Programmed Death-1 Ligand 2-Mediated Regulation of the PD-L1 to PD-1 Axis Is Essential for Establishing CD4(+) T Cell Immunity.

Many pathogens, including Plasmodium spp., exploit the interaction of programmed death-1 (PD-1) with PD-1-ligand-1 (PD-L1) to "deactivate" T cell functions, but the role of PD-L2 remains unclear. We studied malarial infections to understand the contribution of PD-L2 to immunity. Here we have shown that higher PD-L2 expression on blood dendritic cells, from Plasmodium falciparum-infected individuals, correlated with lower parasitemia. Mechanistic studies in mice showed that PD-L2 was indispensable for establishing effective CD4(+) T cell immunity against malaria, because it not only inhibited PD-L1 to PD-1 activity but also increased CD3 and inducible co-stimulator (ICOS) expression on T cells. Importantly, administration of soluble multimeric PD-L2 to mice with lethal malaria was sufficient to dramatically improve immunity and survival. These studies show immuno-regulation by PD-L2, which has the potential to be translated into an effective treatment for malaria and other diseases where T cell immunity is ineffective or short-lived due to PD-1-mediated signaling.

Comparative Analysis of Chemical Descriptors by Machine Learning Reveals Atomistic Insights into Solute-Lipid Interactions.

This study explores the research area of drug solubility in lipid excipients, an area persistently complex despite recent advancements in understanding and predicting solubility based on molecular structure. To this end, this research investigated novel descriptor sets, employing machine learning techniques to understand the determinants governing interactions between solutes and medium-chain triglycerides (MCTs). Quantitative structure-property relationships (QSPR) were constructed on an extended solubility data set comprising 182 experimental values of structurally diverse drug molecules, including both development and marketed drugs to extract meaningful property relationships. Four classes of molecular descriptors, ranging from traditional representations to complex geometrical descriptions, were assessed and compared in terms of their predictive accuracy and interpretability. These include two-dimensional (2D) and three-dimensional (3D) descriptors, Abraham solvation parameters, extended connectivity fingerprints (ECFPs), and the smooth overlap of atomic position (SOAP) descriptor. Through testing three distinct regularized regression algorithms alongside various preprocessing schemes, the SOAP descriptor enabled the construction of a superior performing model in terms of interpretability and accuracy. Its atom-centered characteristics allowed contributions to be estimated at the atomic level, thereby enabling the ranking of prevalent molecular motifs and their influence on drug solubility in MCTs. The performance on a separate test set demonstrated high predictive accuracy (RMSE = 0.50) for 2D and 3D, SOAP, and Abraham Solvation descriptors. The model trained on ECFP4 descriptors resulted in inferior predictive accuracy. Lastly, uncertainty estimations for each model were introduced to assess their applicability domains and provide information on where the models may extrapolate in chemical space and, thus, where more data may be necessary to refine a data-driven approach to predict solubility in MCTs. Overall, the presented approaches further enable computationally informed formulation development by introducing a novel in silico approach for rational drug development and prediction of dose loading in lipids.

Testing meshes in a computer model of a laparoscopic ventral hernia repair.

BACKGROUND: The ideal mesh for hernia repair has yet to be found, in addition our knowledge of the biomechanics of the abdominal wall is poor. The aim of this study was to develop a computer model of a laparoscopic ventral hernia repair and to test different meshes in that model at various intra-abdominal pressures. METHODS: Four meshes were tested in a computer model of a ventral hernia. Mechanical failure testing of each mesh was performed in both the longitudinal and transverse directions. A CT scan of a patient with a 5 cm umbilical hernia was used to generate a 3 dimensional model. Meshes were then applied to the model in an intraperitoneal onlay position with a 5 cm overlap. The model was then tested with intraabdominal pressures for standing, coughing and jumping with and without meshes. RESULTS: Meshes varied significantly (p < 0.001) in both rupture force 14.8 (5.6) to 78 (5) n/cm and force in which they changed from elastic to plastic 1.6 (0.1) to 14.2 (0.2) n/cm. When applied to the computer model all significantly reduced the strain on the abdominal wall from 17.5% without mesh to less than 1% with mesh. All meshes prevented the hernia from bulging in the model. CONCLUSIONS: We have developed a computer model of laparoscopic ventral hernia repair based on engineering principles. This model demonstrated that meshes tested significantly reduced the strain on the abdominal wall. Further studies are required to refine this model in order to best simulate the biomechanics of the abdominal wall.

Novel Biphasic Lipolysis Method To Predict in Vivo Performance of Lipid-Based Formulations.

The absence of an intestinal absorption sink is a significant weakness of standard in vitro lipolysis methods, potentially leading to poor prediction of in vivo performance and an overestimation of drug precipitation. In addition, the majority of the described lipolysis methods only attempt to simulate intestinal conditions, thus overlooking any supersaturation or precipitation of ionizable drugs as they transition from the acidic gastric environment to the more neutral conditions of the intestine. The aim of this study was to develop a novel lipolysis method incorporating a two-stage gastric-to-intestinal transition and an absorptive compartment to reliably predict in vivo performance of lipid-based formulations (LBFs). Drug absorption was mimicked by in situ quantification of drug partitioning into a decanol layer. The method was used to characterize LBFs from four studies described in the literature, involving three model drugs (i.e., nilotinib, fenofibrate, and danazol) where in vivo bioavailability data have previously been reported. The results from the novel biphasic lipolysis method were compared to those of the standard pH-stat method in terms of reliability for predicting the in vivo performance. For three of the studies, the novel biphasic lipolysis method more reliably predicted the in vivo bioavailability compared to the standard pH-stat method. In contrast, the standard pH-stat method was found to produce more predictive results for one study involving a series of LBFs composed of the soybean oil, glyceryl monolinoleate (Maisine CC), Kolliphor EL, and ethanol. This result was surprising and could reflect that increasing concentrations of ethanol (as a cosolvent) in the formulations may have resulted in greater partitioning of the drug into the decanol absorptive compartment. In addition to the improved predictivity for most of the investigated systems, this biphasic lipolysis method also uses in situ analysis and avoids time- and resource-intensive sample analysis steps, thereby facilitating a higher throughput capacity and biorelevant approach for characterization of LBFs.

Relationship between ventral hernia defect area and intra-abdominal pressure: dynamic in vivo measurement.

BACKGROUND: It is an acceptable concept that the ventral hernia defect area will increase with a rise in intra-abdominal pressure (IAP). The literature lacks the evidence about how much this increase is in vivo. The aim of this study was to objectively measure the change in the ventral hernia defect area with increasing intra-abdominal pressure. METHODS: In a prospective study of laparoscopic ventral hernia repair, the area of hernia defect was measured from inside the abdomen using a sterile paper ruler. The horizontal (width) and vertical (length) measurements of the defect were taken at two pressure points: (IAP = 8 mmHg) and (IAP = 15 mmHg). The hernia defect area was calculated as an oval shape using a standard formula. RESULTS: Eighteen consecutive patients with a ventral hernia were included in this study (8 males: 10 females). Median age was 60 years (30-81), body mass index (BMI) was 29.9 (22.6-37.6). Changing the IAP significantly, (P < 0.001) changed the values of horizontal and vertical measurements, and the calculated area of the ventral hernia defect. The median calculated defect area, as an oval shape, was 5.6 cm(2) (Q1-Q3 = 3.5-15.5) and 6.9 cm(2) (Q1-Q3 = 4.5-18.7) at 8 and 15 mmHg IAP, respectively. The calculated area of mesh required to cover the defect with a 5 cm overlap increased by a median of 5% (Q1-Q3 = 3-6%). The change in defect area did not differ significantly between obese and non-obese patients (P = 0.5). CONCLUSIONS: Dynamic, rather than static, measurements of ventral hernia area during laparoscopy provide a simple way of in vivo objective measurement that helps the surgeon choose the appropriate area of mesh. When choosing mesh area, we support the trend toward a larger overlap of at least 5 cm if less precise methods of measuring defect area are been used.

All-atom CHARMM force field and bulk properties of perfluorozinc phthalocyanines.

Classical force fields within the CHARMM parametrized model are developed for zinc phthalocyanines including the parent per-hydro molecule and per-fluoro-alkyl substituted derivatives. Partial atomic charges, 2-body bond lengths, and 3-body angle parameters were obtained from B3LYP-level density functional calculations. Force constants for 2-, 3-, and 4-body interactions were derived from existing fluoroalkane models and incorporated assuming transferability. The force fields were validated by comparing equilibrium molecular geometries from molecular dynamics simulations with density functional theory (DFT) calculations and, where available, published experimental XRD refinements. The models produce molecular geometries for the target materials within 1-2% of expected values. Intermolecular interaction geometries were also investigated using molecular dynamics simulations. The results provide new insight and predictions of the equilibrium stacking and orientational intermolecular interactions of this novel class of modified phthalocyanines.

Mal-positioned nasogastric feeding tubes: are medical students safe to identify them?

OBJECTIVES: Nasogastric tube (NGT) placement is listed against Clinical Imaging in the upcoming Medical Licensing Assessment-compulsory for every graduating UK medical student from 2025. This study aims to establish the ability of medical students to correctly identify the position of an NGT on Chest X-ray (CXR) and to evaluate a learning tool to improve student outcome in this area. METHODS: Fourth-year (MB4) and fifth-year (MB5) medical students were invited to view 20 CXRs with 14 correctly sited and 6 mal-positioned NGT. MB5 students (Intervention) were exposed to an online interactive learning tool, with MB4 students kept as control. One week later, both groups of students were invited to view 20 more CXRs for NGT placement. RESULTS: Only 12 (4.8%) of 249 MB5 students and 5 (3.1%) of 161 MB4 students correctly identified all the NGTs on CXRs. The number of students misidentifying 1 or more mal-positioned NGT as "safe to feed" was 129 (51.8%) for MB5 and 76 (47.2%) for MB4 students. This improved significantly (P < .001) following exposure to the learning tool with 58% scoring all CXRs correctly, while 28% scored 1 or more mal-positioned NGT incorrectly. Students struggled to determine if the NGT tip had adequately passed into the stomach. However, they failed to identify an NG tube in the lung ("never event") in just one out of 1,108 opportunities. CONCLUSION: Medical students' ability to determine if the NGT was in the stomach remains suboptimal despite exposure to over 60 CXRs. Feeding NGT should be formally reported before use. ADVANCES IN KNOWLEDGE: This is the first attempt at quantifying graduating medical students', and by inference junior doctors', competence in safely identifying misplaced nasogastric feeding tubes. An online, experiential learning resource significantly improved their ability.

Predictive computational models for assessing the impact of co-milling on drug dissolution.

Co-milling is an effective technique for improving dissolution rate limited absorption characteristics of poorly water-soluble drugs. However, there is a scarcity of models available to forecast the magnitude of dissolution rate improvement caused by co-milling. Therefore, this study endeavoured to quantitatively predict the increase in dissolution by co-milling based on drug properties. Using a biorelevant dissolution setup, a series of 29 structurally diverse and crystalline drugs were screened in co-milled and physically blended mixtures with Polyvinylpyrrolidone K25. Co-Milling Dissolution Ratios after 15 min (COMDR15 min) and 60 min (COMDR60 min) drug release were predicted by variable selection in the framework of a partial least squares (PLS) regression. The model forecasts the COMDR15 min (R2 = 0.82 and Q2 = 0.77) and COMDR60 min (R2 = 0.87 and Q2 = 0.84) with small differences in root mean square errors of training and test sets by selecting four drug properties. Based on three of these selected variables, applicable multiple linear regression equations were developed with a high predictive power of R2 = 0.83 (COMDR15 min) and R2 = 0.84 (COMDR60 min). The most influential predictor variable was the median drug particle size before milling, followed by the calculated drug logD6.5 value, the calculated molecular descriptor Kappa 3 and the apparent solubility of drugs after 24 h dissolution. The study demonstrates the feasibility of forecasting the dissolution rate improvements of poorly water-solube drugs through co-milling. These models can be applied as computational tools to guide formulation in early stage development.

Predictions of biorelevant solubility change during dispersion and digestion of lipid-based formulations.

Computational approaches are increasingly explored in development of drug products, including the development of lipid-based formulations (LBFs), to assess their feasibility for achieving adequate oral absorption at an early stage. This study investigated the use of computational pharmaceutics approaches to predict solubility changes of poorly soluble drugs during dispersion and digestion in biorelevant media. Concentrations of 30 poorly water-soluble drugs were determined pre- and post-digestion with in-line UV probes using the MicroDISS Profiler™. Generally, cationic drugs displayed higher drug concentrations post-digestion, whereas for non-ionized drugs there was no discernible trend between drug concentration in dispersed and digested phase. In the case of anionic drugs there tended to be a decrease or no change in the drug concentration post-digestion. Partial least squares modelling was used to identify the molecular descriptors and drug properties which predict changes in solubility ratio in long-chain LBF pre-digestion (R2 of calibration = 0.80, Q2 of validation = 0.64) and post-digestion (R2 of calibration = 0.76, Q2 of validation = 0.72). Furthermore, multiple linear regression equations were developed to facilitate prediction of the solubility ratio pre- and post-digestion. Applying three molecular descriptors (melting point, LogD, and number of aromatic rings) these equations showed good predictivity (pre-digestion R2 = 0.70, and post-digestion R2 = 0.68). The model developed will support a computationally guided LBF strategy for emerging poorly water-soluble drugs by predicting biorelevant solubility changes during dispersion and digestion. This facilitates a more data-informed developability decision making and subsequently facilitates a more efficient use of formulation screening resources.

Developing an in vitro lipolysis model for real-time analysis of drug concentrations during digestion of lipid-based formulations.

Understanding the effect of digestion on oral lipid-based drug formulations is a critical step in assessing the impact of the digestive process in the intestine on intraluminal drug concentrations. The classical pH-stat in vitro lipolysis technique has traditionally been applied, however, there is a need to explore the establishment of higher throughput small-scale methods. This study explores the use of alternative lipases with the aim of selecting digestion conditions that permit in-line UV detection for the determination of real-time drug concentrations. A range of immobilised and pre-dissolved lipases were assessed for digestion of lipid-based formulations and compared to digestion with the classical source of lipase, porcine pancreatin. Palatase® 20000 L, a purified liquid lipase, displayed comparable digestion kinetics to porcine pancreatin and drug concentration determined during digestion of a fenofibrate lipid-based formulation were similar between methods. In-line UV analysis using the MicroDISS ProfilerTM demonstrated that drug concentration could be monitored during one hour of dispersion and three hours of digestion for both a medium- and long-chain lipid-based formulations with corresponding results to that obtained from the classical lipolysis method. This method offers opportunities exploring the real-time dynamic drug concentration during dispersion and digestion of lipid-based formulations in a small-scale setup avoiding artifacts as a result of extensive sample preparation.

Laparoscopic resection of paraaortic or paracaval lesions: feasibility and outcome.

BACKGROUND: Laparoscopic retroperitoneal lymph node dissection of paraaortic and paracaval lymph nodes is used to stage nonseminomatous germ cell tumors. Primary tumors can arise from the retroperitoneum, and tumors from nonurologic malignancy also may metastasize to retroperitoneal lymph nodes. This study aimed to describe the authors' experience with laparoscopic resection of these lesions. METHODS: A consecutive series of patients between January 2007 and June 2011 with paraaortic, aortocaval, or paracaval tumors with a maximum diameter smaller than 10 cm and confined to the abdomen were considered for laparoscopic resection. Data were collected on size and pathology of the lesions, anesthesia time, postoperative stay, and postoperative morbidity and mortality. RESULTS: In this study, 25 patients with a median age of 49 years were assessed for laparoscopic resection. Eight patients were considered unsuitable for a laparoscopic approach because of tumor location (n = 5), previous retroperitoneal surgery (n = 1), stoma (n = 1), or lesion not clearly visible on computed tomography (n = 1). Of the 17 patients undergoing laparoscopic resection, 1 was found to have diffuse peritoneal disease at laparoscopy, whereas another was converted to an open procedure due to bleeding. All the laparoscopic patients had an R0 resection. The median hospital stay was significantly shorter in the laparoscopic group (2 days) than in the open group (6 days) (P = 0.009). One patient in the laparoscopic group with a functioning paraganglioma and advanced cardiac disease died on postoperative day 7. CONCLUSION: Laparoscopic paraaortic and paracaval surgery for primary and recurrent tumors of the retroperitoneum is feasible, with clear resection margin rates similar to that observed for open surgery.

Advancing algorithmic drug product development: Recommendations for machine learning approaches in drug formulation.

Artificial intelligence is a rapidly expanding area of research, with the disruptive potential to transform traditional approaches in the pharmaceutical industry, from drug discovery and development to clinical practice. Machine learning, a subfield of artificial intelligence, has fundamentally transformed in silico modelling and has the capacity to streamline clinical translation. This paper reviews data-driven modelling methodologies with a focus on drug formulation development. Despite recent advances, there is limited modelling guidance specific to drug product development and a trend towards suboptimal modelling practices, resulting in models that may not give reliable predictions in practice. There is an overwhelming focus on benchtop experimental outcomes obtained for a specific modelling aim, leaving the capabilities of data scraping or the use of combined modelling approaches yet to be fully explored. Moreover, the preference for high accuracy can lead to a reliance on black box methods over interpretable models. This further limits the widespread adoption of machine learning as black boxes yield models that cannot be easily understood for the purposes of enhancing product performance. In this review, recommendations for conducting machine learning research for drug product development to ensure trustworthiness, transparency, and reliability of the models produced are presented. Finally, possible future directions on how research in this area might develop are discussed to aim for models that provide useful and robust guidance to formulators.

Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary.

Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain. The InPharma network aims to advance a mechanistic, animal-free approach to the assessment of drug developability. This commentary focuses current status and next steps that will be taken in InPharma to identify and fully utilize 'best practice' in vitro and in silico tools for use in physiologically based biopharmaceutic models.

Long-term follow-up of patients undergoing laparoscopic surgery for phaeochromocytoma.

INTRODUCTION: Phaeochromocytomas are rare tumours with a recurrence after open surgery ranging between 6-23 per cent. Long-term follow-up studies after laparoscopic surgery for phaeochromocytoma are lacking. The aim of this study was to look at the long-term oncological outcome of a consecutive series of patients from a single centre undergoing laparoscopic surgery for a phaeochromocytoma. METHODS: Demographic data on all patients with an adrenal tumour or paraganglioma were prospectively kept on a database between September 1999 and December 2017. Electronic hospital records, including imaging from a national linked archiving and communication system, were reviewed for patients with a phaeochromocytoma in November 2021. RESULTS: During the study interval 135 patients with a phaeochromocytoma were operated on in the unit, of which 118 (87.4 per cent) were attempted laparoscopically. Five (4.2 per cent) were converted to open surgery, whereas 117 had a potentially curative operation. There was no peri- or postoperative mortality. At a median follow-up of 10 (interquartile range 6-12.9) years, only 3 (2.6 per cent) patients died from metastatic phaeochromocytoma. One further patient developed lymph node metastases, which were removed at open surgery. No patient had a local recurrence and the only significant predictor of recurrence was the presence of lymph node metastases (P < 0.001). Two patients developed a contralateral adrenal phaeochromocytoma, while one of these also had a paraganglioma. The Kaplan-Meier estimate of phaeochromocytoma-free survival was 96 per cent (95 per cent c.i. 92.2 to 98.8) at 5 years and 92 per cent (95 per cent c.i. 86.7 to 97.3) at 10 years. CONCLUSION: This study demonstrates that long-term oncological outcomes of laparoscopic surgery for patients with a phaeochromocytoma are at least as good as that with an open operation.

On the usefulness of four in vitro methods in assessing the intraluminal performance of poorly soluble, ionisable compounds in the fasted state.

A small-scale two-stage biphasic system, a small-scale two-stage dissolution-permeation system, the Erweka mini-paddle apparatus, and the BioGIT system were evaluated for their usefulness in assessing the intraluminal performance of two low solubility drugs in the fasted state, one with weakly acidic properties (tested in a salt form, diclofenac potassium) and one with weakly alkaline properties [ritonavir, tested as an amorphous solid dispersion (ASD) formulation]. In all in vitro methods, an immediate-release tablet and a powder formulation of diclofenac potassium were both rapidly dissolved in Level II biorelevant media simulating the conditions in the upper small intestine. Physiologically based biopharmaceutics (PBB) modelling for the tablet formulation resulted in a successful simulation of the average plasma profile in adults, whereas for the powder formulation modelling indicated that gastric emptying and transport through the intestinal epithelium limit the absorption rates. Detailed information on the behaviour of the ritonavir ASD formulation under both simulated gastric and upper small intestinal conditions were crucial for understanding the luminal performance. PBB modelling showed that the dissolution and precipitation parameters, estimated from the Erweka mini-paddle apparatus data and the small-scale two-stage biphasic system data, respectively, were necessary to adequately simulate the average plasma profile after administration of the ritonavir ASD formulation. Simulation of the gastrointestinal transfer process from the stomach to the small intestine was necessary to evaluate the effects of hypochlorhydric conditions on the luminal performance of the ritonavir ASD formulation. Based on this study, the selection of the appropriate in vitro method for evaluating the intraluminal performance of ionisable lipophilic drugs depends on the characteristics of the drug substance. The results suggest that for (salts of) acidic drugs (e.g., diclofenac potassium) it is only an issue of availability and ease of operation of the apparatus. For weakly alkaline substances (e.g., ritonavir), the results indicate that the dynamic dissolution process needs to be simulated, with the type of requested information (e.g., dissolution parameters, precipitation parameters, luminal concentrations) being key for selecting the most appropriate method. Regardless of the ionisation characteristics, early in the drug development process the use of small-scale systems may be inevitable, due to the limited quantities of drug substance available.

Radiology and the medical student: do increased hours of teaching translate to more radiologists?

Objectives: The UK has a shortage of Radiologists to meet the increasing demand for radiologic examinations. To encourage more medical students to consider Radiology as a career, increased exposure at undergraduate level has been advocated. The aim of this study was to evaluate if formal Radiology teaching hours at medical school had any association with the number of qualified Radiologists joining the General Medical Council Specialist Register. Methods: Total number of doctors joining the GMC Specialist Register as Clinical Radiologists, and those with a primary medical qualifications awarded in Scotland, was obtained from the GMC (2010-2020). Graduate numbers from all four Scottish Medical Schools (2000-2011) were also obtained. Hours of Radiology teaching for medical schools in Scotland were obtained from validated AToMS study. Results: Two hundred and twenty three (6.6%) of 3347 Radiologists added to the GMC Specialist Register between 2010 and 2020 received their primary medical qualification (PMQ) from Scottish Universities. The number of Radiologists from Scottish Universities joining the GMC specialist register was 2.6% of the total number of Scottish Medical Graduates. There was no association between the number of hours (Range 1-30) Radiology was taught to medical students and the number that joined the specialist register as Radiologists (p = 0.54 chi square trend). Conclusion: Increased exposure to Radiology teaching does not influence medical students' decision to take up Radiology as a career. While continued Radiology exposure remains important, other strategies are required in both the short and long term to ensure radiology services are maintained without detriment to patients. Advances in knowledge: Increased hours of Radiology teaching in medical school was not associated with increased radiologists joining the profession.

Radiology for medical students: Do we teach enough? A national study.

OBJECTIVE: A recent study has shown that the averaged time tabled teaching for a medical student across 5 years in the UK was 4629 hours. Radiology has been demonstrated to be an excellent teaching source, yet the number of hours allocated to this has never been calculated.The aims of this study were to evaluate and quantify the hours allocated to radiology teaching in Scottish Medical Schools and to evaluate if they can fulfil requirements expected from other Clinical disciplines and the upcoming General Medical Council Medical Licensing Assessment (GMC MLA). METHODS: Data pertaining to timetabled teaching for Radiology in Scottish Universities were obtained from the authors of the Analysis of Teaching of Medical Schools (AToMS) survey. In addition, University Lead Clinician Teachers were surveyed on the radiological investigations and skills medical students should have at graduation. RESULTS: Medical students in Scottish Universities were allocated 59 h in Radiology (0.3%) out of a total 19,325 h of timetabled teaching. Hospital-based teaching was variable and ranged from 0 to 31 h. Almost half (15 of 31) of Clinician Teachers felt that there was insufficient radiology teaching in their specialty. Thirteen of 30 conditions included in the GMC MLA were listed by Clinician Teachers, while 23 others not listed by the GMC were considered important and cited by them. CONCLUSION: This study demonstrates that medical students do not receive enough radiology teaching. This needs to be addressed by Universities in collaboration with the NHS in an effort to bring up this up to line with other developed countries and prepare students for the GMC MLA. ADVANCES IN KNOWLEDGE: (1) There is insufficient time allocated in Medical Students' curriculum to Radiology.(2) Radiology teaching in medical schools fall short of University Lead Clinician Teachers' and GMC expectations of medical students at graduation.

Applying Computational Predictions of Biorelevant Solubility Ratio Upon Self-Emulsifying Lipid-Based Formulations Dispersion to Predict Dose Number.

Computational approaches are increasingly utilised in development of bio-enabling formulations, including self-emulsifying drug delivery systems (SEDDS), facilitating early indicators of success. This study investigated if in silico predictions of drug solubility gain i.e. solubility ratios (SR), after dispersion of a SEDDS in biorelevant media could be predicted from drug properties. Apparent solubility upon dispersion of two SEDDS in FaSSIF was measured for 30 structurally diverse poorly water soluble drugs. Increased drug solubility upon SEDDS dispersion was observed in all cases, with higher SRs observed for cationic and neutral versus anionic drugs at pH 6.5. Molecular descriptors and solid-state properties were used as inputs during partial least squares (PLS) modelling resulting in predictive models for SRMC (r2 = 0.81) and SRLC (r2 = 0.77). Multiple linear regression (MLR) facilitated generation of simplified SR equations with high predictivity (SRMC r2 = 0.74; SRLC r2 = 0.69), requiring only three drug properties; partition coefficient at pH 6.5 (logD6.5), melting point (Tm) and aromatic bonds as fraction of total bonds (F-AromB). Through using the equations to inform developability classification system (DCS) classes for drugs that have already been licensed as lipid-based formulations, merits for development with SEDDS was predicted for 2/3 drugs.

Oral biopharmaceutics tools: recent progress from partnership through the Pharmaceutical Education and Research with Regulatory Links collaboration.

OBJECTIVES: To summarise key contributions of the Pharmaceutical Education and Research with Regulatory Links (PEARRL) project (2016-2020) to the optimisation of existing and the development of new biopharmaceutics tools for evaluating the in vivo performance of oral drug products during the development of new drugs and at the regulatory level. KEY FINDINGS: Optimised biopharmaceutics tools: Based on new clinical data, the composition of biorelevant media for simulating the fed state conditions in the stomach was simplified. Strategies on how to incorporate biorelevant in vitro data of bio-enabling drug products into physiologically based pharmacokinetic (PBPK) modelling were proposed. Novel in vitro biopharmaceutics tools: Small-scale two-stage biphasic dissolution and dissolution-permeation setups were developed to facilitate understanding of the supersaturation effects and precipitation risks of orally administered drugs. A porcine fasted state simulated intestinal fluid was developed to improve predictions and interpretation of preclinical results using in vitro dissolution studies. Based on new clinical data, recommendations on the design of in vitro methodologies for evaluating the GI drug transfer process in the fed state were suggested. The optimized design of in vivo studies for investigating food effects: A food effect study protocol in the pig model was established which successfully predicted the food-dependent bioavailability of two model compounds. The effect of simulated infant fed state conditions in healthy adults on the oral absorption of model drugs was evaluated versus the fasted state and the fed state conditions, as defined by regulatory agencies for adults. Using PBPK modelling, the extrapolated fasted and infant fed conditions data appeared to be more useful to describe early drug exposure in infants, while extrapolation of data collected under fed state conditions, as defined by regulators for adults, failed to capture in vivo infant drug absorption. SUMMARY: Substantial progress has been made in developing an advanced suite of biopharmaceutics tools for streamlining drug formulation screening and supporting regulatory applications. These advances in biopharmaceutics were achieved through networking opportunities and research collaborations provided under the H2020 funded PEARRL project.

Radiology for medical students (1925-2018): an overview.

OBJECTIVE: Radiology has been espoused as an excellent tool for educating medical students since 1925. Advances in technology and PACS mean it has never been easier to demonstrate living anatomy and clinical pathology in exquisite detail to students. The aim of this study was to provide an overview of radiologic publications related to teaching medical students and its evolution through time. METHODS: A literature search was performed from inception to November 2018. The search strategies used both text words and relevant indexing related to "radiology", "medical students" and "curriculum". RESULTS: 3589 records were identified of which 377 were included. There was a 100 fold increase in rate of publication over time-most were expository or surveys (60%), with few truly experimental articles. Radiology was used in clinical teaching (67%) and anatomy (33%). Almost half of radiologic anatomy teaching was conducted without the input of a Radiologist. Compulsory clinical clerkships/blocks in radiology was offered infrequently (35%). Female first authorship had increased in the last decade (47%). CONCLUSION: There is a significant increase in articles published on the role of radiology in medical student teaching in the last decade. Research in this area is required in order to investigate the role of radiology in improving the modern medical students' education.