A TCR mimic CAR T cell specific for NDC80 is broadly reactive with solid tumors and hematologic malignancies.

Target identification for chimeric antigen receptor (CAR) T-cell therapies remains challenging due to the limited repertoire of tumor-specific surface proteins. Intracellular proteins presented in the context of cell surface HLA provide a wide pool of potential antigens targetable through T-cell receptor mimic antibodies. Mass spectrometry (MS) of HLA ligands from 8 hematologic and nonhematologic cancer cell lines identified a shared, non-immunogenic, HLA-A*02-restricted ligand (ALNEQIARL) derived from the kinetochore-associated NDC80 gene. CAR T cells directed against the ALNEQIARL:HLA-A*02 complex exhibited high sensitivity and specificity for recognition and killing of multiple cancer types, especially those of hematologic origin, and were efficacious in mouse models against a human leukemia and a solid tumor. In contrast, no toxicities toward resting or activated healthy leukocytes as well as hematopoietic stem cells were observed. This shows how MS can inform the design of broadly reactive therapeutic T-cell receptor mimic CAR T-cell therapies that can target multiple cancer types currently not druggable by small molecules, conventional CAR T cells, T cells, or antibodies.

Vaccine-preventable hospitalisations in adult mental health service users: a population study.

BACKGROUND: Vaccine-preventable conditions cause preventable illness and may increase mortality in people living with mental illness. We examined how risks of hospitalisation for a wide range of vaccine-preventable conditions varied by age and sex among mental health (MH) service users. METHODS: Linked population data from New South Wales (NSW), Australia were used to identify vaccine-preventable hospitalisations (VPH) for 19 conditions from 2015 to 2020. Adult MH service users (n = 418 915) were compared to other NSW residents using incidence rates standardised for age, sex and socioeconomic status. Secondary analyses examined admissions for COVID-19 to September 2021. RESULTS: We identified 94 180 VPH of which 41% were influenza, 33% hepatitis B and 10% herpes zoster. MH service users had more VPH admissions [adjusted incidence rate ratio (aIRR) 3.2, 95% CI 3.1-3.3]. Relative risks were highest for hepatitis (aIRR 4.4, 95% CI 4.3-4.6), but elevated for all conditions including COVID-19 (aIRR 2.0, 95% CI 1.9-2.2). MH service users had a mean age of 9 years younger than other NSW residents at first VPH admission, with the largest age gap for vaccine-preventable pneumonias (11-13 years younger). The highest relative risk of VPH was among MH service users aged 45-65. CONCLUSIONS: MH service users have increased risk of hospitalisation for many vaccine-preventable conditions. This may be due to reduced vaccination rates, more severe illness requiring hospitalisation, greater exposure to infectious conditions or other factors. People living with mental illness should be prioritised in vaccination strategies.

The "Mellanby effect" in alcoholised e-scooter drivers.

PURPOSE: Several studies tried to discuss and clarify the so-called Mellanby effect: Similar blood alcohol concentrations (BACs) supposedly lead to more signs of impairment in the phase of alcohol resorption than elimination. To assess this effect for alcoholised e-scooter driving, results of a real-driving fitness study were subanalysed. METHODS: Sixteen subjects (9 females; 7 males) who completed runs at comparable BACs in the phases of alcohol resorption and elimination were chosen to assess a possible "Mellanby effect". The data of the subjects was taken from a prior e-scooter study by Zube et al., which included 63 subjects in total. RESULTS: In the phase of alcohol resorption, the relative driving performance was approx. 92% of the phase of elimination (p value 0.21). Statistically significant more demerits were allocated to the obstacle "narrowing track" in the phase of resorption than elimination. Subjects also needed significantly more time to pass the obstacles "narrowing track", "driving in circles counterclockwise" and "thresholds" in the phase of resorption than elimination. DISCUSSION: The most relevant obstacle to discriminate between the two different states of alcoholisation was the narrowing track. Insofar, measurements of the standard deviation of the lateral position (SDLP) might also be a sensitive component for the detection of central nervous driving impairment during shorter trips with an e-scooter. Additionally, driving slower during the phase of alcohol resorption seems to be the attempt to compensate alcohol-related deficits. CONCLUSION: The results of the study suggest a slight Mellanby effect in e-scooter drivers.

Blood Flow Restriction Therapy for 2 Weeks Prior to Anterior Cruciate Ligament Reconstruction Did Not Impact Quadriceps Strength Compared to Standard Therapy.

PURPOSE: To evaluate the efficacy of a 2-week home-based blood flow restriction (BFR) prehabiliation program on quadriceps strength and patient-reported outcomes prior to anterior cruciate ligament (ACL) reconstruction. METHODS: Patients presenting with an ACL tear were randomized into two groups, BFR and control, at their initial clinic visit. Quadriceps strength was measured using a handheld dynamometer in order to calculate peak force, average force, and time to peak force during seated leg extension at the initial clinic visit and repeated on the day of surgery. All patients were provided education on standardized exercises to be performed 5 days per week for 2 weeks between the initial clinic visit and date of surgery. The BFR group was instructed to perform these exercises with a pneumatic cuff set to 80% of limb occlusion pressure placed over the proximal thigh. Patient-Reported Outcome Measurement System Physical Function (PROMIS-PF), knee range of motion, and quadriceps circumference were gathered at the initial clinic visit and day of surgery, and patients were monitored for adverse effects. RESULTS: A total 45 patients met inclusion criteria and elected to participate. There were 23 patients randomized to the BFR group and 22 patients randomized into the control group. No significant differences were noted between the BFR and control groups in any demographic characteristics (48% vs 64% male [P = .271] and average age 26.5 ± 12.0 vs 27.0 ± 11.0 [P = .879] in BFR and control, respectively). During the initial clinic visit, there were no significant differences in quadriceps circumference, peak quadriceps force generation, time to peak force, average force, pain, and PROMIS scales (P > .05 for all). Following completion of a 2-week home prehabilitation protocol, all patients indeterminant of cohort demonstrated decreased strength loss in the operative leg compared to the nonoperative leg (P < .05 for both) However, there were no significant differences in any strength or outcome measures between the BFR and control groups (P > .05 for all). There were no complications experienced in either group, and both were compliant with the home-based prehabilitation program. CONCLUSIONS: A 2-week standardized prehabilitation protocol preceding ACL reconstruction resulted in a significant improvement in personal quadriceps peak force measurements, both with and without the use of BFR. No difference in quadriceps circumference, strength, or patient reported outcomes were found between the BFR and the control group. The home-based BFR prehabiliation protocol was found to be feasible, accessible, and well tolerated by patients. LEVEL OF EVIDENCE: Level II, randomized controlled trial with small effect size.

Evaluation of tree-based statistical learning methods for constructing genetic risk scores.

BACKGROUND: Genetic risk scores (GRS) summarize genetic features such as single nucleotide polymorphisms (SNPs) in a single statistic with respect to a given trait. So far, GRS are typically built using generalized linear models or regularized extensions. However, these linear methods are usually not able to incorporate gene-gene interactions or non-linear SNP-response relationships. Tree-based statistical learning methods such as random forests and logic regression may be an alternative to such regularized-regression-based methods and are investigated in this article. Moreover, we consider modifications of random forests and logic regression for the construction of GRS. RESULTS: In an extensive simulation study and an application to a real data set from a German cohort study, we show that both tree-based approaches can outperform elastic net when constructing GRS for binary traits. Especially a modification of logic regression called logic bagging could induce comparatively high predictive power as measured by the area under the curve and the statistical power. Even when considering no epistatic interaction effects but only marginal genetic effects, the regularized regression method lead in most cases to inferior results. CONCLUSIONS: When constructing GRS, we recommend taking random forests and logic bagging into account, in particular, if it can be assumed that possibly unknown epistasis between SNPs is present. To develop the best possible prediction models, extensive joint hyperparameter optimizations should be conducted.

E-scooter driving under the acute influence of alcohol-a real-driving fitness study.

PURPOSE: To assess the effects of alcohol on the ability to drive an e-scooter, driving tests reflecting real-life situations accompanied by medical examinations focusing on balance were conducted at different blood alcohol concentrations (BACs). METHODS: Fifty-seven subjects who consumed alcohol (28 female, 29 male) and 6 consistently sober subjects (3 female, 3 male) participated in the study. Alcohol was administered on a fixed schedule, and the individual drinking quantity was individually calculated in advance using the Widmark formula. Repeated runs through a fixed course were performed. Following each ride, a blood sample was taken for BAC determination, and medical tests were performed. RESULTS: Even at low BACs (0.21-0.60 g/kg), subjects showed a significant decrease in driving performance, to approximately 60% of the initial level. Differences in driving performance at different BAC ranges were observed for different obstacles, especially for the narrowing track, gate passage, slalom, and driving in circles obstacles. Furthermore, worse Romberg and Unterberger test results were correlated with worse driving performance. It cannot be assumed that learning effects during the study had a relevant effect, as shown in the comparison of the driving performance of the alcohol-consuming group with that of the control group. Sex-specific differences were not found. DISCUSSION: Significant deteriorations in driving performance at BACs below 1.10 g/kg confirmed alcohol-related risk potential when using e-scooters. At this time, these findings may lead to the assumption of "relative driving impairment" in Germany. The Romberg and Unterberger tests could be considered a complementary investigation method for the assessment of e-scooter driving impairment. CONCLUSION: Even at rather low BACs between 0.21 and 0.40 g/kg, there was a significant deterioration in driving performance under the influence of alcohol compared to sober, which highlights the negative effects of alcohol on e-scooter driving.

Revisiting the effectiveness of repetitive transcranial magnetic stimulation treatment in depression, again.

Following on from the publication of the Royal Australian and New Zealand Journal of Psychiatry Mood Disorder Clinical Practice Guidelines (2020) and criticisms of how these aberrantly addressed repetitive transcranial magnetic stimulation treatment of depression, questions have continued to be raised in the journal about this treatment by a small group of authors, whose views we contend do not reflect the broad acceptance of this treatment nationally and internationally. In fact, the evidence supporting the use of repetitive transcranial magnetic stimulation treatment in depression is unambiguous and substantial, consisting of an extensive series of clinical trials supported by multiple meta-analyses, network meta-analysis and umbrella reviews. Importantly, the use of repetitive transcranial magnetic stimulation treatment in depression has also been subject to a series of health economic analyses. These indicate that repetitive transcranial magnetic stimulation is a cost-effective therapy and have been used in some jurisdictions, including Australia, in support of public funding. An argument has been made that offering repetitive transcranial magnetic stimulation treatment may delay potentially effective pharmacotherapy. In fact, there is considerably greater danger of the opposite happening. Repetitive transcranial magnetic stimulation is as, if not more effective, than antidepressant medication after two unsuccessful medication trials and should be a consideration for all patients under these circumstances where available. There is no meaningful ongoing debate about the use of repetitive transcranial magnetic stimulation treatment in depression - it is a safe, effective and cost-effective treatment.

A Low-Cost, 3D-Printed Biosensor for Rapid Detection of Escherichia coli.

Detection of bacterial pathogens is significant in the fields of food safety, medicine, and public health, just to name a few. If bacterial pathogens are not properly identified and treated promptly, they can lead to morbidity and mortality, also possibly contribute to antimicrobial resistance. Current bacterial detection methodologies rely solely on laboratory-based techniques, which are limited by long turnaround detection times, expensive costs, and risks of inadequate accuracy; also, the work requires trained specialists. Here, we describe a cost-effective and portable 3D-printed electrochemical biosensor that facilitates rapid detection of certain Escherichia coli (E. coli) strains (DH5α, BL21, TOP10, and JM109) within 15 min using 500 µL of sample, and costs only USD 2.50 per test. The sensor displayed an excellent limit of detection (LOD) of 53 cfu, limit of quantification (LOQ) of 270 cfu, and showed cross-reactivity with strains BL21 and JM109 due to shared epitopes. This advantageous diagnostic device is a strong candidate for frequent testing at point of care; it also has application in various fields and industries where pathogen detection is of interest.

Fetal Electrocardiogram Extraction from the Mother's Abdominal Signal Using the Ensemble Kalman Filter.

Fetal electrocardiogram (fECG) assessment is essential throughout pregnancy to monitor the wellbeing and development of the fetus, and to possibly diagnose potential congenital heart defects. Due to the high noise incorporated in the abdominal ECG (aECG) signals, the extraction of fECG has been challenging. And it is even a lot more difficult for fECG extraction if only one channel of aECG is provided, i.e., in a compact patch device. In this paper, we propose a novel algorithm based on the Ensemble Kalman filter (EnKF) for non-invasive fECG extraction from a single-channel aECG signal. To assess the performance of the proposed algorithm, we used our own clinical data, obtained from a pilot study with 10 subjects each of 20 min recording, and data from the PhysioNet 2013 Challenge bank with labeled QRS complex annotations. The proposed methodology shows the average positive predictive value (PPV) of 97.59%, sensitivity (SE) of 96.91%, and F1-score of 97.25% from the PhysioNet 2013 Challenge bank. Our results also indicate that the proposed algorithm is reliable and effective, and it outperforms the recently proposed extended Kalman filter (EKF) based algorithm.

Can Coupling Multiple Complementary Methods Improve the Spectroscopic Based Diagnosis of Gastrointestinal Illnesses? A Proof of Principle Ex Vivo Study Using Celiac Disease as the Model Illness.

Spectroscopic methods are a promising approach for providing a point-of-care diagnostic method for gastrointestinal mucosa associated illnesses. Such a tool is desired to aid immediate decision making and to provide a faster pathway to appropriate treatment. In this pilot study, Raman, near-infrared, low frequency Raman, and autofluoresence spectroscopic methods were explored alone and in combination for the diagnosis of celiac disease. Duodenal biopsies (n = 72) from 24 participants were measured ex vivo using the full suite of studied spectroscopic methods. Exploratory principal component analysis (PCA) highlighted the origin of spectral differences between celiac and normal tissue with celiac biopsies tending to have higher protein relative to lipid signals and lower carotenoid spectral signals than the samples with normal histology. Classification of the samples based on the histology and overall diagnosis was carried out for all combinations of spectroscopic methods. Diagnosis based classification (majority rule of class per participant) yielded sensitivities of 0.31 to 0.77 for individual techniques, which was increased up to 0.85 when coupling multiple techniques together. Likewise, specificities of 0.50 to 0.67 were obtained for individual techniques, which was increased up to 0.78 when coupling multiple techniques together. It was noted that the use of antidepressants contributed to false positives, which is believed to be associated with increased serotonin levels observed in the gut mucosa in both celiac disease and the use of selective serotonin reuptake inhibitors (SSRIs); however, future work with greater numbers is required to confirm this observation. Inclusion of two additional spectroscopic methods could improve the accuracy of diagnosis (0.78) by 7% over Raman alone (0.73). This demonstrates the potential for further exploration and development of a multispectroscopic system for disease diagnosis.

Predictive analytics for step-up therapy: Supervised or semi-supervised learning?

BACKGROUND: Step-up therapy is a patient management approach that aims to balance the efficacy, costs and risks posed by different lines of medications. While the initiation of first line medications is a straightforward decision, stepping-up a patient to the next treatment line is often more challenging and difficult to predict. By identifying patients who are likely to move to the next line of therapy, prediction models could be used to help healthcare organizations with resource planning and chronic disease management. OBJECTIVE: To compared supervised learning versus semi-supervised learning to predict which rheumatoid arthritis patients will move from the first line of therapy (i.e., conventional synthetic disease-modifying antirheumatic drugs) to the next line of therapy (i.e., disease-modifying antirheumatic drugs or targeted synthetic disease-modifying antirheumatic drugs) within one year. MATERIALS AND METHODS: Five groups of features were extracted from an administrative claims database: demographics, medications, diagnoses, provider characteristics, and procedures. Then, a variety of supervised and semi-supervised learning methods were implemented to identify the most optimal method of each approach and assess the contribution of each feature group. Finally, error analysis was conducted to understand the behavior of misclassified patients. RESULTS: XGBoost yielded the highest F-measure (42%) among the supervised approaches and one-class support vector machine achieved the highest F-measure (65%) among the semi-supervised approaches. The semi-supervised approach had significantly higher F-measure (65% vs. 42%; p < 0.01), precision (51% vs. 33%; p < 0.01), and recall (89% vs. 59%; p < 0.01) than the supervised approach. Excluding demographic, drug, diagnosis, provider, and procedure features reduced theF-measure from 65% to 61%, 57%, 54%, 51% and 49% respectively (p < 0.01). The error analysis showed that a substantial portion of false positive patients will change their line of therapy shortly after the prediction period. CONCLUSION: This study showed that supervised learning approaches are not an optimal option for a difficult clinical decision regarding step-up therapy. More specifically, negative class labels in step-up therapy data are not a robust ground truth, because the costs and risks associated with higher line of therapy impact objective decision making of patients and providers. The proposed semi-supervised learning approach can be applied to other step-up therapy applications.

Renal manifestations of syphilis.

Syphilis is a sexually transmitted disease caused by spirochaete Treponema pallidum. The incidence of syphilis is rising across the globe. It has been described in the literature as a great imitator due to the vast range of clinical manifestations that can occur in the disease. Renal manifestations are rare but a feature of secondary syphilis. It can cause glomerulopathies, tubular pathology and vasculitic lesions in the kidney. Membranous nephropathy is the most commonly reported glomerular lesion associated with syphilis. With two recent cases of secondary membranous nephropathy due to syphilis, it is timely to review the current state of knowledge, and discuss the different renal manifestation of syphilis, its pathology and treatment options.

Biomimetic surgical mesh to replace fascia with tunable force-displacement.

Here we mimic the mechanical properties of native fascia to design surgical mesh for fascia replacement. Despite the widespread acceptance of synthetic materials as tissue scaffolds for pelvic floor disorders, mechanical property mismatch between mesh and adjacent native tissue drives fibrosis and erosion, leading the FDA to remove several surgical meshes from the market. However, autologous tissue does not induce either fibrosis or adjacent tissue erosion, suggesting the potential for biomimetic surgical mesh. In this study, we determined the design rules for mesh that mimics native fascia by mathematically modeling multi-component polymer networks, composed of elastin-like and collagen-like fibers, using a spring-network model. To validate the model, we measured the stress-strain curves of native bovine and nonhuman primate (Macaca mulatta) abdominal fascia in both toe and linear regions. We find that the stiffer collagen-like fibers must remain limp until the elastin-like fibers extend to the initial length of spanning collagen-like fibers under uniaxial tension. Comparing model results to experiment determines the product of fiber volume fraction and elastic modulus, a critical design parameter. Dual fiber mesh with mechanical properties that mimic fascia are feasible. These results have broad application to a wide range of soft tissue replacements including ~200,000 surgeries/year for pelvic floor disorders, because standard-of-care mesh contain only stiffer polymers that behave more like collagen than native tissue.

Pilot Study of the Mirabilis System Prototype for Rapid Noninvasive Uterine Myoma Treatment Using an Ultrasound-Guided Volumetric Shell Ablation Technique.

STUDY OBJECTIVE: The primary objective of this pilot study was to evaluate the safety and acute tissue ablation efficacy of a transabdominal high-intensity focused ultrasound (HIFU) prototype device that uses ultrasound imaging guidance for rapid noninvasive ablation of uterine myomas. The secondary objective was to assess preliminary myoma-related symptom improvement and myoma volume reduction at 3 to 6 months post-treatment in subsets of patients. DESIGN: Multicenter prospective single-arm pilot study (Canadian Task Force classification II-2). SETTING: University-affiliated teaching hospital and private community hospital. PATIENTS: Women with a diagnosis of symptomatic uterine myomas planning to undergo hysterectomy. INTERVENTIONS: Seventy-three women underwent transabdominal ultrasound-guided HIFU treatment using a volumetric ablation technique referred to as "shell ablation," in which the HIFU energy is deposited in patterns that partially encapsulate the peripheral region of the targeted myoma(s). Patients were divided into 2 sequential cohorts, the development cohort (the first 37 patients treated) and the validation cohort (the final 36 patients treated). Development cohort treatments were performed for dose-ranging purposes to identify the optimum HIFU treatment parameters, whereas the validation cohort treatments were performed to validate these final settings. Sixty-five patients (89.0%) received only prophylactic oral, sublingual, or intramuscular analgesia before treatment, sometimes with oral anxiolytics. The remaining 8 patients (11.0%) were anesthetized before treatment. Sixty-seven patients (91.8%) then had scheduled hysterectomies between 0 and 179 days after treatment completion. Adverse events were monitored until study exit, which ranged from 10 to 191 days post-treatment. MEASUREMENTS AND MAIN RESULTS: The primary efficacy endpoint measured in all 73 patients was the nonperfused volume (NPV) of tissue produced, which was assessed between 0 and 7 days post-treatment either by tissue sectioning after hysterectomy or by gadolinium-enhanced magnetic resonance imaging. Secondary efficacy endpoints were also measured in subsets of patients who were prospectively scheduled for delayed hysterectomies: Changes in menstrual blood loss (MBL), symptom severity (SS), and quality of life (QOL) scores were assessed using validated techniques at 3 months post-treatment in 10 patients and changes in treated myoma volume were assessed using magnetic resonance imaging at 3 to 6 months post-treatment in 14 patients. In all 73 patients, there were no reports of any serious adverse device effects, including no damage to any extrauterine collateral tissues or the abdominal skin. In the development cohort, a mean NPV of 17.9 ± 24.9 cm3 (range, 0-123.0) was produced in a mean total treatment time of 4.9 ± 2.4 minutes (range, 1.1-11.3). These metrics improved in the validation cohort, where a mean NPV of 44.9 ± 58.5 cm3 (range, 0-284.7) was produced in a mean total treatment time of 3.6 ± 2.1 minutes (range, 1.5-9.5). In the subsets of patients with data available, there was a significant improvement in QOL score (median, 16.5 point increase; p = .011), an improving trend in SS score (median, 13.5 point decrease; p = .254), and a significant improvement in treated myoma volume (mean, 24.0% decrease; p = .013). In 8 patients who had above-average MBL scores at baseline and regular menstrual cycle lengths during follow-up, there was also a significant improvement in MBL score (median, 40.8% decrease; p = .035). CONCLUSION: Ultrasound-guided HIFU ablation with the prototype device demonstrated an excellent safety profile and produced clinically relevant NPVs in a mean total treatment time of under 4 minutes using the final validated treatment settings. Short-term clinical efficacy metrics assessed in subsets of patients were encouraging, and larger studies should be conducted to confirm these results (ClinicalTrials.gov, NCT01946178).

A review of co-milling techniques for the production of high dose dry powder inhaler formulation.

Drug delivery by inhalation offers several advantages compared to other dosage forms, including rapid clinical onset, high bioavailability, and minimal systemic side effects. Drug delivery to the lung can be achieved as liquid suspensions or solutions in nebulizers and pressurized metered-dose inhalers (pMDI), or as dry powders in dry powder inhalers (DPIs). Compared to other delivery systems, DPIs are, in many cases, considered the most convenient as they are breath actuated and do not require the use of propellants. Currently, the delivery of low drug doses for the treatment of lung conditions such as asthma and chronic obstructive pulmonary disease are well established, with numerous commercial products available on the market. The delivery of low doses can be achieved from either standard carrier- or aggregate-based formulations, which are unsuitable in the delivery of high doses due to particle segregation associated with carrier active site saturation and the cohesiveness of micronized aggregates which have poor flow and de-agglomeration properties. High-dose delivery is required for the treatment of lung infection (i.e. antibiotics) and in the emerging application of drug delivery for the management of systemic conditions (i.e. diabetes). Therefore, there is a demand for new methods for production of high-dose dry powder formulations. This paper presents a review of co-mill processing, for the production of high-efficiency inhalation therapies, including the jet mill, mechanofusion, or ball mill methodologies. We investigate the different techniques, additives, and drugs studied, and impact on performance in DPI systems.

Co-milled API-lactose systems for inhalation therapy: impact of magnesium stearate on physico-chemical stability and aerosolization performance.

CONTEXT: Particle micronization for inhalation can impart surface disorder (amorphism) of crystalline structures. This can lead to stability issues upon storage at elevated humidity from recrystallization of the amorphous state, which can subsequently affect the aerosol performance of the dry powder formulation. OBJECTIVE: The aim of this study was to investigate the impact of an additive, magnesium stearate (MGST), on the stability and aerosol performance of co-milled active pharmaceutical ingredient (API) with lactose. METHODS: Blends of API-lactose with/without MGST were prepared and co-milled by the jet-mill apparatus. Samples were stored at 50% relative humidity (RH) and 75% RH for 1, 5, and 15 d. Analysis of changes in particle size, agglomerate structure/strength, moisture sorption, and aerosol performance were analyzed by laser diffraction, scanning electron microscopy (SEM), dynamic vapor sorption (DVS), and in-vitro aerodynamic size assessment by impaction. RESULTS: Co-milled formulation with MGST (5% w/w) led to a reduction in agglomerate size and strength after storage at elevated humidity compared with co-milled formulation without MGST, as observed from SEM and laser diffraction. Hysteresis in the sorption/desorption isotherm was observed in the co-milled sample without MGST, which was likely due to the recrystallization of the amorphous regions of micronized lactose. Deterioration in aerosol performance after storage at elevated humidity was greater for the co-milled samples without MGST, compared with co-milled with MGST. CONCLUSION: MGST has been shown to have a significant impact on co-milled dry powder stability after storage at elevated humidity in terms of physico-chemical properties and aerosol performance.

Investigation into the Manufacture and Properties of Inhalable High-Dose Dry Powders Produced by Comilling API and Lactose with Magnesium Stearate.

The aim of the study was to understand the impact of different concentrations of the additive material, magnesium stearate (MGST), and the active pharmaceutical ingredient (API), respectively, on the physicochemical properties and aerosol performance of comilled formulations for high-dose delivery. Initially, blends of API/lactose with different concentrations of MGST (1-7.5% w/w) were prepared and comilled by the jet-mill apparatus. The optimal concentration of MGST in comilled formulations was investigated, specifically for agglomerate structure and strength, particle size, uniformity of content, surface coverage, and aerosol performance. Secondly, comilled formulations with different API (1-40% w/w) concentrations were prepared and similarly analyzed. Comilled 5% MGST (w/w) formulation resulted in a significant improvement in in vitro aerosol performance due to the reduction in agglomerate size and strength compared to the formulation comilled without MGST. Higher concentrations of MGST (7.5% w/w) led to reduction in aerosol performance likely due to excessive surface coverage of the micronized particles by MGST, which led to failure in uniformity of content and an increase in agglomerate strength and size. Generally, comilled formulations with higher concentrations of API increased the agglomerate strength and size, which subsequently caused a reduction in aerosol performance. High-dose delivery was achieved at API concentration of >20% (w/w). The study provided a platform for the investigation of aerosol performance and physicochemical properties of other API and additive materials in comilled formulations for the emerging field of high-dose delivery by dry powder inhalation.

Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study.

OBJECTIVE: The incidence and symptoms associated with eosinophilic esophagitis (EoE) varies with geographic location, present in 7-15% dysphagic European or North American adults. We aimed to determine incidence and features of EoE in a dysphagic New Zealand population. MATERIALS AND METHODS: 101 consecutive patients presenting with dysphagia to a New Zealand teaching hospital completed a questionnaire (demographics and history) before upper gastrointestinal endoscopy and esophageal biopsies. RESULTS: The incidence of EoE was 14.1% in those having esophageal biopsies. Patients with EoE were younger (median age 38 years, cohort 58 years: OR 9.2 for age ≤ 40; p < 0.001), more frequently male (19.1% versus 7.4% of females: OR 4.7; p < 0.05), and had longer symptom duration (median 262 weeks versus 130.6 weeks: p = NS) with non-continuous symptoms (continuous symptoms 8.3% EoE versus 16.2% cohort: p = NS). Progressive symptoms, level of dysphagia and history of allergy/atopy occurred with almost identical frequency in those with and without EoE. Classic endoscopic features of EoE had a sensitivity and specificity of 30.6 and 93.2%, respectively. CONCLUSIONS: EoE occurs in an adult dysphagic population in New Zealand with similar frequency to that reported in Europe and North America. Demographics and features of history associated with EoE are described and the need to take esophageal biopsies in this population emphasized by the relatively low sensitivity of endoscopic features for the condition.

Optical nonlinearities and enhanced light transmission in soft-matter systems with tunable polarizabilities.

We demonstrate a new class of synthetic colloidal suspensions capable of exhibiting negative polarizabilities, and observe for the first time robust propagation and enhanced transmission of self-trapped light over long distances that would have been otherwise impossible in conventional suspensions with positive polarizabilities. Such light penetration through the strong scattering environment is attributed to the interplay between optical forces and self-activated transparency effects while no thermal effect is involved. By judiciously mixing colloidal particles of both negative and positive polarizabilities, we show that the resulting nonlinear response of these systems can be fine-tuned. Our experimental observations are in agreement with theoretical analysis based on a thermodynamic model that takes into account particle-particle interactions. These results may open up new opportunities in developing soft-matter systems with engineered optical nonlinearities.

Efficient gene-environment interaction testing through bootstrap aggregating.

Gene-environment (GxE) interactions are an important and sophisticated component in the manifestation of complex phenotypes. Simple univariate tests lack statistical power due to the need for multiple testing adjustment and not incorporating potential interplay between several genetic loci. Approaches based on internally constructed genetic risk scores (GRS) require the partitioning of the available sample into training and testing data sets, thus, lowering the effective sample size for testing the GxE interaction itself. To overcome these issues, we propose a statistical test that employs bagging (bootstrap aggregating) in the GRS construction step and utilizes its out-of-bag prediction mechanism. This approach has the key advantage that the full available data set can be used for both constructing the GRS and testing the GxE interaction. To also incorporate interactions between genetic loci, we, furthermore, investigate if using random forests as the GRS construction method in GxE interaction testing further increases the statistical power. In a simulation study, we show that both novel procedures lead to a higher statistical power for detecting GxE interactions, while still controlling the type I error. The random-forests-based test outperforms a bagging-based test that uses the elastic net as its base learner in most scenarios. An application of the testing procedures to a real data set from a German cohort study suggests that there might be a GxE interaction involving exposure to air pollution regarding rheumatoid arthritis.