Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS: Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS: Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION: Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

A Homochiral Porous Organic Cage-Polymer Membrane for Enantioselective Resolution.

Membrane-based enantioselective separation is a promising method for chiral resolution due to its low cost and high efficiency. However, scalable fabrication of chiral separation membranes displaying both high enantioselectivity and high flux of enantiomers is still a challenge. Here, the authors report the preparation of homochiral porous organic cage (Covalent cage 3 (CC3)-R)-based enantioselective thin-film-composite membranes using polyamide (PA) as the matrix, where fully organic and solvent-processable cage crystals have good compatibility with the polymer scaffold. The hierarchical CC3-R channels consist of chiral selective windows and inner cavities, leading to favorable chiral resolution and permeation of enantiomers; the CC3-R/PA composite membranes display an enantiomeric excess of 95.2% for R-(+)-limonene over S-(-)-limonene and a high flux of 99.9 mg h-1 m-2. This work sheds light on the use of homochiral porous organic cages for preparing enantioselective membranes and demonstrates a new route for the development of next-generation chiral separation membranes.

Accurate prediction of solvent flux in sub-1-nm slit-pore nanosheet membranes.

Nanosheet-based membranes have shown enormous potential for energy-efficient molecular transport and separation applications, but designing these membranes for specific separations remains a great challenge due to the lack of good understanding of fluid transport mechanisms in complex nanochannels. We synthesized reduced MXene/graphene hetero-channel membranes with sub-1-nm pores for experimental measurements and theoretical modeling of their structures and fluid transport rates. Our experiments showed that upon complete rejection of salt and organic dyes, these membranes with subnanometer channels exhibit remarkably high solvent fluxes, and their solvent transport behavior is very different from their homo-structured counterparts. We proposed a subcontinuum flow model that enables accurate prediction of solvent flux in sub-1-nm slit-pore membranes by building a direct relationship between the solvent molecule-channel wall interaction and flux from the confined physical properties of a liquid and the structural parameters of the membranes. This work provides a basis for the rational design of nanosheet-based membranes for advanced separation and emerging nanofluidics.

Osimertinib vs. afatinib as first-line treatment for patients with metastatic non-small cell lung cancer with an EGFR exon 19 deletion or exon 21 L858R mutation.

Background: The optimal treatment sequencing for patients with metastatic epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) remains a subject of debate. In the United States, osimertinib is the preferred EGFR tyrosine kinase inhibitor (TKI) in the first-line setting. However, small retrospective studies suggest that alternative EGFR TKI sequencing strategies may produce similar outcomes. This study aimed to compare the outcomes of patients with metastatic NSCLC harboring an EGFR exon 19 deletion or exon 21 L858R mutation treated with osimertinib vs. afatinib as first-line therapy. Methods: This retrospective, single-institution study examined 86 patients with metastatic EGFR-mutant NSCLC treated with either afatinib (n=15) or osimertinib (n=71) in the first-line setting. The primary outcome was progression-free survival (PFS), and secondary endpoints included time on EGFR TKI, overall survival (OS), and the incidence of adverse events (AEs). Results: There was no difference in the PFS (median: 27.9 vs. 29.0 months, P=0.75), OS (P=0.18), and the median time on first-line EGFR TKI (23.9 vs. 15.2 months, P=0.10) between the afatinib and osimertinib groups, respectively. The number of AEs was also similar between the two treatment groups (P=0.17). Conclusions: In this real-world retrospective study, there were no differences in PFS or OS between patients treated with afatinib or osimertinib in the first-line setting. These findings should be further investigated in larger prospective studies.

Dual-Channel-Ion Conductor Membrane for Low-Energy Lithium Extraction.

The development of energy-efficient and environmentally friendly lithium extraction techniques is essential to meet the growing global demand for lithium-ion batteries. In this work, a dual-channel ion conductor membrane was designed for a concentration-driven lithium-selective ion diffusion process. The membrane was based on a porous lithium-ion conductor, and its pores were modified with an anion-exchange polymer. Thus, the sintered lithium-ion conductors provided highly selective cation transport channels, and the functionalized nanopores with positive charges enabled the complementary permeation of anions to balance the transmembrane charges. As a result, the dual-channel membrane realized an ultrahigh Li+/Na+ selectivity of ∼1389 with a competitive Li+ flux of 21.6 mmol·m-2·h-1 in a diffusion process of the LiCl/NaCl binary solution, which was capable of further maintaining the high selectivity over 7 days of testing. Therefore, this work demonstrates the great potential of the dual-channel membrane design for high-performing lithium extraction from aqueous resources with low energy consumption and minimal environmental impact.

Mental health and life satisfaction among those advised to shield during the COVID-19 pandemic in the UK: a secondary analysis of the Understanding Society longitudinal study.

Introduction: During the COVID-19 pandemic in the UK, those considered most vulnerable to adverse outcomes from infection were designated "clinically extremely vulnerable" and advised to "shield." This involved prolonged confinement at home with strict limits on face-to-face contact, beyond national restrictions. Shielding ended in September 2021 and was considered likely to have harmed mental health and wellbeing. As the UK moved toward a new phase of "living with COVID-19" the mental health and wellbeing experiences of those advised to shield may have diverged from the general population. Methods: This study is a secondary analysis of nine "COVID-19 Survey" waves of Understanding Society, a longitudinal study of UK participants covering April 2020 to September 2021 alongside pre-pandemic baseline data. The prevalence of clinically significant psychological distress (General Health Questionnaire 12) and low life satisfaction were examined at each wave for participants with longitudinal responses across all waves, stratified by receipt of shielding guidance (Received n = 410, Not received n = 6,878). Mixed effects regression modeling examined associations between shielding guidance receipt and mental health and life satisfaction when adjusting for potential confounders including age and sex, pre-pandemic mental health/life satisfaction, and loneliness. Results: Those who received shielding guidance were more likely to experience poor mental health and low life satisfaction during the pandemic. However, this largely reflected differences in pre-pandemic baselines. Variation between waves broadly coincided with the changing burden of COVID-19 and associated restrictions, with similar patterns regardless of shielding guidance receipt. Regression modeling combining data across all waves indicated that receipt of shielding guidance did not independently predict adverse outcomes. However, poor pre-pandemic mental health and low life satisfaction, and frequent loneliness, as well as demographic factors including sex and age, consistently predicted adverse pandemic mental health and wellbeing. Discussion: While those who received shielding guidance did on average experience poorer mental health and life satisfaction during the pandemic, this study suggests this largely reflects existing inequalities. Drawing on data throughout the shielding program, it addresses an existing evidence gap. These findings reinforce the importance of addressing existing mental health inequalities in the recovery from the current pandemic and for future preparedness.

Effect of temperature on the conformation and functionality of poly(N-isopropylacrylamide) (PNIPAM)-grafted nanocellulose hydrogels.

HYPOTHESIS: Poly(N-isopropylacrylamide) [PNIPAM]-grafted cellulose nanofibers (CNFs) are new thermo-responsive hydrogels which can be used for a wide range of applications. Currently, there is no clear understanding of the precise mechanism by which CNFs and PNIPAM interact together. Here, we hypothesize that the physical crosslinking of grafted PNIPAM on CNF inhibits the free movement of individual CNF, which increases the gel strength while sustaining its thermo-responsive properties. EXPERIMENTS: The thermo-responsive behaviour of PNIPAM-grafted CNFs (PNIPAM-g-CNFs), synthesized via silver-catalyzed decarboxylative radical polymerization, and PNIPAM-blended CNFs (PNIPAM-b-CNFs) was studied. Small angle neutron scattering (SANS) combined with Ultra-SANS (USANS) revealed the nano to microscale conformation changes of these polymer hybrids as a function of temperature. The effect of temperature on the optical and viscoelastic properties of hydrogels was also investigated. FINDINGS: Grafting PNIPAM from CNFs shifted the lower critical solution temperature (LCST) from 32 °C to 36 °C. Below LCST, the PNIPAM chains in PNIPAM-g-CNF sustain an open conformation and poor interaction with CNF, and exhibit water-like behaviour. At and above LCST, the PNIPAM chains change conformation to entangle and aggregate nearby CNFs. Large voids are formed in solution between the aggregated PNIPAM-CNF walls. In comparison, PNIPAM-b-CNF sustains liquid-like behaviour below LCST. At and above LCST, the blended PNIPAM phase separates from CNF to form large aggregates which do not affect CNF network and thus PNIPAM-b-CNF demonstrates low viscosity. Understanding of temperature-dependent conformation of PNIPAM-g-CNFs engineer thermo-responsive hydrogels for biomedical and functional applications.

The role of iron in the pathogenesis of endometriosis: a systematic review.

STUDY QUESTION: What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER: Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. WHAT IS KNOWN ALREADY: Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN SIZE DURATION: This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma'). PARTICIPANTS/MATERIALS SETTING METHODS: This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. LIMITATIONS REASONS FOR CAUTION: A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS: Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTERESTS: J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818).

Tailoring the humidity response of cellulose nanocrystal-based films by specific ion effects.

HYPOTHESIS: The optical properties and humidity response of iridescent films made of cellulose nanocrystal (CNC) and polyethylene glycol (PEG) can be tailored by the incorporation of electrolytes chosen based on specific ion effects (SIE). EXPERIMENTS: A series of inorganic salts comprising five different cations and five anions based on the Hofmeister series were mixed with CNC/PEG suspensions, followed by an air-dried process into iridescent solid films. These films were tested in changing relative humidity (RH) environments from 30% to 90% and their photonic properties and mass change monitored. The underlying structures and the mechanism of their formation were quantified in terms of interparticle distance derived from small angle X-ray scattering experiment and pitch size quantified by scanning electron microscope (SEM). FINDINGS: The specific color and color range of CNC/PEG based films are controlled by a specific anion effect achieved by selection of the salt while the specific cation effect is negligible. The salting-in type anions with the same valency result in a red-shift color when films are in the dried state. The salting-in type leads to a greater color changing range during RH changes than the salting-out type. The resultant mass gain/loss trend is consistent with the color change. In contrast, cations do not show any relationships between salting-in effect and the measured properties as observed for anions. The observed SIE can be used to engineer CNC/polymer-based humidity and bio-diagnostic colorimetric indicator devices.

Perspective: rethinking therapeutic strategies in oncology.

Immuno-oncology has revolutionized cancer care, drug development, the design of clinical trials, standard treatment paradigms, and the evaluation of response to therapy. These are all areas, however, that have not fully incorporated principles of tumor immunology. Insufficient emphasis is put on the effect drugs have on the immune system, and specifically, the impact that multiple lines of therapy can have on the functioning of the immune system, hindering a robust anti-tumor immune response. A paradigm shift in how we approach the development of novel immunotherapeutic agents is necessary to facilitate the effective improvements in patient outcomes.

A Phase 1, Open-Label, Dose-Escalation Study of L-DOS47 in Combination With Pemetrexed Plus Carboplatin in Patients With Stage IV Recurrent or Metastatic Nonsquamous NSCLC.

Introduction: L-DOS47, a targeted urease-anti-CEACAM6 immunoconjugate, alters the acidity of the tumor microenvironment by increasing local ammonia production. In vitro, the cytotoxic effects of L-DOS47 were additive when combined with pemetrexed and carboplatin. Methods: This phase I, open-label, dose-escalation study evaluated the safety and tolerability of up to four cycles of L-DOS47 (administered on days 1, 8, and 15 of each cycle at doses ranging from 0.59 to 9.0 µg/kg) combined with pemetrexed and carboplatin in patients with stage IV nonsquamous NSCLC. Continued L-DOS47 treatment after the fourth cycle was allowed at the treating physicians' discretion. Results: A total of 14 patients received at least one dose of L-DOS47. Overall, L-DOS47 was well tolerated. Grade greater than or equal to 3 adverse events (AEs) were typically neutropenia related. Two grade greater than or equal to 3 AEs and no serious AEs were considered at least possibly related to L-DOS47. No dose-limiting toxicities were reported, so the maximum tolerated dose was not reached. The objective response rate was 41.7% with a median duration of response of 187 days. Clinical benefit was observed in 75.0% of the patients. After the first dose, L-DOS47 systemic exposure increased in a generally dose-proportional manner but decreased substantially with repeat dosing. Anti-L-DOS47 antibodies were detectable in 13 of 14 patients by cycle 2 with titers typically increasing with continued treatment. There was an apparent association between best overall response rate and highest anti-L-DOS47 antibody titer measured. Conclusions: L-DOS47 combined with standard pemetrexed and carboplatin chemotherapy is well tolerated in patients with recurrent or metastatic nonsquamous NSCLC at doses up to 9.0 µg/kg.

Extrusion and 3D printing of novel lipid-polymer blends for oral drug applications.

Lipids are interesting biological materials that can offer a number of pharmaceutical benefits when used as carriers for drug delivery. However, 3D printing of lipids alone by fused deposition processing techniques is very difficult as they have very poor mechanical properties that cause their filaments to fail when they are loaded into a fused deposition 3D printer. If this problem could be overcome, then lipids could be 3D printed into bespoke tablets and assist progress towards such personalised medicines. This work aims to improve the mechanical properties of lipid filaments by developing novel lipid-EVA (ethylene vinyl acetate) blends suitable for 3D printing. Different types of lipids in varying proportions were melt blended with EVA and extruded using a micro compounder. The ultimate printability of the materials was tested by feeding the filaments into a material extrusion 3D printer. Flexural testing of the extruded blends demonstrates that a good balance between the strength and flexibility is required for a material to be printable and it was found that a filament has to have a modulus/strength ratio between 8 and 25 in order to be printable. SEM analysis of the fracture surface shows a network structure within the lipid matrix that could be playing a role in the improved properties of the best performing blends. DSC thermograms show a shift in thermal transitions, suggesting some level of miscibility of the components that could have contributed to a more robust structure. The TGA results show an onset of degradation of the blends greater than 200 °C, indicating that the materials can readily withstand the extrusion and printing temperatures. This study demonstrates the successful extrusion and 3D printing of novel EVA-lipid blends with lipid contents of up to 90%.

Detecting subtle yet fast skeletal muscle contractions with ultrasoft and durable graphene-based cellular materials.

Human bodily movements are primarily controlled by the contractions of skeletal muscles. Unlike joint or skeletal movements that are generally performed in the large displacement range, the contractions of the skeletal muscles that underpin these movements are subtle in intensity yet high in frequency. This subtlety of movement makes it a formidable challenge to develop wearable and durable soft materials to electrically monitor such motions with high fidelity for the purpose of, for example, muscle/neuromuscular disease diagnosis. Here we report that an intrinsically fragile ultralow-density graphene-based cellular monolith sandwiched between silicone rubbers can exhibit a highly effective stress and strain transfer mechanism at its interface with the rubber, with a remarkable improvement in stretchability (>100%). In particular, this hybrid also exhibits a highly sensitive, broadband-frequency electrical response (up to 180 Hz) for a wide range of strains. By correlating the mechanical signal of muscle movements obtained from this hybrid material with electromyography, we demonstrate that the strain sensor based on this hybrid material may provide a new, soft and wearable mechanomyography approach for real-time monitoring of complex neuromuscular-skeletal interactions in a broad range of healthcare and human-machine interface applications. This work also provides a new architecture-enabled functional soft material platform for wearable electronics.

Rapid Detection of Gram-Positive and -Negative Bacteria in Water Samples Using Mannan-Binding Lectin-Based Visual Biosensor.

Waterborne bacterial infection is a health threat worldwide, making accurate and timely bacteria detection crucial to prevent waterborne disease outbreaks. Inspired by the intrinsic capability of mannan-binding lectin (MBL) in recognizing the pathogen-associated molecular patterns (PAMPs), a visual biosensor is developed here for the on-site detection of both Gram-positive and -negative bacteria. The biosensor was synthesized by immobilization of the MBL protein onto the blue carboxyl-functionalized polystyrene microparticles (PSM), which is then used in a two-step assay to detect bacterial cells in water samples. The first step involved a 20 min incubation following the MBL-PSM and calcium chloride solution addition to the samples. The second step was to add ethanol to the resultant blue mixture and observe the color change with the naked eye after 15 min. The biosensor had a binary (all-or-none) response, which in the presence of bacterial cells kept its blue color, while in their absence the color changed from blue to colorless. Testing the water samples spiked with four Gram-negative bacteria including Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa and two Gram-positive bacteria of Enterococcus faecalis and Staphylococcus aureus showed that the biosensor could detect all tested bacteria with a concentration as low as 101.5 CFU/ml. The performance of biosensor using the water samples from a water treatment plant also confirmed its capability to detect the pathogens in real-life water samples without the need for instrumentation.

Thermoresponsive Poly(N-isopropylacrylamide) Grafted from Cellulose Nanofibers via Silver-Promoted Decarboxylative Radical Polymerization.

A family of thermoresponsive poly(N-isopropylacrylamide) [PNIPAM]-grafted cellulose nanofibers (CNFs) was synthesized via a novel silver-promoted decarboxylative polymerization approach. This method relies on the oxidative decarboxylation of carboxylic acid groups to initiate free radicals on the surface of CNFs. The polymerization reaction employs relatively mild reaction conditions and can be performed in a one-step, one-pot fashion. This rapid reaction forms a C─C bond between CNF and PNIPAM, along with the formation of free polymer in solution. The degree of functionalization (DF) and the amount of PNIPAM grafted can be controlled by the Ag concentration in the reaction. Similar to native bulk PNIPAM, PNIPAM-grafted CNFs (PNIPAM-g-CNFs) show remarkable thermoresponsive properties, albeit exhibiting a slight hysteresis between the heating and cooling stages. Grafting PNIPAM from CNFs changes its cloud point from about 32 to 36 °C, influenced by the hydrophilic nature of CNFs. Unlike physical blending, covalently tethering PNIPAM transforms the originally inert CNFs into thermosensitive biomaterials. The Ag concentration used does not significantly change the cloud point of PNIPAM-g-CNFs, while the cloud point slightly decreases with fiber concentration. Rheological studies demonstrated the sol-gel transition of PNIPAM-g-CNFs and revealed that the storage modulus (G') above cloud point increases with the amount of PNIPAM grafted. The novel chemistry developed paves the way for the polymerization of any vinyl monomer from the surface of CNFs and carbohydrates. This study validates a novel approach to graft PNIPAM from CNFs for the synthesis of new thermoresponsive and transparent hydrogels for a wide range of applications.

Modulating the chiral nanoarchitecture of cellulose nanocrystals through interaction with salts and polymer.

HYPOTHESIS: The conditions to allow self-assembly of cellulose nanocrystal (CNC) suspensions into chiral nematic structures are based on aspect ratio, surface charge density and a balance between repulsive and attractive forces between CNC particles. EXPERIMENTS: Three types of systems were characterized in suspensions and subsequently in their solid dried films: 1) neat water dialyzed CNC, 2) CNC combined with polyethylene glycol(PEG) (CNC/PEG), and 3) CNC with added salt (CNC/Salt). All suspensions were characterized by polarized optical microscope (POM) and small angle X-ray scattering (SAXS), while the resultant dried films were analyzed by reflectance spectrometer, scanning electron microscope (SEM) and SAXS. FINDINGS: The presence of chiral nematic (CN*) structures was not observed in dialyzed aqueous suspensions of CNC during water evaporation. By introducing salts or a non-adsorbing polymer, chirality was apparent in both suspensions and films. The interaxial angle between CNC rods increased when the suspensions of CNC/PEG and CNC/salt were dried to solid films. The angle was found to be dependent on both species of ions and ionic strength, while the inter-particle distance was only related to the salt concentration, as explained in terms of interaction energies. The CNC suspensions/film chirality can be modulated by controlling the colloidal forces.

A 3D-Printed Polymer-Lipid-Hybrid Tablet towards the Development of Bespoke SMEDDS Formulations.

3D printing is a rapidly growing area of interest within pharmaceutical science thanks to its versatility in creating different dose form geometries and drug doses to enable the personalisation of medicines. Research in this area has been dominated by polymer-based materials; however, for poorly water-soluble lipophilic drugs, lipid formulations present advantages in improving bioavailability. This study progresses the area of 3D-printed solid lipid formulations by providing a 3D-printed dissolvable polymer scaffold to compartmentalise solid lipid formulations within a single dosage form. This allows the versatility of different drugs in different lipid formulations, loaded into different compartments to generate wide versatility in drug release, and specific control over release geometry to tune release rates. Application to a range of drug molecules was demonstrated by incorporating the model lipophilic drugs; halofantrine, lumefantrine and clofazimine into the multicompartmental scaffolded tablets. Fenofibrate was used as the model drug in the single compartment scaffolded tablets for comparison with previous studies. The formulation-laden scaffolds were characterised using X-ray CT and dispersion of the formulation was studied using nephelometry, while release of a range of poorly water-soluble drugs into different gastrointestinal media was studied using HPLC. The studies show that dispersion and drug release are predictably dependent on the exposed surface area-to-volume ratio (SA:V) and independent of the drug. At the extremes of SA:V studied here, within 20 min of dissolution time, formulations with an SA:V of 0.8 had dispersed to between 90 and 110%, and completely released the drug, where as an SA:V of 0 yielded 0% dispersion and drug release. Therefore, this study presents opportunities to develop new dose forms with advantages in a polypharmacy context.

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations.

INTRODUCTION: The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. METHODS: We reviewed the database of the MD Anderson Cancer Center and identified metastatic LUSC with classic EGFR or ALK alterations. RESULTS: There were eight patients with EGFR-mutant LUSC (median age = 58 y) and six patients with EML4-ALK LUSC (median age = 50 y) who received tyrosine kinase inhibitors (TKIs) that were identified. Of the 14 patients, 11 (79%) were females and 12 (86%) were never smokers, similar to the demographics of EGFR or ALK LUAD. With TKI treatment, seven of eight cases of EGFR LUSC and four of six cases of ALK LUSC achieved partial response or stable disease, but the progression-free survival was 4.9 months and 2.9 months for EGFR-mutant and ALK-rearranged LUSC, respectively. In addition, we compared comutation profile of EGFR-mutant LUAD (The Cancer Genome Atlas, n = 46) versus LUSC (n = 19) and found that the comutation patterns are more consistent with squamous disease with a higher incidence of PIK3CA (p = 0.02) and KRAS or BRAF (p = 0.04) alterations. CONCLUSIONS: EGFR or ALK alterations occur in patients with LUSC, especially never-smoker females. TKI treatments render clinical benefit in disease control, but the duration was considerably truncated compared with those historically observed in LUAD.

Assessing the effectiveness and implementation of a chronic disease self-management programme in faith-based organisations in Barbados: protocol for a cluster randomised parallel trial.

INTRODUCTION: In the COVID-19 environment of reduced patient interaction with the healthcare system, evidenced-based self-care of chronic disease is vital. We will evaluate the effect of an online chronic disease self-management programme (CDSMP) plus medication adherence tools on systolic blood pressure (SBP) (primary aim) and, seek to understand the barriers and facilitators to implementation of this modified CDSMP in faith-based organisations (FBOs) (secondary aim). METHODS: We will conduct an unblinded cluster randomised trial in FBOs throughout Barbados. Eligibility: Persons ages 35-70 years; a previous diagnosis of hypertension or currently on antihypertensive therapy and the occurrence of two or more blood pressure readings above 130 mm Hg (systolic) or 80 mm Hg (diastolic) on the day of recruitment. Persons not known to have hypertension but who have two or more blood pressure readings at or above 130 mm Hg (systolic) or 80 mm Hg (diastolic) on two recruitment days at least 1 week apart will also be eligible. The unit of randomisation is a church cluster which consists of 7-9 churches. We will perform block randomisation to assign 24 clusters to intervention or control. The intervention has three components: modified CDSMP workshops, distribution of medication pill boxes and use of social media (WhatsApp V.2.0) to encourage medication adherence. Controls will receive one didactic lecture only. We will determine the mean changes in SBP levels for the intervention group versus controls and compare differences in outcomes 6 months' post intervention using mixed effects regression models. ETHICS AND DISSEMINATION: This project has received ethical approval from the Institutional Review Board of the University of the West Indies in Barbados. Dissemination will use peer-reviewed publications, policy briefs to government and guidelines to leaders of FBOs. We aim to increase the proportion of patients with controlled hypertension and inform implementation of self-management programmes in small populations. TRAIL REGISTRATION NUMBER: NCT04437966.

Keeping it human: Pandemic era psychiatry teaching.

BACKGROUND: Mental health is an important global issue, and doctors in training need a grounding in the principles of psychiatry. Undergraduate clinical placements in psychiatry can develop core knowledge and skills as well as challenging stigma towards mental illness. The onset of the coronavirus pandemic saw disruption to undergraduate clinical placements. In a U.K. medical school, th e authors were tasked with transforming a 6-week clinical placement in psychiatry into a primarily online course. APPROACH: A 4-week online course was developed in preparation for a condensed clinical placement. A range of resources were drawn upon to address key learning objectives and to engage students in broader thinking about mental health. These included videos and blogs describing personal experiences of mental illness, as well as interviews with prominent psychiatrists. Peer- and tutor-led sessions complemented these self-directed elements and reduced social isolation. EVALUATION: Sixty-seven students undertook the course, supported by eight consultant tutors. The content and structure of the course were highly rated; however, students indicated that peer group activities could benefit from further development. Students felt prepared for clinical placements and performed equally well in summative written examinations. Feedback indicated the development of positive attitudes towards mental health and illness. IMPLICATIONS: This course demonstrates how, even when clinical contact is challenged, a strong focus can be maintained on social elements of learning and patients' experiences of mental illness. This approach provides opportunities to develop essential knowledge and skills alongside broader attitudinal learning that may have a de-stigmatising effect.