TraumaFlow-development of a workflow-based clinical decision support system for the management of severe trauma cases.

PURPOSE: The treatment of severely injured patients in the resuscitation room of an emergency department requires numerous critical decisions, often under immense time pressure, which places very high demands on the facility and the interdisciplinary team. Computer-based cognitive aids are a valuable tool, especially in education and training of medical professionals. For the management of polytrauma cases, TraumaFlow, a workflow management-based clinical decision support system, was developed. The system supports the registration and coordination of activities in the resuscitation room and actively recommends diagnosis and treatment actions. METHODS: Based on medical guidelines, a resuscitation room algorithm was developed according to the cABCDE scheme. The algorithm was then modeled using the process description language BPMN 2.0 and implemented in a workflow management system. In addition, a web-based user interface that provides assistance functions was developed. An evaluation study was conducted with 11 final-year medical students and three residents to assess the applicability of TraumaFlow in a case-based training scenario. RESULTS: TraumaFlow significantly improved guideline-based decision-making, provided more complete therapy, and reduced treatment errors. The system was shown to be beneficial not only for the education of low- and medium-experienced users but also for the training of highly experienced physicians. 92% of the participants felt more confident with computer-aided decision support and considered TraumaFlow useful for the training of polytrauma treatment. In addition, 62% acknowledged a higher training effect. CONCLUSION: TraumaFlow enables real-time decision support for the treatment of polytrauma patients. It improves guideline-based decision-making in complex and critical situations and reduces treatment errors. Supporting functions, such as the automatic treatment documentation and the calculation of medical scores, enable the trauma team to focus on the primary task. TraumaFlow was developed to support the training of medical students and experienced professionals. Each training session is documented and can be objectively and qualitatively evaluated.

A comparison between a maximum care university hospital and an outpatient clinic - potential for optimization in arthroscopic workflows?

BACKGROUND: Due to the growing economic pressure, there is an increasing interest in the optimization of operational processes within surgical operating rooms (ORs). Surgical departments are frequently dealing with limited resources, complex processes with unexpected events as well as constantly changing conditions. In order to use available resources efficiently, existing workflows and processes have to be analyzed and optimized continuously. Structural and procedural changes without prior data-driven analyses may impair the performance of the OR team and the overall efficiency of the department. The aim of this study is to develop an adaptable software toolset for surgical workflow analysis and perioperative process optimization in arthroscopic surgery. METHODS: In this study, the perioperative processes of arthroscopic interventions have been recorded and analyzed subsequently. A total of 53 arthroscopic operations were recorded at a maximum care university hospital (UH) and 66 arthroscopic operations were acquired at a special outpatient clinic (OC). The recording includes regular perioperative processes (i.a. patient positioning, skin incision, application of wound dressing) and disruptive influences on these processes (e.g. telephone calls, missing or defective instruments, etc.). For this purpose, a software tool was developed ('s.w.an Suite Arthroscopic toolset'). Based on the data obtained, the processes of the maximum care provider and the special outpatient clinic have been analyzed in terms of performance measures (e.g. Closure-To-Incision-Time), efficiency (e.g. activity duration, OR resource utilization) as well as intra-process disturbances and then compared to one another. RESULTS: Despite many similar processes, the results revealed considerable differences in performance indices. The OC required significantly less time than UH for surgical preoperative (UH: 30:47 min, OC: 26:01 min) and postoperative phase (UH: 15:04 min, OC: 9:56 min) as well as changeover time (UH: 32:33 min, OC: 6:02 min). In addition, these phases result in the Closure-to-Incision-Time, which lasted longer at the UH (UH: 80:01 min, OC: 41:12 min). CONCLUSION: The perioperative process organization, team collaboration, and the avoidance of disruptive factors had a considerable influence on the progress of the surgeries. Furthermore, differences in terms of staffing and spatial capacities could be identified. Based on the acquired process data (such as the duration for different surgical steps or the number of interfering events) and the comparison of different arthroscopic departments, approaches for perioperative process optimization to decrease the time of work steps and reduce disruptive influences were identified.

In vitro evaluation of a computer-assisted decision support system for the primary care of polytrauma patients.

INTRODUCTION: The management of polytraumatized patients is set in a stressful environment with numerous critical decisions in a brief amount of time. Working along a standardised procedure can improve the outcome for these patients and reduce mortality. To help clinical practitioners, we developed "TraumaFlow", a workflow management system for the primary care of polytrauma patients based on the current treatment guidelines. This study sought to validate the system and investigate its effect on user performance and perceived workload. METHODS: The computer-assisted decision support system was tested in two scenarios in a trauma room of a level 1 trauma centre by 11 final-year medical students and 3 residents. In simulated polytrauma scenarios, the participants functioned as a trauma leader. The first scenario was performed without decision support and the second with support by "TraumaFlow" via tablet. During each scenario, the performance was evaluated in a standardized assessment. After each scenario, the participants answered a questionnaire on workload [NASA Raw Task Load Index (NASA RTLX)]. RESULTS: In total, 14 participants (mean 28 ± 4 years, 43% female) managed 28 scenarios. During the first scenario without computer-assisted support, the participants achieved a mean of 6.6 out of 12 points (SD 1.2, range 5 to 9). With the support of TraumaFlow, the mean performance score was significantly higher with 11.6 out of 12 points (SD 0.5, range 11 to 12, p < 0.001). In the 14 scenarios performed without support, there was no run in which no errors were made. In comparison, ten of the 14 scenarios performed with TraumaFlow ran free of relevant errors. The mean improvement in the performance score was 42%. There was a significant decrease in the mean self-reported mental stress level in scenarios with support of TraumaFlow (55, SD 24) as compared to scenarios without support (72, SD 13, p = 0.041). CONCLUSION: In a simulated environment, computer-assisted decision-making improved the performance of the trauma leader, helped to adhere to clinical guidelines, and reduced stress in a fast-acting environment. In reality, this may improve the treatment outcome for the patient.

Ontology-based surgical workflow recognition and prediction.

BACKGROUND: Surgical context-aware systems can adapt to the current situation in the operating room and thus provide computer-aided assistance functionalities and intraoperative decision-support. To interact with the surgical team perceptively and assist the surgical process, the system needs to monitor the intraoperative activities, understand the current situation in the operating room at any time, and anticipate the following possible situations. METHODS: A structured representation of surgical process knowledge is a prerequisite for any applications in the intelligent operating room. For this purpose, a surgical process ontology, which is formally based on standard medical terminology (SNOMED CT) and an upper-level ontology (GFO), was developed and instantiated for a neurosurgical use case. A new ontology-based surgical workflow recognition and a novel prediction method are presented utilizing ontological reasoning, abstraction, and explication. This way, a surgical situation representation with combined phase, high-level task, and low-level task recognition and prediction was realized based on the currently used instrument as the only input information. RESULTS: The ontology-based approach performed efficiently, and decent accuracy was achieved for situation recognition and prediction. Especially during situation recognition, the missing sensor information were reasoned based on the situation representation provided by the process ontology, which resulted in improved recognition results compared to the state-of-the-art. CONCLUSIONS: In this work, a reference ontology was developed, which provides workflow support and a knowledge base for further applications in the intelligent operating room, for instance, context-aware medical device orchestration, (semi-) automatic documentation, and surgical simulation, education, and training.

Measuring and evaluating standardization of scrub nurse instrument table setups: a multi-center study.

OBJECTIVES: In-depth knowledge about surgical processes is a crucial prerequisite for future systems in operating rooms and the advancement of standards and patient safety in surgery. A holistic approach is required, but research in the field of surgical instrument tables, standardized instrument setups and involved personnel, such as nurses, is sparse in general. The goal of this study is to evaluate whether there is an existing standard within clinics for an instrument table setup. We also evaluate to which extent it is known to the personnel and whether it is accepted. MATERIALS AND METHODS: The study makes use of the Nosco Trainer, a scrub nurse training and simulation system developed to analyze various aspects of the workplace of scrub nurses. The system contains a virtual instrument table, which is used to perform and record instrument table setups. We introduce a metric which delivers a measurable score for the similarity of surgical instrument table setups. The study is complemented with a questionnaire covering related aspects. RESULTS: Fifteen scrub nurses of the Otolaryngology departments at three clinics in Germany and Switzerland performed a table setup for a Functional Endoscopic Sinus Surgery intervention and completed the questionnaire. The analysis of the developed metric with a leave one out cross-validation correctly allocated 14 of the 15 participants to their clinic. DISCUSSION: In contrast to the identified similarities of table setups within clinics with the collected data, only a third of the participants confirmed in the questionnaire that there is an existing table setup standard for Functional Endoscopic Sinus Surgery interventions in their facility, but almost three quarters would support a written standard and acknowledge its possible benefits for trainees and new entrants in the operating room. CONCLUSIONS: The structured analysis of the surgical instrument table using a data-driven metric for comparison is a novel approach to gain deeper knowledge about intra-operative processes. The insights can contribute to patient safety by improving the workflow between surgeon and scrub nurse and also open the way for goal-oriented standardization.

Analysis of the paraspinal muscle morphology of the lumbar spine using a convolutional neural network (CNN).

PURPOSE: This single-center study aimed to develop a convolutional neural network to segment multiple consecutive axial magnetic resonance imaging (MRI) slices of the lumbar spinal muscles of patients with lower back pain and automatically classify fatty muscle degeneration. METHODS: We developed a fully connected deep convolutional neural network (CNN) with a pre-trained U-Net model trained on a dataset of 3,650 axial T2-weighted MRI images from 100 patients with lower back pain. We included all qualities of MRI; the exclusion criteria were fractures, tumors, infection, or spine implants. The training was performed using k-fold cross-validation (k = 10), and performance was evaluated using the dice similarity coefficient (DSC) and cross-sectional area error (CSA error). For clinical correlation, we used a simplified Goutallier classification (SGC) system with three classes. RESULTS: The mean DSC was high for overall muscle (0.91) and muscle tissue segmentation (0.83) but showed deficiencies in fatty tissue segmentation (0.51). The CSA error was small for the overall muscle area of 8.42%, and fatty tissue segmentation showed a high mean CSA error of 40.74%. The SGC classification was correctly predicted in 75% of the patients. CONCLUSION: Our fully connected CNN segmented overall muscle and muscle tissue with high precision and recall, as well as good DSC values. The mean predicted SGC values of all available patient axial slices showed promising results. With an overall Error of 25%, further development is needed for clinical implementation. Larger datasets and training of other model architectures are required to segment fatty tissue more accurately.

Language-based translation and prediction of surgical navigation steps for endoscopic wayfinding assistance in minimally invasive surgery.

PURPOSE: In the context of aviation and automotive navigation technology, assistance functions are associated with predictive planning and wayfinding tasks. In endoscopic minimally invasive surgery, however, assistance so far relies primarily on image-based localization and classification. We show that navigation workflows can be described and used for the prediction of navigation steps. METHODS: A natural description vocabulary for observable anatomical landmarks in endoscopic images was defined to create 3850 navigation workflow sentences from 22 annotated functional endoscopic sinus surgery (FESS) recordings. Resulting FESS navigation workflows showed an imbalanced data distribution with over-represented landmarks in the ethmoidal sinus. A transformer model was trained to predict navigation sentences in sequence-to-sequence tasks. The training was performed with the Adam optimizer and label smoothing in a leave-one-out cross-validation study. The sentences were generated using an adapted beam search algorithm with exponential decay beam rescoring. The transformer model was compared to a standard encoder-decoder-model, as well as HMM and LSTM baseline models. RESULTS: The transformer model reached the highest prediction accuracy for navigation steps at 0.53, followed by 0.35 of the LSTM and 0.32 for the standard encoder-decoder-network. With an accuracy of sentence generation of 0.83, the prediction of navigation steps at sentence-level benefits from the additional semantic information. While standard class representation predictions suffer from an imbalanced data distribution, the attention mechanism also considered underrepresented classes reasonably well. CONCLUSION: We implemented a natural language-based prediction method for sentence-level navigation steps in endoscopic surgery. The sentence-level prediction method showed a potential that word relations to navigation tasks can be learned and used for predicting future steps. Further studies are needed to investigate the functionality of path prediction. The prediction approach is a first step in the field of visuo-linguistic navigation assistance for endoscopic minimally invasive surgery.

Surgical workflow simulation for the design and assessment of operating room setups in orthopedic surgery.

BACKGROUND: The design and internal layout of modern operating rooms (OR) are influencing the surgical team's collaboration and communication, ergonomics, as well as intraoperative hygiene substantially. Yet, there is no objective method for the assessment and design of operating room setups for different surgical disciplines and intervention types available. The aim of this work is to establish an improved OR setup for common procedures in arthroplasty. METHODS: With the help of computer simulation, a method for the design and assessment of enhanced OR setups was developed. New OR setups were designed, analyzed in a computer simulation environment and evaluated in the actual intraoperative setting. Thereby, a 3D graphical simulation representation enabled the strong involvement of clinical stakeholders in all phases of the design and decision-making process of the new setup alternatives. RESULTS: The implementation of improved OR setups reduces the instrument handover time between the surgeon and the scrub nurse, the travel paths of the OR team as well as shortens the procedure duration. Additionally, the ergonomics of the OR staff were improved. CONCLUSION: The developed simulation method was evaluated in the actual intraoperative setting and proved its benefit for the design and optimization of OR setups for different surgical intervention types. As a clinical result, enhanced setups for total knee arthroplasty and total hip arthroplasty surgeries were established in daily clinical routine and the OR efficiency was improved.

Increasing efficiency by optimizing table position for elective primary THA and TKA: a prospective monocentric pilot study.

INTRODUCTION: Hip and knee arthroplasties are very frequently performed surgeries with high quality standards and continuous optimization potential. Intraoperative processes can be standardized and simplified by optimization of table setups in the operating room to improve the quality and to increase efficiency. PATIENTS AND METHODS: The existing surgical setups for primary hip and knee arthroplasties in a university maximum care hospital with endoprosthesis center were simulated and analysed with a computer program and optimized setup suggestions were worked out, based on handover times, walking distance and ergonomic aspects determined in the program. In a prospective monocentric analysis, primary hip arthroplasties and knee arthroplasties were examined in currently used and in the new optimized setups (standard procedure according to in-house SOP, senior and main surgeons, no assistants). The surgeries were externally and independently supervised and analysed, whereby the time between incision and suture beginning, handovers per minute and handover times were documented, amongst other things. In addition, an evaluation sheet, which showed the satisfaction with the new setup, was filled by the surgical team. RESULTS: In the period from April 2016 to December 2018, 19 hip arthroplasties in currently used and 15 in the new optimized setup as well as 9 knee arthroplasties in currently used and 13 in the new setup were performed. Attention was paid to constant conditions in the compared groups and disruptive factors (assisted surgeries, complex surgeries, different cementings, etc.) were excluded. In the group of hip arthroplasties, the handover times were significantly different (old 1.82 +/- 1.43 s.; new 1.08 +/- 0.78 s.; p <0.001), as well as the handovers per minute (old 1.62 +/- 0.45 handovers/min.; new 2.10 +/- 0.32 handovers/min.; p = 0,001). The time between incision and suture beginning indicated no significant difference (old 53.89 +/- 18.92 min.; new 49.73 +/- 12.18 min; p = 0.466): During the knee arthroplasties, handovers per minute were significantly different (old 1.83 +/- 0.38 handovers/min.; new 2.40 +/- 0.35 handovers/min.; p = 0.002). The time between incision and suture beginning (old 71.11 +/- 20.72 min.; new 70.69 +/- 17.12 min.; p = 0.959) and the handover times (old 1.06 +/- 0.64 s.; new 0.91 +/- 0.59 s.; p = 0.152) indicated no significant difference. The evaluation of the questionnaires showed a significant difference (p < 0.001) in the group of hip arthroplasties in the category "visibility". For the knee arthroplasties, all items except "visibility" (p = 0.261) differed significantly. Overall, a high level of staff satisfaction with the new setup was achieved. CONCLUSIONS: In both groups, more handovers per minute could be achieved in the optimized setup and in the group of the hip arthroplasties, the handover times were significantly faster. The evaluation sheet showed a high satisfaction of the surgical staff with the new setup. No reduction of the time between incision and suture beginning could be determined. This can be attributed to a certain training effect, the adjustment to the setup modification and the low number of cases. The new setup offers a practical alternative for hip arthroplasties as well as for knee arthroplasties as it optimizes the events in the operating room in many ways. For example, there were more handovers per minute possible and passing of the surgical instruments free from interferences. Moreover, it increases the efficiency and achieves a high satisfaction of the staff.

Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants.

INTRODUCTION: The role of TOMM40-APOE 19q13.3 region variants is well documented in Alzheimer's disease (AD) but remains contentious in dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: We dissected genetic profiles within the TOMM40-APOE region in 451 individuals from four European brain banks, including DLB and PDD cases with/without neuropathological evidence of AD-related pathology and healthy controls. RESULTS: TOMM 40-L/APOE-ε4 alleles were associated with DLB (OR TOMM40 -L = 3.61; P value = 3.23 × 10-9; OR APOE -ε4 = 3.75; P value = 4.90 × 10-10) and earlier age at onset of DLB (HR TOMM40 -L = 1.33, P value = .031; HR APOE -ε4 = 1.46, P value = .004), but not with PDD. The TOMM40-L/APOE-ε4 effect was most pronounced in DLB individuals with concomitant AD pathology (OR TOMM40 -L = 4.40, P value = 1.15 × 10-6; OR APOE - ε 4 = 5.65, P value = 2.97 × 10-8) but was not significant in DLB without AD. Meta-analyses combining all APOE-ε4 data in DLB confirmed our findings (ORDLB = 2.93, P value = 3.78 × 10-99; ORDLB+AD = 5.36, P value = 1.56 × 10-47). DISCUSSION: APOE-ε4/TOMM 40-L alleles increase susceptibility and risk of earlier DLB onset, an effect explained by concomitant AD-related pathology. These findings have important implications in future drug discovery and development efforts in DLB.

Extending BPMN 2.0 for intraoperative workflow modeling with IEEE 11073 SDC for description and orchestration of interoperable, networked medical devices.

PURPOSE: Surgical workflow management in integrated operating rooms (ORs) enables the implementation of novel computer-aided surgical assistance and new applications in process automation, situation awareness, and decision support. The context-sensitive configuration and orchestration of interoperable, networked medical devices is a prerequisite for an effective reduction in the surgeons' workload, by providing the right service and right information at the right time. The information about the surgical situation must be described as surgical process models and distributed to the medical devices and IT systems in the OR. Available modeling languages are not capable of describing surgical processes for this application. METHODS: In this work, the BPMNSIX modeling language for intraoperative processes is technically enhanced and implemented for workflow build-time and run-time. Therefore, particular attention is given to the integration of the recently published IEEE 11073 SDC standard family for a service-oriented architecture of networked medical devices. In addition, interaction patterns for context-aware configuration and device orchestration were presented. RESULTS: The identified interaction patterns were implemented in BPMNSIX for an ophthalmologic use case. Therefore, the examples of the process-driven incorporation and control of device services could be demonstrated. CONCLUSION: The modeling of surgical procedures with BPMNSIX allows the implementation of context-sensitive surgical assistance functionalities and enables flexibility in terms of the orchestration of dynamically changing device ensembles and integration of unknown devices in the surgical workflow management.

Toward a standard ontology of surgical process models.

PURPOSE: The development of common ontologies has recently been identified as one of the key challenges in the emerging field of surgical data science (SDS). However, past and existing initiatives in the domain of surgery have mainly been focussing on individual groups and failed to achieve widespread international acceptance by the research community. To address this challenge, the authors of this paper launched a European initiative-OntoSPM Collaborative Action-with the goal of establishing a framework for joint development of ontologies in the field of SDS. This manuscript summarizes the goals and the current status of the international initiative. METHODS: A workshop was organized in 2016, gathering the main European research groups having experience in developing and using ontologies in this domain. It led to the conclusion that a common ontology for surgical process models (SPM) was absolutely needed, and that the existing OntoSPM ontology could provide a good starting point toward the collaborative design and promotion of common, standard ontologies on SPM. RESULTS: The workshop led to the OntoSPM Collaborative Action-launched in mid-2016-with the objective to develop, maintain and promote the use of common ontologies of SPM relevant to the whole domain of SDS. The fundamental concept, the architecture, the management and curation of the common ontology have been established, making it ready for wider public use. CONCLUSION: The OntoSPM Collaborative Action has been in operation for 24 months, with a growing dedicated membership. Its main result is a modular ontology, undergoing constant updates and extensions, based on the experts' suggestions. It remains an open collaborative action, which always welcomes new contributors and applications.

Ontology-based specification, identification and analysis of perioperative risks.

BACKGROUND: Medical personnel in hospitals often works under great physical and mental strain. In medical decision-making, errors can never be completely ruled out. Several studies have shown that between 50 and 60% of adverse events could have been avoided through better organization, more attention or more effective security procedures. Critical situations especially arise during interdisciplinary collaboration and the use of complex medical technology, for example during surgical interventions and in perioperative settings (the period of time before, during and after surgical intervention). METHODS: In this paper, we present an ontology and an ontology-based software system, which can identify risks across medical processes and supports the avoidance of errors in particular in the perioperative setting. We developed a practicable definition of the risk notion, which is easily understandable by the medical staff and is usable for the software tools. Based on this definition, we developed a Risk Identification Ontology (RIO) and used it for the specification and the identification of perioperative risks. RESULTS: An agent system was developed, which gathers risk-relevant data during the whole perioperative treatment process from various sources and provides it for risk identification and analysis in a centralized fashion. The results of such an analysis are provided to the medical personnel in form of context-sensitive hints and alerts. For the identification of the ontologically specified risks, we developed an ontology-based software module, called Ontology-based Risk Detector (OntoRiDe). CONCLUSIONS: About 20 risks relating to cochlear implantation (CI) have already been implemented. Comprehensive testing has indicated the correctness of the data acquisition, risk identification and analysis components, as well as the web-based visualization of results.

Using Fast Healthcare Interoperability Resources (FHIR) for the Integration of Risk Minimization Systems in Hospitals.

With the growing strain of medical staff and complexity of patient care, the risk of medical errors increases. In this work we present the use of Fast Healthcare Interoperability Resources (FHIR) as communication standard for the integration of an ontology- and agent-based system to identify risks across medical processes in a clinical environment.

Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies.

We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies.

Successful use of Alteplase during cardiopulmonary resuscitation following massive PE in a patient presenting with ischaemic stroke and haemorrhagic transformation.

The management of patients with acute stroke regarding treatment of thromboembolism is supported by a limited evidence base. We present the case of a 55-year-old female patient who initially presented with an ischaemic cerebral infarct with haemorrhagic transformation. Her clinical recovery was complicated by cardiac arrest secondary to massive pulmonary embolism. This was successfully treated with cardiopulmonary resuscitation and thrombolysis using Alteplase, which led to a full recovery to the pre-arrest state with no evidence of haemorrhagic complication. The patient was successfully discharged to a specialist centre for on-going stroke rehabilitation with no additional neurological impact. Despite the limited evidence base we believe this case highlights that thrombolysis can be used in select patients with haemorrhagic transformation of stroke and serious thromboembolic complications to achieve a positive outcome.

Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease.

Mutations in the glucocerebrosidase (GBA) gene have been implicated in increased formation of Lewy bodies (LBs) in Parkinson's disease (PD). We found GBA mutation status not to be significantly associated with the density of cortical LBs, after adjusting for sex, age at death, duration of PD and presence of dementia. Comparison of GBA carriers to PD controls found no difference in Alzheimer's disease pathological findings. Our results do not support GBA carriers to have a more advanced neuropathologic disease i.e. increased density of protein aggregates.

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson's disease.

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher's disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher's disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson's disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson's disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson's disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12-12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant alpha-synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5-6, and had McKeith's limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson's disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson's disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson's disease and suggest that to date, this is the most common genetic factor identified for the disease.