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Introduction: Boerhaave syndrome is a rare condition associated with high morbidity and mortality. Prompt intervention greatly improves outcomes, with surgery traditionally being the mainstay of management. Recent advances in therapeutic endoscopy have led to increasing interest in endoluminal vacuum therapy (EVT), a minimally invasive technique, allowing wound debridement and drainage, encouraging granulation tissue formation. EVT has been associated with positive clinical outcomes, including lower mortality rates compared to surgery and stenting for the management of anastomotic leaks, and to a lesser extent, oesophageal perforations. EVT has been adopted into practice across Europe; however, only few cases have been reported from the UK. Case Presentations: We report three cases of Boerhaave syndrome, successfully managed with EVT, using the Eso-SPONGE ® (B.Braun Medical Ltd, Sheffield, UK). EVT involves the placement of a polyurethane sponge into the wound cavity. The cavity is initially assessed, then an overtube is introduced through which the sponge is inserted, and then the overtube is removed. Sponge position is confirmed and adjusted if necessary. The sponge is connected via a trans-nasal drain to continuous negative pressure suction and is changed every 3–5 days. Having been deemed surgically unfit, all 3 patients were referred for EVT. All patients made excellent recovery and were discharged home. Conclusion: EVT is an effective management strategy for surgically unfit Boerhaave syndrome patients. Eso-SPONGE use aided drainage of the septic focus and closure of the defect, leading to complete recovery. Our findings support the existing evidence that EVT is a promising solution for Boerhaave syndrome.

Objectives: Most prior advance care planning (ACP) interventions lack integration of the social context of patients' ACP process, which patients indicate is critically important. The current study developed the Planning Advance Care Together (PACT) website to foster inclusion of loved ones in the ACP process. Methods: To provide feedback about the PACT website, patients with advanced cancer (N = 11), their caregivers (N = 11), and experts (N = 10) participated in semi-structured interviews. Patients and caregivers also completed standardized ratings of acceptability and usability. Results: Overall, patient (n = 11) and caregiver (n = 11) ratings of acceptability and usability of the website exceeded benchmark cut-offs (≥24 on the Acceptability E-Scale and ≥ 68 on the System Usability Scale). Patients, caregivers, and experts liked the topic of ACP but felt that it could be emotionally challenging. They recommended focusing more on planning and less on end of life. They appreciated being able to include loved ones and recommended adding resources for caregivers. Conclusions: Study findings support the preliminary usability and acceptability of the PACT website. Findings will be used to inform a modified prototype of the PACT website that is interactive and ready for field testing with patients with advanced cancer and their loved ones. Innovation: We utilized a novel application of the shared mind framework to support patients with advanced cancer in engaging their loved ones in the ACP process.

Urban populations of herring gulls (Larus argentatus) are increasing and causing human-wildlife conflict by exploiting anthropogenic resources. Gulls that breed in urban areas rely on varying amounts of terrestrial anthropogenic foods (e.g., domestic refuse, agricultural and commercial waste) to feed themselves. However, with the onset of hatching, many parent gulls switch to sourcing more marine than anthropogenic or terrestrial foods to provision their chicks. Although anthropogenic foods may meet chick calorific requirements for growth and development, some such foods (e.g., bread) may have lower levels of protein and other key nutrients compared to marine foods. However, whether this parental switch in chick diet is driven by chicks’ preference for marine foods, or whether chicks’ food preferences are shaped by the food types provisioned by their parents, remains untested. This study tests whether chick food preferences can be influenced by their provisioned diet by experimentally manipulating the ratio of time for which anthropogenic and marine foods were available (80:20 and vice versa) in the rearing diets of two treatment groups of rescued herring gull chicks. Each diet was randomly assigned to each of the 27 captive-reared chicks for the duration of the study. We tested chicks’ individual food preferences throughout their development in captivity using food arrays with four food choices (fish, cat food, mussels and brown bread). Regardless of the dietary treatment group, we found that all chicks preferred fish and almost all refused to eat most of the bread offered. Our findings suggest that early-life diet, manipulated by the ratio of time the different foods were available, did not influence gull chicks’ food preferences. Instead, chicks developed a strong and persistent preference for marine foods, which appears to match adult gulls’ dietary switch to marine foods upon chick hatching and may reinforce the provisioning of marine foods during chick development. However, whether chicks in the wild would refuse provisioned foods, and to a sufficient extent to influence parental provisioning, requires further study. Longitudinal studies of urban animal populations that track wild individuals’ food preferences and foraging specialisations throughout life are required to shed light on the development and use of anthropogenic resource exploitation.

Natural phytochemicals (PCs) are responsible for the taste, colour, and aroma of many edible plants. Cohort studies have linked higher intake to a reduced risk of chronic degenerative diseases and premature ageing. The ability of foods rich in PCs, such as phytanthocyanins, apigenin, flavonols, flavonoids, bioflavonoids, gallic acid, ellagic acid, quercetin, and ellagitannins, to support physical activity has also been highlighted in a number of published pre-clinical and prospective clinical studies. This literature mostly emphasises the ability of PCs to enhance the adaptive upregulation of antioxidant enzymes (AEs), which reduces exercise-associated oxidative stress, but there are several other mechanisms of benefit that this narrative review addresses. These mechanisms include; protecting joints and tendons from physical trauma during exercise; mitigating delayed-onset muscle symptoms (DOMS) and muscle damage; improving muscle and tissue oxygenation during training; cultivating a healthy gut microbiome hence lowering excess inflammation; cutting the incidence of upper respiratory tract viral infections which disrupt training programmes; and helping to restore circadian rhythm which improves sleep recovery and reduces daytime fatigue, which in turn elevates mood and motivation to train.

Summary: Since the early seminal studies on epithelial solute transport, it has been understood that there must be crosstalk among different members of the transport machinery to coordinate their activity and, thus, generate localized electrochemical gradients that force solute flow in the required direction that would otherwise be thermodynamically unfavorable. However, mechanisms underlying intracellular crosstalk remain unclear. We present evidence that crosstalk between apical and basolateral membrane transporters is mediated by intracellular Ca2+ signaling in insect renal epithelia. Ion flux across the basolateral membrane is encoded in the intracellular Ca2+ oscillation frequency and amplitude modulation and that information is used by the apical membrane to adjust ion flux accordingly. Moreover, imposing experimentally generated intracellular Ca2+ oscillation modulation causes cells to predictably adjust their ion transport properties. Our results suggest that intracellular Ca2+ oscillation frequency and amplitude modulation encode information on transmembrane ion flux that is required for crosstalk.

AbstractWe utilize stakeholder, critical mass, and upper-echelon theories to investigate the effect of female representation on boards as corporate social responsibility (CSR) practices and firm performance of A-share listed companies in China. The indicators used were the proportion of female board members, the average age of female board members, the educational background of female directors, TOBIN Q, asset size, and leverage. We used fixed effects estimates and stationarity, stability, cointegration, and Hausman tests to analyze the data. We find that the proportion of female directors, the average age of female directors, and average educational level of female directors have a significant impact on CSR performance and financial performance, while CSR performance has a significant impact on financial performance. Given that emerging societies and their environments are usually the most susceptible to unethical corporate practices, our findings that female directors have a strategic role in enabling firms to manage their social responsibilities ethically and sustainable practices have important policy implications for regulators and stakeholders.

In ultrashort-pulsed laser processing, surface modification is subject to complex laser and scanning parameter studies. In addition, quality assurance systems for monitoring surface modification are still lacking. Automated laser processing routines featuring machine learning (ML) can help overcome these limitations, but they are largely absent in the literature and still lack practical applications. This paper presents a new methodology for machine learning classification of self-organized surface structures based on light microscopic images. For this purpose, three application-relevant types of self-organized surface structures are fabricated using a 300 fs laser system on hot working tool steel and stainless-steel substrates. Optical images of the hot working tool steel substrates were used to learn a classification algorithm based on the open-source tool Teachable Machine from Google. The trained classification algorithm achieved very high accuracy in distinguishing the surface types for the hot working steel substrate learned on, as well as for surface structures on the stainless-steel substrate. In addition, the algorithm also achieved very high accuracy in classifying the images of a specific structure class captured at different optical magnifications. Thus, the methodology proposed represents a simple and robust automated classification of surface structures that can be used as a basis for further development of quality assurance systems, automated process parameter recommendation, and inline laser parameter control.

Introduction Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities.Methods and analysis 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18–70 with a body mass index 35–50 kg/m2 and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months.Ethics and dissemination This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and all subsequent revisions. Local research ethics approval was granted by London-Central Research Ethics Committee, (Reference 19/LO/0509) on 11 October 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) issued the Letter of No Objection on 8 April 2022 (Reference CI/2022/0008/GB). The trial’s development and progress are monitored by an independent trial steering committee and data monitoring and ethics committee. The researchers plan to disseminate results at conferences, in peer- reviewed journals as well as lay media and to patient organisations.Trial registration number ISRCTN16158402.

Abstract Background Excessive daytime sleepiness (EDS), a primary symptom of obstructive sleep apnea (OSA), negatively affects functioning and quality of life (QoL). EDS can persist despite primary airway therapy, and often remains unmanaged, potentially due to inadequate provider-patient communication. Ethnographic research was conducted to assess provider-patient communication about EDS. Methods Participating physicians (primary care n = 5; pulmonologists n = 5; sleep specialists n = 3) identified adult patients (n = 33) diagnosed with OSA who were prescribed positive airway pressure (PAP) therapy ≥6 months prior and previously reported EDS. Visits and post-visit interviews were video-recorded and analyzed using standardized, validated sociolinguistic techniques. Results Despite 55% of patients (18/33) reporting QoL impacts post-visit, this was discussed during 28% (5/18) of visits. Epworth Sleepiness Scale was administered during 27% (9/33) of visits. Many patients (58% [19/33]) attributed EDS to factors other than OSA. Physicians provided EDS education during 24% of visits (8/33). Prior to the visit, 30% (10/33) of patients were prescribed EDS medication, of which 70% (7/10) reported currently experiencing EDS symptoms. Conclusions EDS was minimally discussed and rarely reassessed or treated after PAP therapy initiation in this study. Patients often attributed EDS to factors other than OSA. The findings suggest physicians and patients may benefit from dialogue tools, routine use of screening tools, and patient education.

BackgroundThe mental wellbeing implications of a prostate cancer diagnosis are increasingly being realised. Significant mental health symptoms such as depression and anxiety, along with related constructs such as fear of cancer recurrence, body image and masculine self-esteem issues are prevalent. However, less is understood about potential prognostic factors for these outcomes in prostate cancer patients. Therefore, this study aims to primarily explore potential treatment, patient and oncological factors associated with mental wellbeing outcomes in the initial prostate cancer follow-up period.MethodsMIND-P is a multi-institutional prospective cohort study recruiting newly diagnosed prostate cancer patients for 12-month follow up. It will aim to recruit a final sample of 300 participants undergoing one of four treatment options: active surveillance, radical prostatectomy, radical radiotherapy, or hormone monotherapy. Questionnaire-based data collection consists of multiple validated mental, physical, and social wellbeing outcomes at baseline and 3-monthly intervals until study completion. Primary analysis will include evaluation of treatment undergone against multiple mental wellbeing outcomes. Secondary analysis will additionally explore multiple patient and oncological prognostic factors of potential importance, along with the cumulative incidence of these outcomes, symptom trajectory and their association with subsequent functional and social outcomes.ConclusionThis cohort study aims to add to the existing limited literature evaluating significant prognostic factors for multiple mental wellbeing outcomes in newly diagnosed prostate cancer patients. This may be of potential use for guiding future prognosis research and of clinical use for identifying individuals potentially requiring additional surveillance or support during routine cancer follow up.Study registrationThis study was prospectively registered on ClinicalTrials.gov (NCT04647474).

Species of the genus Kalanchoe have a long history of therapeutic use in ethnomedicine linked to their remarkable healing properties. Several species have chemical and anatomical similarities, often leading to confusion when they are used in folk medicine. This review aims to provide an overview and discussion of the reported traditional uses, botanical aspects, chemical constituents, and pharmacological potential of the Kalanchoe species. Published scientific materials were collected from the PubMed and SciFinder databases without restriction regarding the year of publication through April 2023. Ethnopharmacological knowledge suggests that these species have been used to treat infections, inflammation, injuries, and other disorders. Typically, all parts of the plant are used for medicinal purposes either as crude extract or juice. Botanical evaluation can clarify species differentiation and can enable correct identification and validation of the scientific data. Flavonoids are the most common classes of secondary metabolites identified from Kalanchoe species and can be correlated with some biological studies (antioxidant, anti-inflammatory, and antimicrobial potential). This review summarizes several topics related to the Kalanchoe genus, supporting future studies regarding other unexplored research areas. The need to conduct further studies to confirm the popular uses and biological activities of bioactive compounds is also highlighted.

Abstract Background After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209–040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3–4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. Methods The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. Discussion The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. Trial registration EudraCT Number: 2018–000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .

Neurophysiological studies in humans and nonhuman primates have revealed movement representations in both the contralateral and ipsilateral hemispheres. Inspired by clinical observations, we ask if this bilateral representation differs for the left and right hemispheres. Electrocorticography was recorded in human participants during an instructed-delay reaching task, with movements produced with either the contralateral or ipsilateral arm. Using a cross-validated kinematic encoding model, we found stronger bilateral encoding in the left hemisphere, an effect that was present during preparation and was amplified during execution. Consistent with this asymmetry, we also observed better across-arm generalization in the left hemisphere, indicating similar neural representations for right and left arm movements. Notably, these left hemisphere electrodes were centered over premotor and parietal regions. The more extensive bilateral encoding in the left hemisphere adds a new perspective to the pervasive neuropsychological finding that the left hemisphere plays a dominant role in praxis.

Changing technology, and the pervasive demand created by a greater need in the population for access to mental health interventions, has led to the development of technologies that are shifting the traditional way in which therapy is provided. This study investigated the efficacy of a behavioral couples therapy program conducted via videoconferencing, as compared to face-to-face. There were 60 participants, in couples, ranging in age from 21 to 69 years old. Couples had been in a relationship for between 1 to 49 years. The 30 couples were randomly allocated to the face-to-face or videoconferencing group. They all took part in Couple CARE—a couples behavioral education program which promotes self-change in order to increase relationship satisfaction. The six session manualized intervention was offered in an identical manner to all clients, in each condition. Data analysis was based on several questionnaires completed by each couple at pre, post and 3-months follow-up. Results showed that therapeutic alliance ratings did not differ between groups, but increased significantly over time for both groups. Additionally, the results indicated improvements in relationship satisfaction, mental health, and all other outcome scores over time, which did not differ based on condition. This study uniquely contributes to the literature exploring the use of technology to provide therapy. Specifically, the study provides evidence for couples therapy via videoconferencing as a viable alternative to face-to-face interventions, especially for those couples who may not have access to the treatment they require. It is anticipated that the results of this study will contribute to the field of online therapy, and add to fostering confidence in agencies to allow expansion of services conducted via videoconferencing.

Abstract Objective: Length of hospital stay (LOS) is considered a vital component for successful colorectal surgery treatment. Evidence of an association between hospital surgery volume and LOS has been mixed. Data modelling techniques may give inconsistent results that adversely impact conclusions. This study applied techniques to overcome possible modelling drawbacks. Method: An additive quantile regression model formulated to isolate hospital contextual effects was applied to every colorectal surgery for cancer conducted in Victoria, Australia, between 2005 and 2015, involving 28,343 admissions in 90 Victorian hospitals. The model compared hospitals’ operational efficiencies regarding LOS. Results: Hospital LOS operational efficiencies for colorectal cancer surgery varied markedly between the 90 hospitals and were independent of volume. This result was adjusted for pertinent patient and hospital characteristics. Conclusion: No evidence was found that higher annual surgery volume was associated with lower LOS for patients undergoing colorectal cancer surgery. Our model showed strong evidence that differences in LOS efficiency between hospitals was driven by hospital contextual effects that were not predicted by provider volume. Further study is required to elucidate these inherent differences between hospitals. Implications for public health: Our model indicated improved efficiency would benefit the patient and medical system by lowering LOS and reducing expenditure by more than $3 million per year.

The viscoelastic nature of polymeric formulations utilised in drug products imparts unique thermomechanical attributes during manufacturing and over the shelf life of the product. Nevertheless, it adds to the challenge of understanding the precise mechanistic behaviour of the product at the microscopic and macroscopic level during each step of the process. Current thermomechanical and rheological characterisation techniques are limited to assessing polymer performance to a single phase and are especially hindered when the polymers are undergoing thermomechanical transitions. Since pharmaceutical processing can occur at these transition conditions, this study successfully proposes a thermomechanical characterisation approach combining both mechanical and rheological data to construct a comprehensive profiling of polymeric materials spanning both glassy and rubbery phases. This approach has been used in this study to assess the mechanical and rheological behaviour of heterogenous polymer blends of hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) over a shearing rate range of 0.1–100 s−1 and a temperature range of 30–200 °C. The results indicate that HPC and HPMC do not appear to interact when mixing and that their mixture exhibits the mechanistic properties of the two individual polymers in accordance with their ratio in the mixture. The ability to characterise the behaviour of the polymers and their mixtures before, throughout, and after the glassy to rubbery phase transition by application of the combined techniques provides a unique insight towards a quality-by-design approach to this and other polymer-based solid dosage forms, designed with the potential to accelerate their formulation process through obviating the need for multiple formulation trials.

Biomass is a promising alternative for the reduction of global dependency on fossil fuels. However, there are some issues with the direct application of raw biomass such as high moisture content, low heating value, and poor grindability. To alleviate the problems, biomass-derived biocoal is introduced and utilised as fuel in power plants. Oil palm trunk biocoal (OPTC) is produced from pyrolysis of oil palm trunk biomass (OPTB) in a top-lit, updraft reactor at a constant air flowrate of 4.63 L/min and maximum temperature of 550 °C. OPTC is co-combusted at temperatures between 600 and 900 °C with sub-bituminous coal (SBC). Pollutant emission and ash production from combustion of fuel blends containing 20% and 50% biocoal are analysed and compared with pure SBC, OPTB and OPTC. NOx and SO2 emission profiles from all tested fuel blends are well below the limits imposed under Environmental Quality (Clean Air) Regulation 2014 of 296 and 190 ppm respectively. Response surface methodology (RSM) analysis indicates that the operation of combustion is optimised with 92.16% efficiency at 774 °C and air flowrate of 16.6 SCFH to emit 16.38% CO2, and the findings are validated against experimental results. The optimised combustion process produces ash with 67.9% silicon compounds.

Decellularized porcine corneal scaffolds are a potential alternative to human cornea for keratoplasty. Although clinical trials have reported promising results, there can be corneal haze or scar tissue. Here, we examined if recellularizing the scaffolds with human keratocytes would result in a better outcome. Scaffolds were prepared that retained little DNA (14.89 ± 5.56 ng/mg) and demonstrated a lack of cytotoxicity by in vitro. The scaffolds were recellularized using human corneal stromal cells and cultured for between 14 in serum-supplemented media followed by a further 14 days in either serum free or serum-supplemented media. All groups showed full-depth cell penetration after 14 days. When serum was present, staining for ALDH3A1 remained weak but after serum-free culture, staining was brighter and the keratocytes adopted a native dendritic morphology with an increase (p < 0.05) of keratocan, decorin, lumican and CD34 gene expression. A rabbit anterior lamellar keratoplasty model was used to compare implanting a 250 μm thick decellularized lenticule against one that had been recellularized with human stromal cells after serum-free culture. In both groups, host rabbit epithelium covered the implants, but transparency was not restored after 3 months. Post-mortem histology showed under the epithelium, a less-compact collagen layer, which appeared to be a regenerating zone with some α-SMA staining, indicating fibrotic cells. In the posterior scaffold, ALDH1A1 staining was present in all the acellular scaffold, but in only one of the recellularized lenticules. Since there was little difference between acellular and cell-seeded scaffolds in our in vivo study, future scaffold development should use acellular controls to determine if cells are necessary.

We conducted a systematic review of the literature on the effects of cordycepin on cell survival and proliferation, inflammation, signal transduction and animal models. A total of 1204 publications on cordycepin were found by the cut-off date of 1 February 2021. After application of the exclusion criteria, 791 papers remained. These were read and data on the chosen subjects were extracted. We found 192 papers on the effects of cordycepin on cell survival and proliferation and calculated a median inhibitory concentration (IC50) of 135 µM. Cordycepin consistently repressed cell migration (26 papers) and cellular inflammation (53 papers). Evaluation of 76 papers on signal transduction indicated consistently reduced PI3K/mTOR/AKT and ERK signalling and activation of AMPK. In contrast, the effects of cordycepin on the p38 and Jun kinases were variable, as were the effects on cell cycle arrest (53 papers), suggesting these are cell-specific responses. The examination of 150 animal studies indicated that purified cordycepin has many potential therapeutic effects, including the reduction of tumour growth (37 papers), repression of pain and inflammation (9 papers), protecting brain function (11 papers), improvement of respiratory and cardiac conditions (8 and 19 papers) and amelioration of metabolic disorders (8 papers). Nearly all these data are consistent with cordycepin mediating its therapeutic effects through activating AMPK, inhibiting PI3K/mTOR/AKT and repressing the inflammatory response. We conclude that cordycepin has excellent potential as a lead for drug development, especially for age-related diseases. In addition, we discuss the remaining issues around the mechanism of action, toxicity and biodistribution of cordycepin.

Fuzzy set theory has shown potential for reducing uncertainty as a result of data sparsity and also provides advantages for quantifying gradational changes like those of pollutant concentrations through fuzzy clustering based approaches. The ability to lower the sampling frequency and perform laboratory analyses on fewer samples, yet still produce an adequate pollutant distribution map, would reduce the initial cost of new remediation projects. To assess the ability of fuzzy modeling to make spatial predictions using fewer sample points, its predictive ability was compared with the ordinary kriging (OK) and inverse distance weighting (IDW) methods under increasingly sparse data conditions. This research used a Takagi–Sugeno (TS) fuzzy modelling approach with fuzzy c-means (FCM) clustering to make spatial predictions of the lead concentrations in soil. The performance of the TS model was very dependent on the number of outliers in the respective validation set. For modeling under sparse data conditions, the TS fuzzy modeling approach using FCM clustering and constant width Gaussian shaped membership functions did not show any advantages over IDW and OK for the type of data tested. Therefore, it was not possible to speculate on a possible reduction in sampling frequency for delineating the extent of contamination for new remediation projects.

Abstract In the unconscious patient, there is a diagnostic void between the neurologic physical exam, and more invasive, costly and potentially harmful investigations. Transcranial color-coded sonography and two-dimensional transcranial Doppler imaging of the brain have the potential to be a middle ground to bridge this gap for certain diagnoses. With the increasing availability of point-of-care ultrasound devices, coupled with the need for rapid diagnosis of deteriorating neurologic patients, intensivists may be trained to perform point-of-care transcranial Doppler at the bedside. The feasibility and value of this technique in the intensive care unit to help rule-in specific intra-cranial pathologies will form the focus of this article. The proposed scope for point-of-care transcranial Doppler for the intensivist will be put forth and illustrated using four representative cases: presence of midline shift, vasospasm, raised intra-cranial pressure, and progression of cerebral circulatory arrest. We will review the technical details, including methods of image acquisition and interpretation. Common pitfalls and limitations of point-of-care transcranial Doppler will also be reviewed, as they must be understood for accurate diagnoses during interpretation, as well as the drawbacks and inadequacies of the modality in general.

When the fungus Candida albicans proliferates in the oropharyngeal cavity during experimental oropharyngeal candidiasis (OPC), it undergoes large-scale genome changes at a much higher frequency than when it grows in vitro. Previously, we identified a specific whole chromosome amplification, trisomy of Chr6 (Chr6x3), that was highly overrepresented among strains recovered from the tongues of mice with OPC. To determine the functional significance of this trisomy, we assessed the virulence of two Chr6 trisomic strains and a Chr5 trisomic strain in the mouse model of OPC. We also analyzed the expression of virulence-associated traits in vitro. All three trisomic strains exhibited characteristics of a commensal during OPC in mice. They achieved the same oral fungal burden as the diploid progenitor strain but caused significantly less weight loss and elicited a significantly lower inflammatory host response. In vitro, all three trisomic strains had reduced capacity to adhere to and invade oral epithelial cells and increased susceptibility to neutrophil killing. Whole genome sequencing of pre- and post-infection isolates found that the trisomies were usually maintained. Most post-infection isolates also contained de novo point mutations, but these were not conserved. While in vitro growth assays did not reveal phenotypes specific to de novo point mutations, they did reveal novel phenotypes specific to each lineage. These data reveal that during OPC, clones that are trisomic for Chr5 or Chr6 are selected and they facilitate a commensal-like phenotype.

PURPOSE: The objective of this study was to develop a self-microemulsifying drug delivery system (SMEDDS) formulation for the oral delivery of CRV431, a non-immunosuppressive analogue of cyclosporine A. Relative to cyclosporine A, CRV431 is poorly soluble in lipid solvents and thusly presents a challenge for the development of a formulation of sufficient oral bioavailability for clinical use. METHODS: The solubility of CRV431, a cyclosporine derivative, was determined in a range of commonly used surfactants, oils and co-solvents. A pseudo-ternary phase diagram was constructed from the most soluble excipients and prototype formulations, SERIES 1 and SERIES 2 were developed. The pharmacokinetics, following single oral doses of 1 and 3 mg/kg of CRV431 SMEDDS, was studied in healthy human volunteers using liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). RESULTS: The maximum drug load for the SERIES 1 formulations was less than 40 mg/ml. Manipulation of the excipient ratios allowed for the development of SERIES 2 formulations, which had higher drug loading capacity and stability for CRV431 compared to SERIES 1. Further improvements allowed for the development of an optimized SMEDDS formulation containing up to 90 mg/ml CRV431 and which generated a microemulsion mean particle size of 25 nm when dispersed into aqueous media. The pharmacokinetics of the optimized CRV431 SMEDDS displayed excellent total body exposure and dose-proportional effects in humans, and high drug levels in the liver of rats. CONCLUSIONS: The developed SMEDDS formulation should allow for effective clinical development of CRV431, targeted to the treatment of liver diseases including hepatitis B (HBV), fibrosis, and hepatocellular carcinoma.