A class of low-cost alternatives to kifunensine for increasing high mannose N-linked glycosylation for monoclonal antibody production in Chinese hamster ovary cells.

N-linked glycosylation of therapeutic monoclonal antibodies is an important product quality attribute for drug safety and efficacy. An increase in the percent of high mannose N-linked glycosylation may be required for drug efficacy or to match the glycosylation profile of the innovator drug during the development of a biosimilar. In this study, the addition of several chemical additives to a cell culture process resulted in high mannose N-glycans on monoclonal antibodies produced by Chinese hamster ovary (CHO) cells without impacting cell culture performance. The additives, which include known mannosidase inhibitors (kifunensine and deoxymannojirimycin) as well as novel inhibitors (tris, bis-tris, and 1-amino-1-methyl-1,3-propanediol), contain one similar molecular structure: 2-amino-1,3-propanediol, commonly referred to as serinol. The shared chemical structure provides insight into the binding and inhibition of mannosidase in CHO cells. One of the novel inhibitors, tris, is safer compared to kifunensine, 35x as cost-effective, and stable at room temperature. In addition, tris and bis-tris provide multiple low-cost alternatives to kifunensine for manipulating glycosylation in monoclonal antibody production in a cell culture process with minimal impact to productivity or cell health.

Modulation of transmembrane pressure in manufacturing scale tangential flow filtration N-1 perfusion seed culture.

Mammalian cells were grown to high density in a 3,000 L culture using perfusion with hollow fibers operated in a tangential flow filtration mode. The high-density culture was used to inoculate the production stage of a biomanufacturing process. At constant permeate flux operation, increased transmembrane pressures (TMPs) were observed on the final day of the manufacturing batches. Small scale studies suggested that the filters were not irreversibly fouled, but rather exposed to membrane concentration polarization that could be relieved by tangential sweeping of the hollow fibers. Studies were undertaken to analyze parameters that influence the hydrodynamic profile within hollow fibers; including filter area, cell density, recirculation flow rate, and permeate flow rate. Results indicated that permeate flow rate had the greatest influence on modulating TMP. Further evaluation showed a significant decrease in TMP when permeate flow was reduced, and this occurred without any negative effect on cell growth or viability. Hence, a 30% reduction of permeate flow rate was implemented at manufacturing scale. A stable operation was achieved as TMP was successfully reduced by 75% while preserving all critical factors for performance in the perfusion bioreactor.

Effect of copper variation in yeast hydrolysate on C-terminal lysine levels of a monoclonal antibody.

The ability to control charge heterogeneity in monoclonal antibodies is important to demonstrate product quality comparability and consistency. This article addresses the control of C-terminal lysine processing through copper supplementation to yeast hydrolysate powder, a raw material used in the cell culture process. Large-scale production of a murine cell line exhibited variation in the C-terminal lysine levels of the monoclonal antibody. Analysis of process data showed that this variation correlated well with shifts in cell lactate metabolism and pH levels of the production culture. Small-scale studies demonstrated sensitivity of the cells to copper, where a single low dose of copper to the culture impacted cell lactate metabolism and C-terminal lysine processing. Subsequent analytical tests indicated that the yeast hydrolysate powder, added to the basal media and nutrient feed in the process, contained varying levels of trace copper across lots. The measured copper concentrations in yeast hydrolysate lots correlated well with the variation in lactate and pH trends and C-terminal lysine levels of the batches in manufacturing. Small-scale studies further demonstrated that copper supplementation to yeast hydrolysate lots with low concentrations of copper can shift the metabolic performance and C-terminal lysine levels of these cultures to match the control, high copper cultures. Hence, a strategy of monitoring, and if necessary supplementing, copper in yeast-hydrolysate powders resulted in the ability to control and ensure product quality consistency. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:463-468, 2017.

Age-related differences in dynamic balance control during stair descent and effect of varying step geometry.

The incidence of stairway falls and related injuries remains persistently high; however, the risk of stair injuries could be reduced through improved stairway design. The current study investigated dynamic balance control during stair descent and the effects of varying the step geometry. Data were collected from 20 healthy young and 20 older adults as they descended three staircases (riser heights of 7, 7.5 and 8 inches (178, 190 and 203 mm, respectively)). At each riser height, the tread run length was varied between 8 and 14 inches (203 mm and 356 mm) in one-inch (25 mm) increments. Kinematic data provided measures of segmental and whole-body dynamic control. Results demonstrated that older adults had greater lateral tilt of the upper body than young adults, but actually had larger margins of stability than the young in the antero-posterior direction as a result of their slower cadence. Nonetheless, for both age groups, the longer run lengths were found to provide the largest margins of stability. In addition, increase in run length and decrease in riser height tended to reduce forward upper body tilt. These results help to explain the underlying biomechanical factors associated with increased risk of falls and the relationship with step geometry. Considering the importance of stair ambulation in maintaining independence and activity in the community, this study highlights the definite need for safer stair design standards to minimize the risk of falls and increase stair safety across the lifespan.

Hand hygiene monitoring technology: a systematic review of efficacy.

Electronic and video monitoring systems (EMS/VMS) may improve hand hygiene by providing feedback, real-time reminders or via the Hawthorne effect. The aim of this systematic review was to assess the efficacy of EMS/VMS in improving hand hygiene or reducing the incidence of healthcare-associated infection (HCAI). Experimental and quasi-experimental studies were included if they measured any hand hygiene outcome and/or HCAI incidence. Of the studies included, seven used system-defined compliance (SDC) (N = 6) or hand hygiene event rate (N = 1) as their outcome. SDC differed for all systems. Most (N = 6) were single ward studies. Two uncontrolled pretest‒post-test studies evaluating EMS that provided voice prompts showed increases in SDC, but risk of bias was high. Two uncontrolled time-series analyses of VMS that provided aggregate feedback demonstrated large, sustained improvement in SDC and were at moderate risk of bias. One non-randomized controlled trial of EMS with aggregate feedback found no difference in hand hygiene frequency but was at high risk of bias. Two studies evaluated EMS providing individual feedback and real-time reminders. A pretest‒post-test study at high risk of bias showed an increase in SDC. An RCT at low risk of bias showed 6.8% higher SDC in the intervention arm partially due to a fall in SDC in the control arm. In conclusion, the overall study quality was poor. The study at lowest risk of bias showed only a small increase in SDC. VMS studies at moderate risk of bias showed rapid and sustained increases in SDC. Data were insufficient to recommend EMS/VMS. Future studies should prioritize testing of VMS using stronger study designs including control arms and validated, system-independent measures of hand hygiene.

Detecting objective and subjective cognitive effects of electroconvulsive therapy: intensity, duration and test utility in a large clinical sample.

BACKGROUND: Electroconvulsive therapy (ECT) is an effective treatment for depression but the extent and persistence of cognitive side-effects remain uncertain. It has been reported that there is little evidence that impairments last longer than up to 15 days post-ECT. However, relatively few studies have followed patients for even as long as 1 month post-ECT. Here we report results from a brief cognitive battery given prior to ECT and repeated five times up to 6 months post-ECT. METHOD: In a retrospective case-note study of routinely collected clinical data 126 patients treated with ECT completed two neuropsychological tests [Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial recognition memory (SRM) and Mini Mental State Examination (MMSE)] and two subjective reports of memory function, prior to ECT. Patients were reassessed following ECT and at 1, 3 and 6 months post-ECT although not all patients completed all assessments. RESULTS: Performance relative to pre-ECT baseline was significantly poorer at each post-ECT assessment up to 3 months post-ECT using the CANTAB SRM, but was improved at 6 months. Conversely, MMSE score showed improvements relative to baseline from 1 month post-ECT. Mood and subjective memory scores improved following ECT and were correlated with one another, but not with either neuropsychological measure. CONCLUSIONS: The CANTAB SRM task revealed reversible cognitive deficiencies relative to a pre-ECT baseline for at least 3 months following ECT, while MMSE score and patients' subjective reports showed only improvement. Visuospatial memory scores eventually exceeded baseline 6 months post-ECT.

Acceptability of a wearable hand hygiene device with monitoring capabilities.

Transmisssion of infection within healthcare institutions is a significant threat to patients and staff. One of the most effective means of prevention is good hand hygiene. A research team at Toronto Rehabilitation Institute, Ontario, Canada, developed a wearable hand disinfection system with monitoring capabilities to enhance hand wash frequency. We present the findingsof the first phase of a larger study addressing the hypothesis that an electronic hand hygiene system with monitoring and reminding propertieswill increase hand hygiene compliance. This first phase focused on the acceptability and usability of the wearable electronic hand wash device ina clinical environment. The feedback from healthcare staff to the first prototype has provided evidence for the research team to continue with the development of this technology.

Consent and the individual detained in custody.

It has been acknowledged that autonomy is one of the prima facie principles in modern medical practice and integral to the interchange between doctor and patient even if that meeting does not fulfil the normal criteria for a consultation. The lead having been taken by other jurisdictions, the General Medical Council, the UK national regulatory body for doctors, has now acknowledged the concept of informed consent that was first espoused in cases such as Rogers v. Whitaker. In regard to the concept of informed consent, there are three pertinent issues that the Forensic Physician should consider in deciding upon the adequacy of this: Did that person have capacity in the eyes of the law? The Forensic Physician may be asked to examine individuals whose age span ranges from the newly born to the elderly and there will be potential conflict of interest between parent and child or elderly people and their carers. Even if adequate information was imparted, did a person under the (significant) influence of alcohol or drugs understand the likely implications that would flow from their decision? Was the individual concerned given appropriate information beforehand--in other words, was the consent truly informed? Was the consent given voluntarily? Voluntariness is probably the most significant ethical worry likely to confront the doctor, particularly when examining an individual for fitness to be detained or fitness to be interviewed, both categories of which make up the main work load in this sub-specialty. The thorny ethical dilemmas faced in this specialty are considered and how the professional standard originally defined in Hunter v Hanley and re-iterated in the Bolam test (with subsequent modification in Bolitho) affect the way in which the clinician deals with the problems is likely to face.

Understanding and measuring powered wheelchair mobility and manoeuvrability. Part I. Reach in confined spaces.

PURPOSE: To determine: (1) what wheelchair manoeuvrability factors are important and (2) the effects of powered wheelchair design on the ability to reach in a confined space. METHOD: The relative importance of five aspects of wheelchair manoeuvrability was determined through a survey of users of wheelchairs (N = 52) and health care professionals and others (N = 89). A single young, non-disabled subject undertook repeated trials of reach distance on to a counter at the end of a corridor whose width could be adjusted by moving Styrofoam walls. RESULTS: Reaching, moving in confined spaces and avoiding collisions were more important than speed and avoiding the need to drive backwards. The rear wheel drive powered wheelchair was found to allow the greatest reach when driving backwards into the space and the wheelchair which moved in a sideways direction allowed greatest reach in the narrowest corridor. CONCLUSIONS: The survey concluded that manoeuvring in small spaces and reaching without collisions were important. The powered wheelchair with sideways capability afforded the greatest reach in confined spaces except when the rear wheel drive chair was driven in backwards. The survey respondents did not place a high priority on avoiding backwards driving but some people find this difficult to do safely.

Neuropsychological impairment as a consequence of football (soccer) play and football heading: preliminary analyses and report on university footballers.

Previous research has claimed neuropsychological impairment occurs as a result of professional and amateur football play, and, specifically, football heading. However, much of this research exhibits substantial methodological problems. By investigating less committed amateur level footballers, the current study sought to gain some insight into the developmental history of any neuropsychological consequences of football play. University football, rugby and noncontact sports players were compared on a range of biographical and neuropsychological test variables. While playing their chosen sports, rugby players sustained many more head injuries than footballers and noncontact sportsmen, but footballers did not sustain significantly more head injuries than noncontact sportsmen. The number of head injuries sustained predicted Trails B and TAP Divided Attention latencies in a positive fashion. After controlling for the number of head injuries sustained, sport group effects were detected with TAP Divided Attention accuracy scores, with footballers exhibiting poorest performance. After controlling for the number of head injuries sustained, the total amount of heading done by footballers predicted the number of Wisconsin Card Sorting category shifts in a negative fashion. Nevertheless, over interpretation of all of these results should be resisted because of the exploratory nature of the analyses and the possibility that the sport groups may differ in ways other than just the nature of their sports activities.

The use of artificial intelligence in the design of an intelligent cognitive orthosis for people with dementia.

Dementia often reduces a person's ability to perform activities of daily living because he or she becomes confused and cannot remember the sequence of steps to perform. The current solution is to have a caregiver continually supervise and assist the person using verbal reminders or cues. This loss of privacy and increased dependency may cause the affected person to become embarrassed and agitated. We propose that this situation might be improved by using a computerized device that monitors progress and provides the reminders needed. The COACH is a first prototype of such a device. It uses artificial intelligence to observe a user, learn from his or her actions, and issue prerecorded cues of varying detail. The device was developed using a personal computer and a video camera that unobtrusively tracked the user. Preliminary testing with subjects who simulated confused behavior as they washed their hands showed that the device was performing its functions with an efficacy of approximately 95%. More extensive clinical testing and evaluation has begun, and the results will be reported in future publications.

Product development: using a 3D computer model to optimize the stability of the Rocket powered wheelchair.

A three-dimensional (3D) lumped-parameter model of a powered wheelchair was created to aid the development of the Rocket prototype wheelchair and to help explore the effect of innovative design features on its stability. The model was developed using simulation software, specifically Working Model 3D. The accuracy of the model was determined by comparing both its static stability angles and dynamic behavior as it passed down a 4.8-cm (1.9") road curb at a heading of 45 degrees with the performance of the actual wheelchair. The model's predictions of the static stability angles in the forward, rearward, and lateral directions were within 9.3, 7.1, and 3.8% of the measured values, respectively. The average absolute error in the predicted position of the wheelchair as it moved down the curb was 2.2 cm/m (0.9" per 3'3") traveled. The accuracy was limited by the inability to model soft bodies, the inherent difficulties in modeling a statically indeterminate system, and the computing time. Nevertheless, it was found to be useful in investigating the effect of eight design alterations on the lateral stability of the wheelchair. Stability was quantified by determining the static lateral stability angles and the maximum height of a road curb over which the wheelchair could successfully drive on a diagonal heading. The model predicted that the stability was more dependent on the configuration of the suspension system than on the dimensions and weight distribution of the wheelchair. Furthermore, for the situations and design alterations studied, predicted improvements in static stability were not correlated with improvements in dynamic stability.

The efficacy of head immobilization techniques during simulated vehicle motion.

STUDY DESIGN: Laboratory experiment. OBJECTIVE: To compare the efficacy of different head immobilization techniques during motion simulating ambulance transport. BACKGROUND: A significant number of neurologic injuries associated with cervical spine fractures arise or are aggravated during emergency extrication or patient transport. Previous studies have not addressed the effect of head immobilization on the passive motion that could occur across the neck during transport. METHODS: Three different head-immobilization methods were compared in six healthy young adults by using a computer-controlled moving platform to simulate the swaying and jarring movements that can occur during ambulance transport. In all tests, the trunk was secured by means of a commonly used "criss-cross" strapping technique. Efficacy of head immobilization was evaluated using measures of head motion and neck rotation. RESULTS: None of the three immobilization techniques was successful in eliminating head motion or neck rotation. Movement of the trunk contributed substantially to the lateral bending that occurred across the neck. A new product involving the placement of wedges underneath the head provided some small, but statistically significant improvements in fixation of the head to the fracture board; however, there was no improvement in terms of the relative motion occurring across the neck. CONCLUSIONS: Somewhat improved fixation of the head to the fracture board can be achieved by placing wedges under the head; however, the benefits of any fixation method, in terms of cervical spine immobilization, are likely to be limited unless the motion of the trunk is also controlled effectively. Future research and development should address techniques to better control head and trunk motion.

Mechanical response of the lumbar spine to seated postural loads.

STUDY DESIGN: In vitro force and deformation measurements formed the basis for determinate, quasistatic analysis of principal forces in the seated lumbar spine. OBJECTIVES: To explore the relationship between seated postures and the mechanical response in component tissues of lumbar intervertebral joints. SUMMARY OF BACKGROUND DATA: Despite the high prevalence of low back pain syndrome, the precise mechanisms relating specific mechanical loads to spinal degeneration are not well understood. Simultaneous, time-dependent measurement of anterior column forces and articular facet forces has not been presented previously. consequently, a determinate analysis of principal component forces has not been possible. METHODS: Twelve lumbar spines (L1-S1) were subjected to constant loading conditions while in flexed and extended seated postures. Time-dependent forces were measured in the anterior column at the L4 and L5 superior endplates and in the four facets of the L3-L4 and L4-L5 motion segments. A quasi-static analysis of sagittal plane forces was used to compute the remaining principal joint forces, including ligament, disc shear, and facet impingement forces. RESULTS: Component forces changed under static loading in both postures. There were significant differences between the mechanical responses of the two postures. Although the vertical creep displacement was greater in the extended seated posture (3.22 mm versus 2.11 mm), the escalation of forces was more severe in the flexed posture. CONCLUSIONS: The results suggest a mechanism of force balancing in lordotic postures under static loads, whereas flexed postures produce large increases to the tensile forces in the region of the posterior anulus.

A guideline for the design of a four-wheeled walker.

More people use assistive technology devices to compensate for mobility impairments than for any other general type of impairment. Increasing numbers of people with mobility or balance problems use walkers with four wheels. Four-wheeled walkers are often outfitted with seats to make it possible to travel longer distances with intermediate resting periods. The dangers of sitting on a parked walker are well known. Many physiotherapists tell walker users to park the walker against a wall to prevent injury in case the user forgets to apply the brakes or the brakes fail. To design a safer walker that can be used for sitting, the demands placed on it must be measured. With these data, three modes of walker instability must be considered: first, the brakes may hold but the wheels may slide along the ground; second, the entire walker may tip over; and third, the brakes may fail to hold the wheels in place, and they may begin to roll. Mathematical models can be constructed to simulate how different walker designs will perform. By this process, design improvements can be made for existing walkers, and future walker designs can also be proposed.

An interface to enhance mobility for people with hemispatial neglect.

The objective was to develop and test a control interface to enable people with hemispatial neglect to maneuver a powered wheelchair with increased attention to their environment. A single case study was conducted using a female (aged 72 years) who had a right cerebro vascular accident five years earlier. She drove a powered wheelchair through 20 different test courses (mazes) while a computer recorded frequency of looking to the left (left checks) and an observer recorded visual targets missed and wheelchair collisions with walls and obstacles. The Mann-Whitney test was used to determine significant differences in left checks, left collisions, right collisions, and percent left checks targets missed between baseline and strategy phases. With the interface strategy, the subject significantly increased the number of left checks and missed fewer left targets in the test course. These results indicate that a powered-wheelchair control interface shows promise in enabling people with mild hemispatial neglect to maneuver a powered chair with greater environmental awareness and ease.

In vivo measurement of lumbar spinal creep in two seated postures using magnetic resonance imaging.

STUDY DESIGN: A magnetic resonance imaging technique was developed to measure creep in the lumbar spine in different seated postures. Owing to the fixed size and horizontal orientation constraints of the magnetic resonance imaging system bore, gravitational force was simulated in the horizontal plane while the subject assumed each of two near-seated postures: 1) flexed lumbar, and 2) extended lumbar. OBJECTIVES: One experimental subject was used to determine the feasibility of this technique designed to correlate spinal creep with different seated postures. SUMMARY OF BACKGROUND DATA: Although epidemiologic and pathologic studies have linked the seated posture with low back pain and disc degeneration, few in vivo studies have explored the mechanical response of the lumbar spine to seated postures. METHODS: Creep displacement of four lumbar discs (L3-S1) was measured from unloaded and loaded scans separated by 30 minutes of constant loading. Forty-eight images were measured from three trials in each posture, four sagittal slices per trial. RESULTS: Creep while in an extended posture (3.58 mm) was greater than creep while in a flexed posture (2.92 mm). System resolution was 0.78 mm. CONCLUSION: This technique can be used to discern between creep displacements in different postures.

The impact of new lifting technology in long term care: a pilot study.

1. The researchers conducted a pilot study to test a new lifting system developed with the assistance of nurses. 2. The lift system consists of a portable battery operated power unit that the nurse carries to the bedside and attaches to an overhead track; the ability to share the portable power unit among several track locations is economical. 3. The new lifting system was found to reduce the number of staff necessary to execute patient lifts. This staff saving amounted to 50% of one full time equivalent person per nursing unit. 4. Nurses perceived that less effort was required using the new lifting system compared to a conventional floor model wheeled lifting device.

Technology to assist elderly people's safe mobility.

A grab bar shape has been presented that appears to provide an effective alternative to knurled finishes. This grab bar has been incorporated into a system that can be easily positioned anywhere in a room to help an ambulatory disabled person rise from a bed or other surface. The problem of lifting nonambulatory elderly people has been addressed by means of a modular mobile lifting system that offers the advantage of overhead lifting at lower cost than traditional movement devices for nonambulatory people. The author suggests that low-technology solutions are worthy of academic effort and that movement devices for elderly people must also address the needs of their formal and informal caregivers.