Impact of material properties and process parameters on tablet quality in a continuous direct compression line

The current paper shows how excipient properties impact the process parameters and the final tablet properties in a fully integrated continuous direct compression line. Blend properties of low-dose (1% w/w) and high-dose (40% w/w) paracetamol formulations were evaluated and linked to the blending and tableting performance via multivariate models (Partial Least Squares analysis, PLS). Feeding behavior was analyzed separately, as the amount of active pharmaceutical ingredient (API) that ended into tablets was driven by random fluctuations in the API feeding behavior. The developed PLS models elucidated that formulation behavior was mainly driven by the concentration of the active pharmaceutical ingredient (API), explained by the distinct API properties. Excipient properties also had a substantial impact on formulation behavior. Generally, formulations with microcrystalline cellulose as a filler showed better compactability, lower hold-up mass, lower flowability and higher cohesion than formulations with different lactose grades. The relative performance of a formulation with different fillers differed for 1% w/w and 40% w/w drug loading. Granular and spray dried lactose grades increased in compactability ranking compared to anhydrous lactose when evaluating higher drug loading, due to the difference in morphology. It was shown that besides understanding the impact of excipients on the formulation performance, processability of ingredients is crucial for formulation design.</p

Exacerbated inflammatory signaling underlies aberrant response to BMP9 in pulmonary arterial hypertension lung endothelial cells

Imbalanced transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) signaling are postulated to favor a pathological pulmonary endothelial cell (EC) phenotype in pulmonary arterial hypertension (PAH). BMP9 is shown to reinstate BMP receptor type-II (BMPR2) levels and thereby mitigate hemodynamic and vascular abnormalities in several animal models of pulmonary hypertension (PH). Yet, responses of the pulmonary endothelium of PAH patients to BMP9 are unknown. Therefore, we treated primary PAH patient-derived and healthy pulmonary ECs with BMP9 and observed that stimulation induces transient transcriptional signaling associated with the process of endothelial-to-mesenchymal transition (EndMT). However, solely PAH pulmonary ECs showed signs of a mesenchymal trans-differentiation characterized by a loss of VE-cadherin, induction of transgelin (SM22α), and reorganization of the cytoskeleton. In the PAH cells, a prolonged EndMT signaling was found accompanied by sustained elevation of pro-inflammatory, pro-hypoxic, and pro-apoptotic signaling. Herein we identified interleukin-6 (IL6)-dependent signaling to be the central mediator required for the BMP9-induced phenotypic change in PAH pulmonary ECs. Furthermore, we were able to target the BMP9-induced EndMT process by an IL6 capturing antibody that normalized autocrine IL6 levels, prevented mesenchymal transformation, and maintained a functional EC phenotype in PAH pulmonary ECs. In conclusion, our results show that the BMP9-induced aberrant EndMT in PAH pulmonary ECs is dependent on exacerbated pro-inflammatory signaling mediated through IL6

Een vrouw met hevige buikpijn en eerdere endometriose

A 44yearold woman came to the emergency department with severe pain in the right upper abdomen. Her medical history mentioned a low anterior resection 8 years ago because of severe endometriosis. The CT scan showed a ruptured right hemidiaphragm with herniation of the small intestine

Gross handling of pulmonary resection specimen: Maintaining the 3-dimensional orientation

There is limited literature on the gross handling of lung resection specimens. Microscopic examination of the specimen, TNM staging and predictive biomarker testing are fully dependent on an adequate gross handling. In this paper, we present a 3-dimensional (3D) grossing method of oncological lung resection specimens, which ensures proper fixation of the tumor tissue, but also enables accurate correlation with the pre-surgical imaging

Gross handling of pulmonary resection specimen: Maintaining the 3-dimensional orientation

There is limited literature on the gross handling of lung resection specimens. Microscopic examination of the specimen, TNM staging and predictive biomarker testing are fully dependent on an adequate gross handling. In this paper, we present a 3-dimensional (3D) grossing method of oncological lung resection specimens, which ensures proper fixation of the tumor tissue, but also enables accurate correlation with the pre-surgical imaging

Saved from a fatal flight: A ruptured splenic artery aneurysm in a pregnant woman

Introduction: The reported prevalence of a SAA varies between 0.01 and 10.4% [1], and since SAAs often remain asymptomatic, the true prevalence is uncertain. The reported SAAs occur more frequently in younger patients, with 58% diagnosed in women of childbearing age; 95% of these are diagnosed during pregnancy. Presentation of case: A 26-year-old woman, thirty-one weeks pregnant, was about to board an airplane for a three hour flight from the Netherlands to Turkey. Just before entering the plane, she suddenly felt a severe abdominal pain. Ultrasound guided aspiration of the abdominal fluid showed blood and supported the decision to perform urgent laparotomy. A caesarean section was performed. After further inspection a ruptured SAA was encountered. The splenic artery was ligated proximally and distally to the rupture in order to stop the bleeding. As the hilar localization of the aneurysm interfered with a primary vascular reconstruction, a splenectomy was performed. The mother and baby survived. Discussion: Although rupture of a SAA is rare, its consequences can be devastating for both mother and child. The literature shows a higher incidence of ruptured SAA in pregnant women, although there is a difficulty in recognizing hemodynamic instability in pregnancy due to the increase in circulating volume. Conclusion: In case of pregnant women with acute abdomen and hypovolemia, emergency physicians, surgeons, anesthesiologists, and gynecologists should be aware of the possibility of a ruptured SAA, apart from more common causes like placental abruption, placenta percreta, or uterine rupture. Early recognition and prompt multidisciplinary treatment might save the life of mother and child

Salvage surgery for local recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: a systematic review

Introduction: Stereotactic body (or ablative) radiotherapy (SBRT/SABR) is now a guideline-recommended treatment for medically inoperable patients with peripherally-located, stage I non-small cell lung cancer (NSCLC), and for medically operable patients who decline surgery. The 5-year local failure rate after SBRT is about 10% and in highly selected patients, surgery has been used as a salvage therapy. We performed a systematic review to address the feasibility, safety, and outcome of salvage surgery for locally recurrent early stage NSCLC after SBRT. Methods: A systematic literature search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed, Embase and Cochrane databases were searched and two authors independently assessed the articles. A total of seven eligible articles were identified. Results: All seven articles were retrospective case series, representing a total of 47 patients. Surgery was completed in all patients. Where reported in sufficient detail, morbidity (four studies) was between 29 and 50% (series of two patients) and 90-day mortality (six studies) was between 0% (four studies) and 11% ( n = 1, disease progression). Median ( n = 5)/mean ( n = 1) reported or calculated follow ups were 7–54.5/17.3 months. Median overall survival was reported in three studies and ranged between 13.6–82.7 months. Crude survival in three others was 2–35 months. Conclusion: Limited, low-level evidence prevents firm conclusions, but based on the existing data, salvage surgery after local recurrence of NSCLC following SBRT appears technically feasible, with acceptable morbidity and mortality in appropriately selected and counselled patients who are fit enough and who accept the risks (level of evidence 4, strength of recommendation C)