Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates

Preclinical development of vaccine candidates is an important link between the discovery and manufacture of vaccines for use in human clinical trials. Here, an exploratory clinical study utilizing multiple gp120 envelope proteins as vaccine antigens was pursued, which required a harmonized platform development approach for timely and efficient manufacture of the combined HIV vaccine product.Development of cell lines, processes, and analytical methods was initiated with a transmitted founder envelope protein (CH505TF), then applied to produce three subsequent gp120 Env (envelope) variants. Cell lines were developed using the commercially available Freedom CHO DG44 kit (Life Technologies). The fed-batch cell culture production process was based on a commercially-available medium with harmonized process parameters across the variants. A platform purification process was developed utilizing a mixed mode chromatography capture step, with ceramic hydroxyapatite and ion exchange polishing steps. A suite of analytical methods was developed to establish and monitor the Quality Target Profile (QTP), release and long-term stability testing of the vaccine products.The platform development strategy was successfully implemented to produce four gp120 envelope protein variants. In some cases, minor changes to the platform were required to optimize for a particular variant; however, baseline conditions for the processes (cell line type, media & feed system, chromatography resins, and analytical approaches) remained constant, leading to successful transfer and manufacture of all four proteins in a cGMP facility.This body of work demonstrates successful pursuit of a platform development approach to manufacture important vaccine candidates and can be used as a model for other vaccine glycoproteins, such as HIV gp140 trimers or other viral glycoproteins with global health implications.Clinical trial identifier.NCT03220724, NCT03856996.     

Tuber-to-Anterior Process Angle (TAPA): A cadaveric study and surgical technique for placing axial calcaneal screws

We describe results of a cadaveric study and an accompanying surgical technique which simplifies posterior-to-anterior axial screw placement into the calcaneus, often utilized during fixation of displaced intra-articular calcaneus fractures or calcaneal osteotomies. By defining the Tuber-to-Anterior Process Angle (TAPA), this technique facilitates axial screw placement, thereby decreasing reliance on intraoperative fluoroscopy and reducing operative time.     

Chondrocytes from Different Zones Exhibit Characteristic Differences in High Density Culture

Superficial and middle/deep zone chondrocytes were isolated from goat femoral cartilage by a zonal abrasion method. The cells were expanded 100-fold through two passages, then seeded into agarose wells to form high-density constructs through a self-assembling process. After 4 weeks in culture, the superficial zone constructs contracted into a dense cell mass, while middle/deep zone chondrocytes formed constructs with four distinct regions. Middle/deep zone chondrocytes produced 250% more glycosaminoglycans per dry weight and more collagen per dry weight than superficial zone chondrocytes. The superficial and middle/deep zone chondrocytes were found to retain characteristic differences even after 100-fold expansion, as evidenced by construct morphology and extracellular matrix content. This study uniquely demonstrated the ability of expanded superficial and middle/deep zone chondrocytes to form constructs of distinct characteristics without a scaffold. The goal of tissue engineering different zones of cartilage is to eventually replicate the specific function of each zone.     

Clinical implementation of systematic medication reconciliation and review as part of the Lund Integrated Medicines Management model – impact on all‐cause emergency department revisits

What is known and objective: Interventions involving medication reconciliation and review by clinical pharmacists can reduce drug‐related problems and improve therapeutic outcomes. The objective of this study was to examine the impact of routine admission medication reconciliation and inpatient medication review on emergency department (ED) revisits after discharge. Secondary outcomes included the combined rate of post‐discharge hospital revisits or death. Methods: This prospective, controlled study included all patients hospitalized in three internal medicine wards in a university hospital, between 1 January 2006 and 31 May 2008. Medication reconciliation on admission and inpatient medication review, conducted by clinical pharmacists in a multiprofessional team, were implemented in these wards at different times during 2007 and 2008 (intervention periods). A discharge medication reconciliation was undertaken in all the study wards, during both control and intervention periods. Patients were included in the intervention group (n = 1216) if they attended a ward with medication reconciliation and review, whether they had received the intervention or not. Control patients (n = 2758) attended the wards before implementation of the intervention. Results and Discussion: No impact of medication reconciliation and reviews on ED revisits [hazard ratio (HR), 0·95; 95% confidence interval (CI), 0·86–1·04]or event‐free survival (HR, 0·96; 95% CI, 0·88–1·04) was demonstrated. In the intervention group, 594 patients (48·8%) visited the ED, compared with 1416 (51·3%) control patients. In total, 716 intervention (58·9%) and 1688 (61·2%) control patients experienced any event (ED visit, hospitalization or death). Because the time to a subsequent ED visit was longer for the control as well as the intervention groups in 2007 than in 2006 (P < 0·05), we re‐examined this cohort of patients; the proportion of patients revisiting the ED was similar in both groups in 2007 (P = 0·608). What is new and conclusion: Routine implementation of medication reconciliation and reviews on admission and during the hospital stay did not appear to have any impact on ED revisits, re‐hospitalizations or mortality over 6‐month follow‐up.     

Investigation of the effects of process variables on derived properties of spray dried solid-dispersions using polymer based response surface model and ensemble artificial neural network models

The objective of this study was to use different statistical tools to understand and optimize the spray drying process to prepare solid dispersions. In this study we investigated the relationship between input variables (inlet temperature, feed concentration, flow rate, solvent and atomization parameters) and quality attributes (yield, outlet temperature and mean particle size) of spray dried solid dispersions (SSDs) using response surface model and ensemble artificial neural network. The Box Behnken design was developed to investigate the effect of various input variables on quality attributes of final products. Moreover, Pearson correlation analysis, self organizing map, contour plots and response surface plot were used to illustrate the relationship between input variables and quality attributes. The influence of different physicochemical properties of solvent on the quality attributes of spray dried products was also investigated. Final validation of prepared models was done using binary SSDs of six model drugs with PVP. Results demonstrated the effectiveness of proposed PVP based model which can help scientists to gain detailed understanding of spray drying process of solid dispersion using minimal resources and time during early formulation development stage. It will also help them to ensure consistent quality of SSDs using broad range of input variables.     

Learning in Psychotherapy Group Supervision: Transcending Complementarity and the Generative Potential of Group Conflict

At the site of interpersonal conflict resides the potential for learning. This paper presents psychodynamic theories, empirical research and a fictional case study of psychotherapy group supervision. Supervision is discussed in terms of teaching and learning, triangular relations, and group and organizational perspectives. We examine the interconnectedness of patterns of distress that emerge within dynamic relational systems at the levels of the macro‐social, organizational, group and individual. The concepts of equivalence, parallel process and reflection process provide frameworks for this discussion. We explore the constraints and dynamic influence of the organization upon the supervision relationship and the ethical tensions that construct im/possible positions for the supervisor. The case study tells a fictional story of a supervision group situated in an organizational context – a university psychotherapy education programme. A collapse of the group into complementarity, that is into polarized conflicted positions, proffers a vitalizing opportunity for learning. Through the clinical discussion, we reveal how this is contingent on the group's capacity to think together about the meaning of their struggle and to transcend a binary conflict and achieve ‘the third’.     

Autopage and the Use of Computer Scripts to Automate Microtasks

Paging referring clinicians with imaging results is a frequently repeated “microtask” performed by practicing radiologists. Many institutions use online alpha-paging systems to provide this integral part of safe and efficient patient care. Although sending an alpha-page can often be accomplished within one minute, current tools may disrupt workflow by distracting users with a series of tedious mouse clicks. We describe the development, evaluation, and updates of a portable tool that sends alpha-pages to referring clinicians using two keystrokes. This software integrates study information obtained from the Picture Archiving and Communication System (PACS) with an existing hospital paging system.     

“The Gaze Heuristic:” Biography of an Adaptively Rational Decision Process

This article is a case study that describes the natural and human history of the gaze heuristic. The gaze heuristic is an interception heuristic that utilizes a single input (deviation from a constant angle of approach) repeatedly as a task is performed. Its architecture, advantages, and limitations are described in detail. A history of the gaze heuristic is then presented. In natural history, the gaze heuristic is the only known technique used by predators to intercept prey. In human history the gaze heuristic was discovered accidentally by Royal Air Force (RAF) fighter command just prior to World War II. As it was never discovered by the Luftwaffe, the technique conferred a decisive advantage upon the RAF throughout the war. After the end of the war in America, German technology was combined with the British heuristic to create the Sidewinder AIM9 missile, the most successful autonomous weapon ever built. There are no plans to withdraw it or replace its guiding gaze heuristic. The case study demonstrates that the gaze heuristic is a specific heuristic type that takes a single best input at the best time (take the best²). Its use is an adaptively rational response to specific, rapidly evolving decision environments that has allowed those animals/humans/machines who use it to survive, prosper, and multiply relative to those who do not.