In Vitro Blood-Brain Barrier Models for Neuroinfectious Diseases: A Narrative Review.

The blood-brain barrier (BBB) is a complex, dynamic, and adaptable barrier between the peripheral blood system and the central nervous system. While this barrier protects the brain and spinal cord from inflammation and infection, it prevents most drugs from reaching the brain tissue. With the expanding interest in the pathophysiology of BBB, the development of in vitro BBB models has dramatically evolved. However, due to the lack of a standard model, a range of experimental protocols, BBB-phenotype markers, and permeability flux markers was utilized to construct in vitro BBB models. Several neuroinfectious diseases are associated with BBB dysfunction. To conduct neuroinfectious disease research effectively, there stems a need to design representative in vitro human BBB models that mimic the BBB's functional and molecular properties. The highest necessity is for an in vitro standardised BBB model that accurately represents all the complexities of an intact brain barrier. Thus, this in-depth review aims to describe the optimization and validation parameters for building BBB models and to discuss previous research on neuroinfectious diseases that have utilized in vitro BBB models. The findings in this review may serve as a basis for more efficient optimisation, validation, and maintenance of a structurally- and functionally intact BBB model, particularly for future studies on neuroinfectious diseases.

Liquid resistivity of pharmaceutical propellants using novel resistivity cell.

Metered-dose inhalers employ propellants to produce pharmaceutical aerosols for treating respiratory conditions like asthma. In the liquid phase, the DC volume resistivity of pharmaceutical propellants, including R134a, R152a, and R227ea, was studied at saturation pressures and room temperature (not vapour phase). These measurements are essential for industries like refrigerants. Aerosols from metered dose inhalers (MDIs) with these propellants become electrically charged, affecting medicament deposition in lung. The resistivity was measured using a novel concentric cylinder-type capacitance cell designed in-house. The resistivity for the propellants (R134a, R152a, and R227ea) was found to be 3.02 × 1010 Ωm, 2.37 × 109 Ωm and 1.31 × 1010 Ωm, respectively. The electrical resistivity data obtained was found to be at least two orders of magnitude higher than the limited data available in the literature. Challenges in the resistivity cell's development and performance are discussed, with a focus on various propellants and their mixtures with ethanol and moisture concentrations. The resistivity of propellant mixtures containing moisture concentrations ranging from 5 to 500 ppm and ethanol concentrations ranging between 1000 and 125,000 ppm was determined. The resistivity was tested across 10-min and 1-h periods and was performed in accordance with the contemporary IEC 60247 standard.

Pertuzumab Plus Trastuzumab in Patients With Endometrial Cancer With ERBB2/3 Amplification, Overexpression, or Mutation: Results From the TAPUR Study.

PURPOSE: The TAPUR Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with endometrial cancer (EC) with ERBB2 or ERBB3 (ERBB2/3) amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced EC, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2/3 amplification, overexpression, or mutation. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16 weeks (SD16+) duration. Secondary end points include safety, duration of response, duration of SD, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-eight patients were enrolled from March 2017 to November 2019; all patients were evaluable for efficacy and toxicity. Seventeen patients had tumors with ERBB2/3 amplification and/or overexpression, eight with both ERBB2 amplification and ERBB2/3 mutations, and three with only ERBB2 mutations. Ten patients had DC (two partial response and eight SD16+); all 10 had ERBB2 amplification, and 6 of the 10 patients with DC had >1 ERBB2/3 alteration. DC and OR rates were 37% (95% CI, 21 to 50) and 7% (95% CI, 1 to 24), respectively; the median PFS and median OS were 16 weeks (95% CI, 10-28) and 61 weeks (95% CI, 24-105), respectively. One patient experienced a grade 3 serious adverse event (muscle weakness) at least possibly related to P + T. CONCLUSION: P + T has antitumor activity in heavily pretreated patients with EC with ERBB2 amplification and warrants additional study.

Two-dimensional study of the inclusions of skirt sand and deep cement piles to improve the load‒displacement behavior of circular foundations on soft clay soil.

The bearing capacity of clayey soils is low, and the induced settlements play an important role in estimating the stability of structures built on these weak soils. Therefore, these clayey soils need improved mechanical strength. In this study, a two-dimensional finite element model was used to improve the bearing capacity and settlement of soft clay soil by employing skirt sand piles, and the results were compared with reinforced cement piles. Skirt sand piles consisting of thick sand cores and closed tubes placed under a circular shallow foundation with a steel plate of suitable dimensions, as well as reinforced cement piles of different lengths and in nondrained situations were studied. These calculations were carried out using PLAXIS 2D software, and a series of finite element analyses were performed. The Mohr‒Coulomb and hardening soil models were used to model the fine-grained and granular soils, respectively. A linear elastic model was used to simulate the circular plate and skirt components. Previous experimental studies were used to validate the numerical model. The experimental test and the 2D axisymmetric model agree well. According to the assumptions, the efficiency of skirt sand piles is superior to that of deep cement piles. In addition, increasing the length of SSP skirt sand piles has a significantly greater effect on improving the bearing capacity than increasing the length of deep cement piles. As a consequence, the failure modes of piles with skirt sand were determined. It was found that the failure mode when skirt sand piles were tied into clayey soils occurred in the underlying sandy soil layer as a general shear failure.

Intravitreal methotrexate in vemurafenib-induced uveitis.

PURPOSE: Vemurafenib, a BRAF inhibitor, has revolutionized the prognosis of late-stage melanoma patients, rising at the same time concerns about its potential adverse effects. Here is a case of vemurafenib-induced uveitis, peculiar in both its presentation and management. METHODS: Case report, diagnostic and therapeutic challenge. RESULTS: Uveitis is a known side effect of vemurafenib. It is generally bilateral, moderate, manageable with topical steroids and does not require cancer therapy cessation. We present a patient who suffered from a unilateral, severe uveitis following vemurafenib treatment that fully recovered thanks to intravitreal methotrexate injections, as conventional corticosteroid therapy was contraindicated. CONCLUSION: Uveitis can be a serious ocular adverse effect of vemurafenib, while its risks factors and mechanisms remain unknown. As BRAF inhibitors are now used on a regular basis, it is important for clinicians to be aware of this potentially sight-threatening side effect. Intravitreal methotrexate injections may be considered as an effective treatment choice in severe targeted agents-induced uveitis.

Positive Pressure and Negative Pressure Irrigation Dynamics with Different Needle Designs Using Computational Fluid Dynamics

@#This study aimed to investigate the irrigation dynamics of the positive pressure side-vented (SV) needle, EndoVac (micropores) needle and modified apical negative pressure (mANP) open-ended needle using computational fluid dynamics (CFD). A simulation of a prepared root canal (conical frustum) of 15 mm length with an apical diameter of 0.40 mm following Protaper F4 apical preparation was created using three-dimensional (3D) CAD software. The 3D simulated needle of SV 30G needle, EndoVac with micropores needle and mANP, 30G flat open-ended needle were also created. The irrigation dynamics were evaluated through transient CFD simulations. In addition, the irrigation dynamics of mANP at 0.2 mm, 0.5 mm, and 1.0 mm short from the working length were also assessed. The EndoVac and mANP showed negative apical static pressure and streamline patterns able to reach the apical region, thus indicating negligible extrusion. Meanwhile, SV showed positive apical static pressure and almost nonexistent streamlines beyond the needle tip. The SV showed the highest wall shear stress (WSS) magnitude of 1030Pa whereas Endovac (161 Pa) and mANP1 (258 Pa). However, SV revealed lower average WSS (10 Pa) compared to mANP1 (13 Pa) and mANP2 (11 Pa). This is due to SV developed a localised maximum WSS opposite the open vent area only therefore, uneven distribution of WSS. The EndoVac system developed a localised maximum WSS in the pair of micropores furthest away from the apical. CFD analysis of the EndoVac, mANP and SV showed different technique approach, needle design and needle depths insertion affect the irrigation dynamics pattern and magnitude.

Sustainability effect of geogrid reinforced tire-shred sand mixtures on the load pressure-settlement response of shallow footing.

This study aims to observe the possibility of using tire shreds as sustainable waste materials by including a geogrid wrap-around sheet to improve the response of load-settlement of the sandy bed. Therefore, a series of physical modeling tests were conducted to investigate the behavior of tyre-shred-geogrid reinforced sand under static plate loading. Experimental tests on tire-shred sand reinforced with geogrid sheets were carried out in the first step. Next, laboratory tests were conducted on tire-shredded sand with geogrid wraparound sheets, and the results were compared with the initial experiment. In terms of the parameters studied, the total depth of the tire-shred with planar and wraparound layers, the length and overlaps of the wraparound layers, and the space between the wraparound geogrid sheets were analyzed. According to the results, the inclusion of tire-shields in reinforced soil foundations with wraparound geogrid layers significantly improved the load-bearing capacity. Additionally, both planar and folded geogrid sheets had bearing capacity ratios greater than 3 and 4.5. The carrying capacity of soil-tire shred reinforced with inclusion of geogrid sheet is superior to that of geogrid-reinforced soil without tire shred.

Post-COVID-19 Secondary Sclerosing Cholangitis: A Rare but Severe Condition with no Treatment Besides Liver Transplantation.

BACKGROUND The incidence of abnormal liver function, mainly aspartate aminotransferase and alanine aminotransferase elevations, in patients with COVID-19 is not uncommon, but persistent liver damage after the acute phase of the disease is uncommon and has been recently recognized as a new entity named post-COVID-19 cholangiopathy. CASE REPORT We report a clinical case with progressive cholestatic disease following severe COVID-19. AST and ALT peaked at hospital admission and while its serum concentration went down, bilirubin and cholestatic liver enzymes started to increase, reaching the maximum at day 122. Magnetic resonance imaging (MRI) revealed a diffuse irregularity of intra- and extrahepatic bile ducts, with multiple focal strictures alternating with mild focal dilations of the biliary tree, suggesting a sclerosing cholangiopathy. A transjugular liver biopsy showed a prominent bile ductular reaction, cholangiocyte injury, inflammatory infiltrate rich in neutrophils, biliary infarctions, marked cholestasis, and portal fibrosis, suggesting the diagnosis of post-Covid-19 secondary sclerosing cholangitis. The patient evolved with a continuous deterioration of liver functions, but liver transplantation was not performed due to his poor clinical condition. CONCLUSIONS Post-COVID-19 SSC is a severe disease with no effective clinical treatment and has liver transplantation as the only treatment for a few selected patients.

Pulmonary haemorrhage as the earliest sign of severe leptospirosis in hamster model challenged with Leptospira interrogans strain HP358.

BACKGROUND: Severe leptospirosis is challenging as it could evolve rapidly and potentially fatal if appropriate management is not performed. An understanding of the progression and pathophysiology of Leptospira infection is important to determine the early changes that could be potentially used to predict the severe occurrence of leptospirosis. This study aimed to understand the kinetics pathogenesis of Leptospira interrogans strain HP358 in the hamster model and identify the early parameters that could be used as biomarkers to predict severe leptospirosis. METHODOLOGY/PRINCIPAL FINDINGS: Male Syrian hamsters were infected with Leptospira interrogans strain HP358 and euthanized after 24 hours, 3, 4, 5, 6 and 7 days post-infection. Blood, lungs, liver and kidneys were collected for leptospiral detection, haematology, serum biochemistry and differential expression of pro- and anti-inflammatory markers. Macroscopic and microscopic organ damages were investigated. Leptospira interrogans strain HP358 was highly pathogenic and killed hamsters within 6-7 days post-infection. Pulmonary haemorrhage and blood vessel congestion in organs were noticed as the earliest pathological changes. The damages in organs and changes in biochemistry value were preceded by changes in haematology and immune gene expression. CONCLUSION/SIGNIFICANCE: This study deciphered haemorrhage as the earliest manifestation of severe leptospirosis and high levels of IL-1ß, CXCL10/IP-10, CCL3/MIP-α, neutrophils and low levels of lymphocytes and platelets serve as a cumulative panel of biomarkers in severe leptospirosis.

Measurement of gross alpha and beta activity concentration in groundwater of Jordan: groundwater quality, annual effective dose and lifetime risk assessment.

The current study was conducted to measure the activity concentration of the gross alpha and beta in 87 groundwater samples collected from the productive aquifers that constitute a major source of groundwater to evaluate the annual effective dose and the corresponding health impact on the population and to investigate the quality of groundwater in Jordan. The mean activity concentration of gross alpha and beta in groundwater ranges from 0.26 ± 0.03 to 3.58 ± 0.55 Bq L-1 and from 0.51 ± 0.07 to 3.43 ± 0.46 Bq L-1, respectively. A very strong relationship was found between gross alpha and beta activity concentrations. The annual effective dose for alpha and beta was found in the range of 0.32-2.40 mSv with a mean value of 0.89 mSv, which is nine times higher than the World Health Organization (WHO) recommended limit and one and half times higher than the national regulation limit. The mean lifetime risk was found to be 45.47 × 10-4 higher than the Jordanian estimated upper-bound lifetime risk of 25 × 10-4. The data obtained in the study would be the baseline for further epidemiological studies on health effects related to the exposure to natural radioactivity in Jordan.

Implementation and Outcomes of a Molecular Tumor Board at Herbert-Herman Cancer Center, Sparrow Hospital.

OBJECTIVE: This paper describes our experience and outcomes from 54 cases presented to the (Molecular tumor board) MTB. METHODS: 54 Cases presented between July 2017 and April 2018 were included in this analysis. These patients had different types of cancers that had either failed standard therapy or were expected to fail and physicians were looking for future options for anticipated progression. Patients who had obvious mutations and were candidates for Targeted Agent and Profiling Utilization Registry or Molecular Analysis for Treatment Choice clinical trials were not included. Oncologists presented the cases virtually and Foundation Medicine scientific and clinical team discussed the molecular pathways to find targeted options or trials. Tumor board attendees included oncologists, nurses, pharmacists, mid-level providers, residents and staff of the Cancer Center. RESULTS: Amongst the 54 cases presented 81% had one or more potentially actionable alteration. 12 (22%) patients received genomically matched therapy as per MTB recommendations. Additional 13 (24%) patients have options available when they progress. Out of 12 patients who got treatment six are alive at the time of this analysis. Genomically matched therapy or Clinical Trials option were offered to the 46% of patients based on the MTB discussion. CONCLUSION: More widespread use of molecular diagnostics, better physician education and multidisciplinary collaboration between the staff involved in diagnosis and treatment, as well as third party payers are necessary for consensus on treatment and care of oncology patients.

Statistical relationship between activity concentrations of radionuclides 226Ra, 232Th, 40K, and 137Cs and geological formations in surface soil of Jordan.

An extensive study was conducted to determine the activity concentrations of natural and artificial radionuclides 226Ra, 232Th, 40K, and 137Cs in soil samples of each governate of Jordan. A total of 370 samples have been measured using a high-purity germanium detector. The activity concentration for 226Ra, 232Th, 40K, and 137Cs has mean values of 42 ± 3, 23 ± 3, 309 ± 21, and 3.7 ± 0.9 Bq kg-1, respectively. The highest mean activity concentration for 226Ra was found to be 138 ± 4 Bq kg-1 in the Alkarak governate. In the Ajloun and Jarash governates, the highest mean activity concentration was 35 ± 3 Bq kg-1 for 232Th, and 14.2 ± 1.9 Bq kg-1 for 137Cs, respectively. Geological influence on the activity concentrations was investigated using the one-way analysis of variance (ANOVA) and independent samples. The ANOVA results indicate that there are strong significant differences between the activity concentrations of 232Th, 40K, and 137Cs based on geological formations the radionuclides occur. The main contribution to gamma dose rate was due to 226Ra activity concentration. Radium equivalent and external hazard index are associated with a mean value of 98 Bq kg-1, and 0.266, respectively.

Checkpoint inhibitors in the treatment of brain metastases of non-small-cell lung cancer and melanoma.

Brain metastases (BMs) are representing a new challenge for the oncologist; their incidence is increasing due to the better overall survival and systemic disease control in many malignancies, consequent to new potent cytotoxic and targeted therapies. In the era of immunotherapies, checkpoint inhibitors are representing a new therapeutic option in different solid tumors and settings; preliminary results showed potential activity of these agents in patients with BM, when administered as single agent or in combination with radiation therapy. After presenting the arguments in favor of this new strategy, we reported the preliminary results of the trials evaluating these agents in BM, we described the ongoing trials and we discussed the potential role of these agents in the BM treatment.

Learning from the "tsunami" of immune checkpoint inhibitors in 2015.

2015 was marked by the tsunami of immune checkpoint inhibitors revealed by numerous FDA approvals, publications and abstracts in relation with these drugs in different cancers and settings. First, we reported all new indications of anti-CTLA4 and anti-PD1 approved by the FDA, the positive clinical trials published and the abstracts with promising results at important scientific meetings during 2015. Then, we discussed different critical issues of these new agents going from their predictive factors, combination therapies, tumor response patterns, efficacy in particular settings, side effect management to cost and economic burden.

In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci.

BACKGROUND: Studies have shown the efficacy of intra-partum antibiotics in preventing early-onset group B streptococcal sepsis. This approach results in a high intra-partum antibiotic use. Worryingly, the same antibiotics used in prophylaxis are also first-line treatment for neonatal sepsis, and antibiotic exposure in the peri-natal period has been shown to be a risk factor for late-onset serious bacterial infections and allergic disease. Antibiotic exposure in the peri-natal period is becoming a major public health issue; alternative strategies are needed. Garlic has been traditionally used to treat vaginal infections. Allicin is the main antibacterial agent isolated from garlic. OBJECTIVES: The aim of the study was to investigate the in vitro activity of a novel allicin extract in aqueous and gel formulation against 76 clinical isolates of Lancefield group B streptococci (GBS). METHODS: MICs and MBCs of allicin were determined for 76 GBS isolates by agar dilution and microtitre plate methods. Killing kinetics were determined for a selected 16 of the 76 strains. Agar diffusion tests were compared for allicin liquid and gel (500 mg/L). RESULTS AND CONCLUSIONS: MICs and MBCs of allicin liquid were 35 to 95 mg/L and 75 to 315 mg/L, respectively. Time/dose kill curves produced a 2-3 log reduction in cfu/mL within 3 h and no detectable growth at 8 and 24 h. A novel 500 mg/L allicin gel produced an average zone size of 23+/-6 mm compared with 21+/-6 mm for allicin in water. Aqueous allicin is bactericidal against GBS isolates and maintains activity in a novel gel formulation.