Pull me - push you? The disparate financing mechanisms of drug research in global health.

BACKGROUND: There is an inconsistency in the way pharmaceutical research is financed. While pull mechanisms are predominantly used to incentivize later-stage pharmaceutical research for products with demand in the Global North, so-called neglected diseases are chiefly financed by push funding. This discrepancy has so far been ignored in the academic debate, and any compelling explanation for why we draw the line between push and pull at poor people is lacking. MAIN BODY: Clinical development of new pharmaceuticals is chiefly financed by free market pull mechanisms. Even in cases where markets fail to deliver adequate incentives, demand enhancement mechanisms are used to replicate pull funding artificially, for example, with subscription models for antibiotics. Push funding in clinical research is almost always used when the poverty of patients means that markets fail to create sufficient demand. The general question of whether push or pull generally is the more efficient way to conduct pharmaceutical research arises. CONCLUSIONS: If the state is efficient in directing limited budgets for pharmaceutical research, push funding should be expanded to global diseases. If private industry is the more efficient actor, there would be enormous value in experimenting more aggressively with different approaches to enhance market demand artificially for neglected diseases.

Impact of Portal Vein Resection (PVR) in Patients Who Underwent Curative Intended Pancreatic Head Resection.

The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients' outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon.

Open source fraction collector/MALDI spotter for proteomics.

We describe a complete open-source hardware/software solution for high performance thermostatted peptide fraction collection to support mass spectrometry experiments with complex proteomes. The instrument is easy to assemble using parts readily available through retail channels at a fraction of the cost compared to typical commercial systems. Control software is written in Python allowing for rapid customization. We demonstrate several useful applications, including the automated deposition of LC separated peptides for matrix-assisted laser desorption ionization mass spectrometry (MALDI-MS) as well as collection and concatenation of peptide fractions from nanoflow HPLC separations.

The history of renal transplantation in Canada: A urologic perspective.

While the urologist's involvement in kidney transplantation varies from center to center and country to country, urologists remain integral to many programs across Canada. From the early days of kidney transplant to contemporary times, the leadership, vision, and skillset of Canadian urologists have helped progress the field. In this review of Canadian urologists' role in kidney transplantation, the achievements of this professional group are highlighted and celebrated. Original contributors to the field, as well as notable achievements are highlighted, with a focus on the impact of Canadian urologists.

Rapid acquisition of dynamic control over DLPFC using real-time fMRI feedback.

It has been postulated that gaining control over activity in the dorsolateral prefrontal cortex (DLPFC), a key region of the working memory brain network, may be beneficial for cognitive performance and treatment of certain psychiatric disorders. Several studies have reported that, with neurofeedback training, subjects can learn to increase DLPFC activity. However, improvement of dynamic control in terms of switching between low and high activity in DLPFC brain states may potentially constitute more effective self-regulation. Here, we report on feasibility of obtaining dynamic control over DLPFC, meaning the ability to both in- and decrease activity at will, within a single functional MRI scan session. Two groups of healthy volunteers (N = 24) were asked to increase and decrease activity in the left DLPFC as often as possible during fMRI scans (at 7 Tesla), while receiving real-time visual feedback. The experimental group practiced with real-time feedback, whereas the control group received sham feedback. The experimental group significantly increased the speed of intentionally alternating DLPFC activity, while performance of the control group did not change. Analysis of the characteristics of the BOLD signal during successful trials revealed that training with neurofeedback predominantly reduced the time for the DLPFC to return to baseline after activation. These results provide a preliminary indication that people may be able to learn to dynamically down-regulate the level of physiological activity in the DLPFC, and may have implications for psychiatric disorders where DLPFC plays a role.

CMOS detector arrays in a virtual 10-kilopixel camera for coherent terahertz real-time imaging.

We demonstrate the principle applicability of antenna-coupled complementary metal oxide semiconductor (CMOS) field-effect transistor arrays as cameras for real-time coherent imaging at 591.4 GHz. By scanning a few detectors across the image plane, we synthesize a focal-plane array of 100×100 pixels with an active area of 20×20 mm2, which is applied to imaging in transmission and reflection geometries. Individual detector pixels exhibit a voltage conversion loss of 24 dB and a noise figure of 41 dB for 16 µW of the local oscillator (LO) drive. For object illumination, we use a radio-frequency (RF) source with 432 µW at 590 GHz. Coherent detection is realized by quasioptical superposition of the image and the LO beam with 247 µW. At an effective frame rate of 17 Hz, we achieve a maximum dynamic range of 30 dB in the center of the image and more than 20 dB within a disk of 18 mm diameter. The system has been used for surface reconstruction resolving a height difference in the µm range.

Role of the renin-angiotensin system in the compensation of quinpirole-induced blood pressure decrease.

The dopamine D(2)-like receptor agonist quinpirole has been reported to lower blood pressure. This effect appears to be mediated via activation of presynaptic D(2)-like receptors inhibiting the stimulated neural norepinephrine release. The aim of the present study was to investigate the role of renal nerves and the renin-angiotensin system (RAS) in the blood pressure lowering effect of quinpirole. Therefore, clearance experiments using different doses of quinpirole (0.3 to 100 microg/kg/min) were performed in thiopental-anesthetized rats with intact kidneys (INN) or 5 to 7 days after bilateral renal denervation (DNX). The functional involvement of the RAS in the blood pressure lowering effect of quinpirole was determined in rats pretreated with a subpressor dose of angiotensin II (10 microg/kg/min) or in rats pretreated with the angiotensin II (AT(1)) receptor antagonist losartan, in a subdepressor dose (10 microg/kg/min). Quinpirole dose-dependently decreased mean arterial blood pressure (MAP) by up to 29%. This blood pressure lowering effect of quinpirole was observed at lower doses in DNX rats when compared with INN animals (ED(50): 0.98 microg/kg/min in DNX vs. 6.02 microg/kg/min in INN animals). Quinpirole in a dose of 3 microg/kg/min, which did not affect MAP in vehicle treated INN rats, significantly reduced MAP in rats with losartan pretreatment. In DNX rats pretreated with angiotensin II the MAP-response to the infusion of 3 microg/kg/min quinpirole was clearly attenuated in comparison with untreated DNX animals. Our data show that stimulation of dopamine D(2)-like receptors dose-dependently decreased blood pressure, which was potentiated by both interruption of the renal innervation and AT(1) receptor blockade, while exogenous ANG II restored the enhancement of the blood pressure response to quinpirole. We conclude that the increased vasodilatory effect of quinpirole after renal denervation might depend on a decreased activity of the RAS.