pakistan. The study relies on secondary dataset downloaded from the US Geological Survey (1991, 2001, 2011, and 2017 imageries) and the United Nations Office for the Coordination of Humanitarian Affairs (UN OCHA) website. Maximum likelihood technique under supervised image classification was opted to analyze the LULC changes in between 1991 and 2017. The results were based on six major land use classes including agriculture built-up area, vegetation cover, water bodies, snow cover, and barren land. The results from 1991 to 2017 show a substantial reduction in snow cover and barren land which is consequence of climate change. A known change has been recorded in built-up area which shows an increase from 1.02 to 6.2% with a change of 5.18% of the total land. The vegetation cover water bodies were also showing increase in area. The vegetation cover increased from 28.89 to 44.67% while barren land decreased from 45.68 to 40.29% of the total area. Furthermore, the built-up area increased from 1.02 to 6.2%, whereas water covers increased from 0.63% (1991) to 0.86% (2017) of the total area. The study concludes that there is an immense need for planning to preserve the natural habitat for sustainable development in the area.

Lopinavir-Loaded Self-Nanoemulsifying Drug Delivery System for Enhanced Solubility: Development, Characterisation and Caco-2 Cell Uptake.

BACKGROUND: The antiretroviral protease inhibitor drug, lopinavir (LPV), is used to treat HIV-1 infection. LPV is known to have limited oral bioavailability, which may be attributed to its poor aqueous solubility, low efficacy and high first-pass metabolism. Self-nanoemulsifying drug delivery systems (SNEDDS) for LPV have been developed and optimised to counter the current issues. METHODS: The titration method was used to prepare LPV-loaded SNEDDS (LPV-SNEDDS). Six different pseudo-ternary phase diagrams were constructed to identify the nanoemulsifying region. The developed formulations were chosen in terms of globule size < 100 nm, dispersity ≤ 0.5, dispersibility (Grade A) and% transmittance > 85. Heating-cooling cycle, freeze-thaw cycle, and centrifugation studies were performed to confirm the stability of the developed SNEDDS. RESULTS: The final LPV-SNEDDS (L-14) droplet size was 58.18 ± 0.62 nm, with polydispersity index, zeta potential, and entrapment efficiency (EE%) values of 0.326 ± 0.005, -22.08 ± 1.2 mV, and 98.93 ± 1.18%, respectively. According to high-resolution transmission electron microscopy (HRTEM) analysis, the droplets in the optimised formulation were < 60 nm in size. The selected SNEDDS released nearly 99% of the LPV within 30 min, which was significantly (p < 0.05) higher than the LPV-suspension in methylcellulose (0.5% w/v). It indicates the potential use of SNEDDS to enhance the solubility of LPV, which eventually could help improve the oral bioavailability of LPV. The Caco-2 cellular uptake study showed a significantly (p < 0.05) higher LPV uptake from the SNEEDS (LPV-SNEDDS-L-14) than the free LPV (LPV-suspension). CONCLUSION: The LPV-SNEDDS could be a potential carrier for LPV oral delivery.

Recent advancements in engineered biopolymeric-nanohybrids: A greener approach for adsorptive-remediation of noxious metals from aqueous matrices.

Industrial wastewater is causing serious health problems due to presence of large concentrations of toxic metals. Removal of these metals is still a big challenge using pristine natural biopolymers due to their low surface area, water solubility, and poor recovery. Developing biopolymeric composites with other materials has attained attention because they possess a high surface area and structural porosity, high reactivity, and less water solubility. In simple words, biopolymeric nanohybrids have great adsorption capacity for heavy metals. Biopolymeric materials are abundant, low cost, biodegradable, and possess different functional moieties (carboxyl, amine, hydroxyl, and carbonyl) which play a vital role to adsorb metal ions through various inter-linkages (i.e., electrostatic, hydrogen bonding, ion exchange, chelation, etc.). Biopolymeric nanohybrids have been proven a potent tool in environmental remediation such as the abatement of heavy metal ions from polluted water. Herein, we have reported the adsorption potential of various biopolymers (cellulose, chitosan, pectin, gelatin, and silk proteins) for the removal of heavy metals. This review discusses the suitability of biopolymeric nanohybrids as an adsorbent for heavy metals, their synthesis, modification, adsorption potential, and adsorption mechanism along with best fitted thermodynamic and kinetic models. The influence of pH, contact time, and adsorbent dose on adsorption potential has also been discussed in detail. Lastly, the challenges, research gaps and recommendations have been presented. This review concludes that biopolymers in combination with other materials such as metal-based nanoparticles, clay, and carbon-based materials are excellent materials to remove metallic ions from wastewater. Significant adsorption of heavy metals was obtained at a moderate pH (5-6). Contact time and adsorbent dose also affect the adsorption of heavy metals in certain ways. The Pseudo-first order model fits the data for the initial period of the first step of the reaction. Kinetic studies of different adsorption processes of various biopolymeric nanohybrids described that for majority of bionanohybrids, Pseudo-second order fitted the experimental data very well. Functionalized biopolymeric nanohybrids being biodegradable, environment friendly, cost-effective materials have great potential to adsorb heavy metal ions. These may be the future materials for environmental remediation.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Exploration of Black Boxes of Supervised Machine Learning Models: A Demonstration on Development of Predictive Heart Risk Score.

Machine learning (ML) often provides applicable high-performance models to facilitate decision-makers in various fields. However, this high performance is achieved at the expense of the interpretability of these models, which has been criticized by practitioners and has become a significant hindrance in their application. Therefore, in highly sensitive decisions, black boxes of ML models are not recommended. We proposed a novel methodology that uses complex supervised ML models and transforms them into simple, interpretable, transparent statistical models. This methodology is like stacking ensemble ML in which the best ML models are used as a base learner to compute relative feature weights. The index of these weights is further used as a single covariate in the simple logistic regression model to estimate the likelihood of an event. We tested this methodology on the primary dataset related to cardiovascular diseases (CVDs), the leading cause of mortalities in recent times. Therefore, early risk assessment is an important dimension that can potentially reduce the burden of CVDs and their related mortality through accurate but interpretable risk prediction models. We developed an artificial neural network and support vector machines based on ML models and transformed them into a simple statistical model and heart risk scores. These simplified models were found transparent, reliable, valid, interpretable, and approximate in predictions. The findings of this study suggest that complex supervised ML models can be efficiently transformed into simple statistical models that can also be validated.

Double-Edged Nanobiotic Platform with Protean Functionality: Leveraging the Synergistic Antibacterial Activity of a Food-Grade Peptide to Mitigate Multidrug-Resistant Bacterial Pathogens.

While persistent efforts are being made to develop a novel arsenal against bacterial pathogens, the development of such materials remains a formidable challenge. One such strategy is to develop a multimodel antibacterial agent which will synergistically combat bacterial pathogens, including multidrug-resistant bacteria. Herein, we used pediocin, a class IIa bacteriocin, to decorate Ag° and developed a double-edged nanoplatform (Pd-SNPs) that inherits intrinsic properties of both antibacterial moieties, which engenders strikingly high antibacterial potency against a broad spectrum of bacterial pathogens including the ESKAPE category without displaying adverse cytotoxicity. The enhanced antimicrobial activity of Pd-SNPs is due to their higher affinity with the bacterial cell wall, which allows Pd-SNPs to penetrate the outer membrane, inducing membrane depolarization and the disruption of membrane integrity. Bioreporter assays revealed the upregulation of cpxP, degP, and sosX genes, triggering the burst of reactive oxygen species which eventually cause bacterial cell death. Pd-SNPs prevented biofilm formation, eradicated established biofilms, and inhibited persister cells. Pd-SNPs display unprecedented advantages because they are heat-resistant, retain antibacterial activity in human serum, and alleviate vancomycin intermediate Staphylococcus aureus (VISA) infection in the mouse model. In addition, Pd-SNPs wrapped in biodegradable nanofibers mitigated Listeria monocytogenes in cheese samples. Collectively, Pd-SNPs exhibited excellent biocompatibility and in vivo therapeutic potency without allowing foreseeable resistance acquisition by pathogens. These findings underscore new avenues for using a potent biocompatible nanobiotic platform to combat a wide range of bacterial pathogens.

Optimization of a Cefuroxime Axetil-Loaded Liquid Self-Nanoemulsifying Drug Delivery System: Enhanced Solubility, Dissolution and Caco-2 Cell Uptake.

Cefuroxime axetil (CA) is an oral cephalosporin which hydrolyzes rapidly to the active parent compound cefuroxime. CA is known to have incomplete oral bioavailability (30−50%) due to its poor solubility and enzymatic conversion to cefuroxime in the gut lumen. In order to overcome these drawbacks, a lipid-based self-nanoemulsifying drug delivery system (SNEDDS) has been developed and optimized. The SNEDDS formulations were prepared using the aqueous phase titration method. The greatest self-emulsifying area was found in the 2:1 Smix ratio. As a result, different SNEDDS formulations were carefully selected from this phase diagram based on their smaller droplet size < 100 nm, polydispersity index ≤ 0.5, dispersibility (Grade A), and transmittance (%) > 85%. Thermodynamic stability tests were carried out in order to rule out any metastable/unstable SNEDDS formulations. The droplet size, polydispersity index, zeta potential, and entrapment efficiency (% EE) of optimized CA-loaded SNEDDS (C-3) were 18.50 ± 1.83 nm, 0.064 ± 0.008, −22.12 ± 1.20 mV, and 97.62 ± 1.06%, respectively. In vitro release studies revealed that the SNEDDS formulation had increased CA solubility. CA-SNEDDS-C3 increased CA cellular uptake, possibly due to increased CA solubility and the inhibition of enzymatic conversion to cefuroxime. Finally, in terms of the improvement of oral bioavailability, CA-loaded-SNEDDS could be a viable alternative to commercially available CA formulations.

Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula.

BACKGROUND: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. RESULTS: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P = .45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P = .37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P = .05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P < .001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P = .020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P = .604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P = .693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. CONCLUSION: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.

Spatiotemporal valuation of cultural and natural landscapes contributing to Pakistan's cultural ecosystem services.

Cultural ecosystem services are the non-material benefits that people obtain from ecosystems and these services are subject to tremendous anthropogenic and climatic pressures. This study evaluates the spatiotemporal economic valuation of selected cultural and natural landscapes in Pakistan using net present value method. The results indicate that both cultural landscapes and mountain ecosystems are the most significant contributors to Pakistan's cultural ecosystem services. The net present value of our study area was USD 96/ha, while this value is ranged from USD 0.000242/ha to USD 138,997/ha in the 42 previous studies selected for comparison. Service flow, population, and visitor numbers were the most significant indicators of cultural ecosystem services. The promotion of cultural ecosystem services as an inclusive service and the application of discounted rates are identified as key approaches for ensuring sustainable resource use and enhanced intergenerational benefits by incorporating cultural ecosystem services into the national policy framework.

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-ß (Aß) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aß, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-ß 42 (Aß42)/Aß40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aß clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Knowledge, attitude, and practice regarding treatment of group a beta haemolytic tonsillo pharyngitis and prevention of rheumatic fever among doctors in Karachi, Pakistan: A perspective study.

OBJECTIVE: To assess knowledge and practices associated with rheumatic fever among medical practitioners in an urban setting. METHODS: The cross-sectional study was conducted at five major hospitals in Karachi from August to November 2019, and comprised house officers, postgraduate trainees, and general physicians of either gender. The subjects were given a questionnaire assessing their knowledge and perception regarding acute rheumatic fever as well as prophylaxis. Data was analysed using SPSS 25. RESULTS: Of the 247 respondents, 173(70%) were house officers, 31(13%) were postgraduate trainees and 43(17%) were general physicians. Overall, 202(82%) subjects were associated with some teaching hospital. Significantly more postgraduate trainees and general physicians answered correctly when asked to identify clinical and laboratory findings suggestive of Group A streptococcal throat infection than house officers (p<0.001). Among the house officers 49(28.3%), and among the postgraduate trainees 11(35.4%) knew the correct way to prescribe penicillin to prevent rheumatic fever. Among the general physicians, 20(46.5%) had accurate knowledge regarding the prescription. CONCLUSIONS: Knowledge and practices of medical practitioners regarding rheumatic fever were less than ideal and may play a part in misdiagnoses of Group A streptococcal infections and, hence, prophylaxis.

External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. METHODS: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. RESULTS: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. CONCLUSION: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.