Amyotrophic lateral sclerosis-associated mutant VAPBP56S perturbs calcium homeostasis to disrupt axonal transport of mitochondria

A proline-to-serine substitution at position 56 in the gene encoding vesicle-associated membrane protein-associated protein B (VAPB; VAPBP56S) causes some dominantly inherited familial forms of motor neuron disease, including amyotrophic lateral sclerosis (ALS) type-8. Here, we show that expression of ALS mutant VAPBP56S but not wild-type VAPB in neurons selectively disrupts anterograde axonal transport of mitochondria. VAPBP56S-induced disruption of mitochondrial transport involved reductions in the frequency, velocity and persistence of anterograde mitochondrial movement. Anterograde axonal transport of mitochondria is mediated by the microtubule-based molecular motor kinesin-1. Attachment of kinesin-1 to mitochondria involves the outer mitochondrial membrane protein mitochondrial Rho GTPase-1 (Miro1) which acts as a sensor for cytosolic calcium levels ([Ca2+]c); elevated [Ca2+]c disrupts mitochondrial transport via an effect on Miro1. To gain insight into the mechanisms underlying the VAPBP56S effect on mitochondrial transport, we monitored [Ca2+]c levels in VAPBP56S-expressing neurons. Expression of VAPBP56S but not VAPB increased resting [Ca2+]c and this was associated with a reduction in the amounts of tubulin but not kinesin-1 that were associated with Miro1. Moreover, expression of a Ca2+ insensitive mutant of Miro1 rescued defective mitochondrial axonal transport and restored the amounts of tubulin associated with the Miro1/kinesin-1 complex to normal in VAPBP56S-expressing cells. Our results suggest that ALS mutant VAPBP56S perturbs anterograde mitochondrial axonal transport by disrupting Ca2+ homeostasis and effecting the Miro1/kinesin-1 interaction with tubulin

'They Survive Despite The Organizational Culture, Not Because Of It': A Longitudinal Study Of New Staff Perceptions Of What Constitutes Support During The Transition To An Acute Tertiary Facility

Increasing difficulties of recruitment and retention of nursing staff strongly indicate that organizations should identify factors that contribute to successful transition of new staff to the workplace. Although many studies have identified problems facing new staff, fewer studies have articulated best practices. The purpose of this longitudinal study was to ascertain what new staff perceived as supportive elements implemented by the organization to assist their integration. Sixteen staff in Phase I and 12 staff in Phase II attended focus groups. The focus groups at 2-3 months provided specific information, with particular emphasis on negative interactions with other staff members and inadequate learning assistance and support. Different themes emerged within the focus groups at 6-9 months. Staff discussed being "self-reliant" and "getting to know the system". Participants indicated that these skills might be beneficial to new staff in the development of organizational "know how" and resourcefulness, rather than relying on preceptor support that, unfortunately, cannot be always guaranteed

Engineering a Microsurgical Training Tool for Vasectomy Reversals

We describe the development of an elastomer-molded vas model as a microsurgical training tool, particularly for vasectomy reversals. This microsurgical training tool is formed by molding polydimethylsiloxane into a vas deferens shape with a patent lumen through the use of a 3D printed mold and simple monofilament wires. The expanded use of our vas model as a microsurgical training tool will allow urologists in training to improve and develop their microsurgical skills outside of patient caseloads and without the need for extensive cadaveric or animal model practice

Digital Flexible Ureteroscope: Evaluating Factors Responsible for Damage and Implementing a Mandatory Certification Program for Usage

Objective: Digital flexible ureteroscopes (DFUs) play a crucial role in endourological procedures, and scope breakages are often avoidable with proper measures in place. We aimed to evaluate the effect of mandatory training on DFU durability and to assess the influence of various factors on instrument damage. Materials and Methods: Mandatory training involving instructional videos on DFU care was introduced for all processing and operating room staff handling DFUs. Only certified personnel were allowed to handle DFUs, with meticulous usage documentation. The average annual usage of each DFU was compared pre and post program implementation. We examined factors such as patient demographics, procedure details, and operator experience impacting scope life using negative binomial regression. Results: The average usage of DFU increased by 21%, from 6.38 to 7.74 cases. We found that post-graduate year stood out as a significant predictive factor (estimate = 3.28, p = 0.04). Moreover, the streamlined model revealed that previous ureteral-stent use (estimate = 0.94, p < 0.001), struvite stones (estimate = 3.08, p = 0.01), and a higher number of stones (estimate = 0.11, p = 0.04) were associated with an increased number of procedures before DFU breakage, whreas in situ lithotripsy in the lower calyx was associated with a reduced number of procedures before DFU breakage (estimate = -1.11, p = 0.003). Conclusion: Implementing a mandatory training program showed an increase in DFU durability by 21%, suggesting a potential reduction in annual repair and replacement costs by the same percentage. Furthermore, outcomes were more favorable when experienced practitioners conducted treatments, especially in cases involving struvite stones.Objective: Digital flexible ureteroscopes (DFUs) play a crucial role in endourological procedures, and scope breakages are often avoidable with proper measures in place. We aimed to evaluate the effect of mandatory training on DFU durability and to assess the influence of various factors on instrument damage. Materials and Methods: Mandatory training involving instructional videos on DFU care was introduced for all processing and operating room staff handling DFUs. Only certified personnel were allowed to handle DFUs, with meticulous usage documentation. The average annual usage of each DFU was compared pre and post program implementation. We examined factors such as patient demographics, procedure details, and operator experience impacting scope life using negative binomial regression. Results: The average usage of DFU increased by 21%, from 6.38 to 7.74 cases. We found that post-graduate year stood out as a significant predictive factor (estimate = 3.28, p = 0.04). Moreover, the streamlined model revealed that previous ureteral-stent use (estimate = 0.94, p < 0.001), struvite stones (estimate = 3.08, p = 0.01), and a higher number of stones (estimate = 0.11, p = 0.04) were associated with an increased number of procedures before DFU breakage, whreas in situ lithotripsy in the lower calyx was associated with a reduced number of procedures before DFU breakage (estimate = -1.11, p = 0.003). Conclusion: Implementing a mandatory training program showed an increase in DFU durability by 21%, suggesting a potential reduction in annual repair and replacement costs by the same percentage. Furthermore, outcomes were more favorable when experienced practitioners conducted treatments, especially in cases involving struvite stones