Ghana 3D Telemedicine International MDT: A proof-of-concept study.

A real-time 3D Telemedicine system - leveraging Microsoft's Holoportation™ communication technology - enabled an international multidisciplinary team meeting (MDT) to consult with complex reconstructive patients before, during, and after an overseas surgical collaboration. METHODS: A proof-of-concept international 3D MDT clinic took place in November 2022, between the Canniesburn Plastic Surgery Unit, UK, and the National Reconstructive Plastic Surgery and Burns Centre, Korle Bu Teaching Hospital, Ghana. The 3D system was utilised 1) previsit to assess patients and enable logistical planning, 2) on-site in Ghana to further allow patients to see themselves and proposed operations in 3D, and 3) post visit to debrief the team and patients. RESULTS: Four Ghana patients were followed through their patient journey (mandibular ameloblastoma, sarcoma thigh, maxillary tumour, sarcoma back). Thirteen participants (four patients, four Ghana clinicians, and five UK clinicians) completed feedback on the 3D MDT. Outcome measures were rated highly with satisfaction 84.31/100, perceived benefit 4.54/5, overall quality 127.3/147 (Telehealth Usability Questionnaire), and usability 83.2/100 (System Usability Scale). These data show close alignment with that previously published on high-income countries. CONCLUSIONS: This novel technology has the potential to enhance the delivery of overseas surgical visits to low-to-middle-income countries, by improving planning, informed discussion with patients, expert consensus on complex cases, and fostering engagement with professionals who may be thousands of miles away. This is the first demonstration that real-time 3D Telemedicine can both work, and enhance care within an international MDT clinic, and may thus enable change in the approach to overseas surgical collaborations.

Participatory development of a 3D telemedicine system during COVID: The future of remote consultations.

BACKGROUND: The COVID pandemic brought the need for more realistic remote consultations into focus. 2D Telemedicine solutions fail to replicate the fluency or authenticity of in-person consultations. This research reports on an international collaboration on the participatory development and first validated clinical use of a novel, real-time 360-degree 3D Telemedicine system worldwide. The development of the system - leveraging Microsoft's Holoportation™ communication technology - commenced at the Canniesburn Plastic Surgery Unit, Glasgow, in March 2020. METHODS: The research followed the VR CORE guidelines on the development of digital health trials, placing patients at the heart of the development process. This consisted of three separate studies - a clinician feedback study (23 clinicians, Nov-Dec 2020), a patient feedback study (26 patients, Jul-Oct 2021), and a cohort study focusing on safety and reliability (40 patients, Oct 2021-Mar 2022). "Lose, Keep, and Change" feedback prompts were used to engage patients in the development process and guide incremental improvements. RESULTS: Participatory testing demonstrated improved patient metrics with 3D in comparison to 2D Telemedicine, including validated measures of satisfaction (p<0.0001), realism or 'presence' (Single Item Presence scale, p<0.0001), and quality (Telehealth Usability Questionnaire, p = 0.0002). The safety and clinical concordance (95%) of 3D Telemedicine with a face-to-face consultation were equivalent or exceeded estimates for 2D Telemedicine. CONCLUSIONS: One of the ultimate goals of telemedicine is for the quality of remote consultations to get closer to the experience of face-to-face consultations. These data provide the first evidence that Holoportation™ communication technology brings 3D Telemedicine closer to this goal than a 2D equivalent.

Concurrent presentation of brain arteriovenous malformation, peripheral arteriovenous malformation, and cerebellar astrocytoma: Case report.

BACKGROUND: We report a rare case of a 19-year-old female progressively affected by a peripheral arteriovenous malformation (pAVM), a midline cerebellar astrocytoma, and a brain arteriovenous malformation (bAVM). CASE DESCRIPTION: She presented with a pulsatile mass on her left cheek, which was classified as a pAVM through angiography. Following treatment with embolization and surgical resection, she returned with enlargement of the mass and imaging incidentally identified a cerebellar astrocytoma. Suboccipital craniotomy, C1 laminectomy, and endoscopic third ventriculostomy were subsequently performed. She was later treated again for growth of her pAVM, and angiography revealed the presence of a left temporal bAVM, which was resected via a pterional craniotomy. CONCLUSIONS: Pathological staining identified activation of mTOR and RAS/MAPK pathway in the patient's pAVM and bAVM tissue samples. Furthermore, genetic sequencing demonstrated an activating MAPK21 (K57N) mutation in the pAVM and a gain of distal chromosome 7q in the pilocytic astrocytoma. No germline mutation was identified to explain all pathologies. This case demonstrates the need for continued development and further integration of multi-disciplinary genetic, radiological, and neurological treatment teams to effectively care for such complex presentations.

Biopharmaceutical Industry Approaches to Facility Segregation for Viral Safety: An Effort from the Consortium on Adventitious Agent Contamination in Biomanufacturing.

Appropriate segregation within manufacturing facilities is required by regulators and utilized by manufacturers to ensure that the final product has not been contaminated with (a) adventitious viruses, (b) another pre-/postviral clearance fraction of the same product, or (c) another product processed in the same facility. However, there is no consensus on what constitutes appropriate facility segregation to minimize these risks. In part, this is due to the fact that a wide variety of manufacturing facilities and operational practices exist, including single-product and multiproduct manufacturing, using traditional segregation strategies with separate rooms for specific operations that may use stainless steel or disposable equipment to more modern ballroom-style operations that use mostly disposable equipment (i.e., pre- and postviral clearance manufacturing operations are not physically segregated by walls). Further, consensus is lacking around basic definitions and approaches related to facility segregation. For example, given that several unit operations provide assurance of virus clearance during downstream processing, how does one define pre- and postviral clearance and at which point(s) should a viral segregation barrier be introduced? What is a "functionally closed" system? How can interventions be conducted so that the system remains functionally closed? How can functionally closed systems be used to adequately isolate a product stream and ensure its safety? To address these issues, the member companies of the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) have conducted a facility segregation project with the following goals: define "pre- and postviral clearance zones" and "pre- and postviral clearance materials"; define "functionally closed" manufacturing systems; and identify an array of facility segregation approaches that are used for the safe and effective production of recombinant biologics as well as plasma products. This article reflects the current thinking from this collaborative endeavor.LAY ABSTRACT: Operations in biopharmaceutical manufacturing are segregated to ensure that the final product has not been contaminated with adventitious viruses, another fraction of the same product, or with another product from within the same facility. Yet there is no consensus understanding of what appropriate facility segregation looks like. There are a wide variety of manufacturing facilities and operational practices. There are existing facilities with separate rooms and more modern approaches that use disposable equipment in an open ballroom without walls. There is also no agreement on basic definitions and approaches related to facility segregation approaches. For example, many would like to claim that their manufacturing process is functionally closed, yet exactly how a functionally closed system may be defined is not clear. To address this, the member companies of the Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) have conducted a project with the goal of defining important manufacturing terms relevant to designing an appropriately segregated facility and identifying different facility segregation approaches that are used for the safe and effective production of recombinant biologics as well as plasma products.

Lack of P-glycoprotein-mediated efflux and the potential involvement of an influx transport process contributing to the intestinal uptake of deltamethrin, cis-permethrin, and trans-permethrin.

The effectiveness and widespread use of pyrethroid insecticides has lead to concerns regarding their safety. Human ingestion of these potentially neurotoxic compounds is typically through hand-to-mouth contact or consumption of contaminated foods. A substantial proportion of ingested pyrethroids are eliminated in feces, suggesting that absorption is limited, possibly by the action of the efflux transporter P-glycoprotein (P-gp). We utilized caco-2 cells as a model system for intestinal enterocytes and qualitatively and quantitatively assessed the transport of deltamethrin (DLM), cis-permethrin (CPM), and trans-permethrin (TPM). Caco-2 cell uptake of the P-gp substrate R6G was increased by the P-gp inhibitors cyclosporine A (CSA) and ritonavir but not by DLM, CPM, and TPM. Unexpectedly, CSA and ritonavir significantly reduced the uptake of DLM, CPM, and TPM. Permeability coefficients (P app) and directional flux of DLM, CPM, or TPM were greater in the absorptive than the secretory (efflux) direction when measured across caco-2 monolayers grown on Transwell inserts. When CSA was applied to the monolayers' apical (AP) side, the AP to basolateral (BL) P app was significantly reduced, with no change in the BL to AP P app. Kinetic analysis demonstrated saturable transport kinetics for all 3 pyrethroids. These findings indicate that the cellular uptake of DLM, CPM, and TPM is not limited by P-gp efflux but undergo absorptive influx transport as a contributing mechanism for cellular uptake. However, the overall P app values for DLM, CPM, and TPM are consistent with the low permeability/low absorption compound mannitol, suggesting limited gastrointestinal absorption potential.

Overloading ion-exchange membranes as a purification step for monoclonal antibodies.

The present study examined the overloading of ion-exchange membrane adsorbers, a form of frontal chromatography, as the final purification step in the production of mAbs (monoclonal antibodies) produced from CHO (Chinese-hamster ovary) cells. Preferential binding of impurities over antibody product was exploited using commercially available cation- and anion-exchange membranes. Three different antibody feedstreams previously purified over Protein A and ion-exchange column chromatography were tested. Feedstream conductivity and pH were adjusted to induce product and impurity adsorption. Membranes were then overloaded in a normal flow mode, resulting in retention of impurities and breakthrough of purified antibody. Although some amount of the product also binds to the membranes (usually < or =30 g mAb/l membrane), yields of > or =99% were achieved by marginalizing the losses, typically by loading more than 3 kg mAb/l membrane. Analyses of the purified pools show consistent removal of impurities despite strong mAb-ligand interactions and high membrane loadings. The clearance of host cell proteins was affected by pH and conductivity, but was unaffected by flow rate, membrane properties or scale. The importance of the present study lies in our demonstration of an alternative use of ion-exchange membranes for fast, effective and high yielding purification of mAbs.

Increasing parvovirus filter throughput of monoclonal antibodies using ion exchange membrane adsorptive pre-filtration.

Pre-filtration using ion exchange membrane adsorbers can improve parvovirus filter throughput of monoclonal antibodies (mAbs). The membranes work by binding trace foulants, and although some antibody product also binds, yields > or =99% are easily achieved by overloading. Results show that foulant adsorption is dependent on pH and conductivity, but independent of scale and adsorber brand. The ability to use ion exchange membranes as pre-filters is significant because it provides a clean, well defined, chemically stable option for enhancing throughput. Additionally, ion exchange membranes facilitate characterization of parvovirus filter foulants. Examination of adsorber elution samples using sedimentation velocity analysis and SEC-MALS/QELS revealed the presence of high molecular weight species ranging from 8 to 13 nm in hydrodynamic radius, which are similar in size to parvoviruses and thus would be expected to plug the pores of a parvovirus filter. A study of two identical membranes in-series supports the hypothesis that the foulants are soluble, trace level aggregates in the feed. This study's significance lies in a previously undiscovered application of membrane chromatography, leading to a more cost effective and robust approach to parvovirus filtration for the production of monoclonal antibodies.

A consensus rating method for small virus-retentive filters. I. Method development.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. One goal of the task force was to develop a test method for small virus-retentive filters. Because small virus-retentive filters present unique technical challenges, the test method development process was guided by laboratory studies to determine critical variables such as choice of bacteriophage challenge, choice of model protein, filtration operating parameters, target log10 reduction value, and filtration endpoint definition. Based on filtration, DLS, electrospray differential mobility analysis, and polymerase chain reaction studies, a final rating based on retention of bacteriophage PP7 was chosen by the PDA Virus Filter Task Force. The detailed final consensus filter method was published in the 2008 update of PDA Technical Report 41. Virus Filtration.

A consensus rating method for small virus-retentive filters. II. Method evaluation.

Virus filters are membrane-based devices that remove large viruses (e.g., retroviruses) and/or small viruses (e.g., parvoviruses) from products by a size exclusion mechanism. In 2002, the Parenteral Drug Association (PDA) organized the PDA Virus Filter Task Force to develop a common nomenclature and a standardized test method for classifying and identifying viral-retentive filters. A test method based on bacteriophage PP7 retention was chosen based on developmental studies. The detailed final consensus filter method is published in the 2008 update of PDA Technical Report 41: Virus Filtration. Here, we evaluate the method and find it to be acceptable for testing scaled-down models of small virus-retentive filters from four manufacturers. Three consecutive lots of five filter types were tested (Pegasus SV4, Viresolve NFP, Planova 20N and 15N, Virosart CPV). Each passed the criteria specified in the test method (i.e., >4 log10 PP7 retention, >90% intravenous immunoglobulin passage, and passing integrity/installation testing) and was classified as PP7-LRV4.

Intraorbital arteriovenous fistulae of the ophthalmic veins treated by transvenous endovascular occlusion: technical case report.

OBJECTIVE AND IMPORTANCE: Intraorbital arteriovenous fistulas (AVF) of the ophthalmic veins are an extremely rare phenomenon. This article describes two such cases treated solely by transvenous occlusion and not hitherto described in the literature. METHODS AND RESULTS: Two women, aged 51 and 63 years old, presented with proptosis and chemosis mimicking a carotid-cavernous fistula. In both cases, cerebral angiography revealed an intraorbital dural AVF of the superior and inferior ophthalmic vein, respectively. Both patients underwent transvenous ablation of the dural AVF retrograde via the facial vein and subsequently had complete resolution of the presenting symptoms. CONCLUSION: Ophthalmic vein fistulas are a rare form of AVF with presenting symptoms mimicking those of carotid cavernous fistulae. This report describes two cases of ophthalmic vein fistulas successfully treated and angiographically obliterated via transvenous embolization with resolution of the patient's presenting symptoms.

Performance of a membrane adsorber for trace impurity removal in biotechnology manufacturing.

Membrane adsorbers provide an attractive alternative to traditional bead-based chromatography columns used to remove trace impurities in downstream applications. A linearly scalable novel membrane adsorber family designed for the efficient removal of trace impurities from biotherapeutics, are capable of reproducibly achieving greater than 4 log removal of mammalian viruses, 3 log removal of endotoxin and DNA, and greater than 1 log removal of host cell protein. Single use, disposable membrane adsorbers eliminate the need for costly and time consuming column packing and cleaning validation associated with bead-based chromatography systems, and minimize the required number and volume of buffers. A membrane adsorber step reduces process time, floor space, buffer usage, labor cost, and improves manufacturing flexibility. This "process compression" effect is commonly associated with reducing the number of processing steps. The rigid microporous structure of the membrane layers allows for high process flux operation and uniform bed consistency at all processing scales.

Parallel venous channel as the recipient pouch in transverse/sigmoid sinus dural fistulae.

OBJECTIVE: The most common location for dural arteriovenous fistulae (AVFs) is the transverse/sigmoid sinus. We describe our prospective analysis of data for 10 patients with recipient fistulae parallel to the transverse/sigmoid sinus. Recognition of this entity allows embolization of the fistula with preservation of the parent sinus. This report reviews the presentation and angiographic characteristics of the "parallel venous channel" and the treatment results for this series of patients. METHODS: Between 1995 and June 2002, at the medical center of the University of California, San Francisco, we identified 10 patients with a parallel venous channel as the recipient pouch for all arterial input into a transverse/sigmoid sinus AVF. The clinical presentations, angiographic features, endovascular treatments, and outcomes are described. Angiographic follow-up monitoring was performed for 1 to 6 years for all patients with cortical venous drainage (5 of 10 patients). Clinical follow-up periods ranged from 1 to 7 years. RESULTS: All patients presented with pulsatile tinnitus disruptive to sleep. Other symptoms included severe headaches, papilledema and visual disturbances, hemiparesis, and mastoid pain. All 10 parallel venous channels communicated with the transverse or sigmoid sinus. Cortical venous drainage was present in 50% of cases. Endovascular ablative procedures, using either coils or ethanol, were performed for all patients. The parallel venous channel was successfully embolized, with preservation of the transverse/sigmoid sinus, for all 10 patients. There were no major complications. All patients experienced resolution of their symptoms, with no recurrence. CONCLUSION: The existence of a parallel venous channel as the recipient pouch for all arterial inflow in a series of 10 transverse/sigmoid sinus AVFs is described. Endovascular obliteration of the parallel channel, with preservation of the parent sinus, was successfully performed for all 10 patients. Recognition of the parallel venous channel is clinically important for the treatment of transverse/sigmoid AVFs.

Angioplasty for intracranial symptomatic vertebrobasilar ischemia.

OBJECTIVE: Although anterior circulation disease has both medical and surgical treatment options, management of vertebrobasilar disease has predominantly had only medical options. Some patients remain symptomatic despite medical treatment, and angioplasty has been demonstrated to relieve critical stenoses. However, the elative safety and effectiveness of medical and surgical treatments is not clearly known. This report reviews the clinical characteristics, indications, and procedural risks of intracranial angioplasty in a series of patients with symptomatic posterior circulation ischemia. METHODS: All patients undergoing angioplasty for critical intracranial vertebral or basilar artery stenosis at the University of California at San Francisco Medical Center between June 1986 and July 1999 were included in a retrospective record review. Clinical features and procedural complications were recorded. RESULTS: Angioplasty was performed on 25 vessel lesions in 25 patients in whom medical therapy had failed. The patients ranged in age from 50 to 87 years. Of the 25 stenoses, 10 were intracranial vertebral, 9 vertebrobasilar junction, and 6 basilar in location. Angioplasty was effective in reducing the degree of stenosis by more than 40% in all 25 vessels. The overall risk of stroke or death was 28%, and the risk of disabling stroke or death was 16%. CONCLUSION: Intracranial posterior circulation angioplasty is effective in the reduction of stenosis and can be performed with relative safety. Angioplasty can be considered as a treatment option in patients with recurrent ischemic symptoms despite medical therapy.