Collective Space-Sensing Coordinates Pattern Scaling in Engineered Bacteria.

Scale invariance refers to the maintenance of a constant ratio of developing organ size to body size. Although common, its underlying mechanisms remain poorly understood. Here, we examined scaling in engineered Escherichia coli that can form self-organized core-ring patterns in colonies. We found that the ring width exhibits perfect scale invariance to the colony size. Our analysis revealed a collective space-sensing mechanism, which entails sequential actions of an integral feedback loop and an incoherent feedforward loop. The integral feedback is implemented by the accumulation of a diffusive chemical produced by a colony. This accumulation, combined with nutrient consumption, sets the timing for ring initiation. The incoherent feedforward is implemented by the opposing effects of the domain size on the rate and duration of ring maturation. This mechanism emphasizes a role of timing control in achieving robust pattern scaling and provides a new perspective in examining the phenomenon in natural systems.

Modelling midline shift and ventricle collapse in cerebral oedema following acute ischaemic stroke.

In ischaemic stroke, a large reduction in blood supply can lead to the breakdown of the blood-brain barrier and to cerebral oedema after reperfusion therapy. The resulting fluid accumulation in the brain may contribute to a significant rise in intracranial pressure (ICP) and tissue deformation. Changes in the level of ICP are essential for clinical decision-making and therapeutic strategies. However, the measurement of ICP is constrained by clinical techniques and obtaining the exact values of the ICP has proven challenging. In this study, we propose the first computational model for the simulation of cerebral oedema following acute ischaemic stroke for the investigation of ICP and midline shift (MLS) relationship. The model consists of three components for the simulation of healthy blood flow, occluded blood flow and oedema, respectively. The healthy and occluded blood flow components are utilized to obtain oedema core geometry and then imported into the oedema model for the simulation of oedema growth. The simulation results of the model are compared with clinical data from 97 traumatic brain injury patients for the validation of major model parameters. Midline shift has been widely used for the diagnosis, clinical decision-making, and prognosis of oedema patients. Therefore, we focus on quantifying the relationship between ICP and midline shift (MLS) and identify the factors that can affect the ICP-MLS relationship. Three major factors are investigated, including the brain geometry, blood-brain barrier damage severity and the types of oedema (including rare types of oedema). Meanwhile, the two major types (stress and tension/compression) of mechanical brain damage are also presented and the differences in the stress, tension, and compression between the intraparenchymal and periventricular regions are discussed. This work helps to predict ICP precisely and therefore provides improved clinical guidance for the treatment of brain oedema.

Dynamic cerebral autoregulation is governed by two time constants: Arterial transit time and feedback time constant.

Dynamic cerebral autoregulation (dCA) is the mechanism that describes how the brain maintains cerebral blood flow approximately constant in response to short-term changes in arterial blood pressure. This is known to be impaired in many different pathological conditions, including ischaemic and haemorrhagic stroke, dementia and traumatic brain injury. Many different approaches have thus been used both to analyse and to quantify this mechanism in a range of healthy and diseased subjects, including data-driven models (in both the time and the frequency domain) and biophysical models. However, despite the substantial body of work on both biophysical models and data-driven models of dCA, there remains little work that links the two together. One of the reasons for this is proposed to be the discrepancies between the time constants that govern dCA in models and in experimental data. In this study, the processes that govern dCA are examined and it is proposed that the application of biophysical models remains limited due to a lack of understanding about the physical processes that are being modelled, partly due to the specific model formulation that has been most widely used (the equivalent electrical circuit). Based on the analysis presented here, it is proposed that the two most important time constants are arterial transit time and feedback time constant. It is therefore time to revisit equivalent electrical circuit models of dCA and to develop a more physiologically realistic alternative, one that can more easily be related to experimental data. KEY POINTS: Dynamic cerebral autoregulation is governed by two time constants. The first time constant is the arterial transit time, rather than the traditional 'RC' time constant widely used in previous models. This arterial transit time is approximately 1 s in the brain. The second time constant is the feedback time constant, which is less accurately known, although it is somewhat larger than the arterial transit time. The equivalent electrical circuit model of dynamic cerebral autoregulation should be replaced with a more physiologically representative model.

Individual Patient Data Meta-Analysis of Dynamic Cerebral Autoregulation and Functional Outcome After Ischemic Stroke.

BACKGROUND: The relationship between dynamic cerebral autoregulation (dCA) and functional outcome after acute ischemic stroke (AIS) is unclear. Previous studies are limited by small sample sizes and heterogeneity. METHODS: We performed a 1-stage individual patient data meta-analysis to investigate associations between dCA and functional outcome after AIS. Participating centers were identified through a systematic search of the literature and direct invitation. We included centers with dCA data within 1 year of AIS in adults aged over 18 years, excluding intracerebral or subarachnoid hemorrhage. Data were obtained on phase, gain, coherence, and autoregulation index derived from transfer function analysis at low-frequency and very low-frequency bands. Cerebral blood velocity, arterial pressure, end-tidal carbon dioxide, heart rate, stroke severity and sub-type, and comorbidities were collected where available. Data were grouped into 4 time points after AIS: <24 hours, 24 to 72 hours, 4 to 7 days, and >3 months. The modified Rankin Scale assessed functional outcome at 3 months. Modified Rankin Scale was analyzed as both dichotomized (0 to 2 versus 3 to 6) and ordinal (modified Rankin Scale scores, 0-6) outcomes. Univariable and multivariable analyses were conducted to identify significant relationships between dCA parameters, comorbidities, and outcomes, for each time point using generalized linear (dichotomized outcome), or cumulative link (ordinal outcome) mixed models. The participating center was modeled as a random intercept to generate odds ratios with 95% CIs. RESULTS: The sample included 384 individuals (35% women) from 7 centers, aged 66.3±13.7 years, with predominantly nonlacunar stroke (n=348, 69%). In the affected hemisphere, higher phase at very low-frequency predicted better outcome (dichotomized modified Rankin Scale) at <24 (crude odds ratios, 2.17 [95% CI, 1.47-3.19]; P<0.001) hours, 24-72 (crude odds ratios, 1.95 [95% CI, 1.21-3.13]; P=0.006) hours, and phase at low-frequency predicted outcome at 3 (crude odds ratios, 3.03 [95% CI, 1.10-8.33]; P=0.032) months. These results remained after covariate adjustment. CONCLUSIONS: Greater transfer function analysis-derived phase was associated with improved functional outcome at 3 months after AIS. dCA parameters in the early phase of AIS may help to predict functional outcome.

Modelling Drug Delivery to the Small Airways: Optimization Using Response Surface Methodology.

AIM: The aim of this in silico study was to investigate the effect of particle size, flow rate, and tidal volume on drug targeting to small airways in patients with mild COPD. METHOD: Design of Experiments (DoE) was used with an in silico whole lung particle deposition model for bolus administration to investigate whether controlling inhalation can improve drug delivery to the small conducting airways. The range of particle aerodynamic diameters studied was 0.4 - 10 µm for flow rates between 100 - 2000 mL/s (i.e., low to very high), and tidal volumes between 40 - 1500 mL. RESULTS: The model accurately predicted the relationship between independent variables and lung deposition, as confirmed by comparison with published experimental data. It was found that large particles (~ 5 µm) require very low flow rate (~ 100 mL/s) and very small tidal volume (~ 110 mL) to target small conducting airways, whereas fine particles (~ 2 µm) achieve drug targeting in the region at a relatively higher flow rate (~ 500 mL/s) and similar tidal volume (~ 110 mL). CONCLUSION: The simulation results indicated that controlling tidal volume and flow rate can achieve targeted delivery to the small airways (i.e., > 50% of emitted dose was predicted to deposit in the small airways), and the optimal parameters depend on the particle size. It is hoped that this finding could provide a means of improving drug targeting to the small conducting airways and improve prognosis in COPD management.

A network-based model of dynamic cerebral autoregulation.

Cerebrovascular diseases continue to be one of the leading causes of morbidity and mortality in humans. Abnormalities in dynamic cerebral autoregulation (dCA) have been implicated in many of these disease conditions. Accurate models are therefore needed to better understand the complex pathophysiology behind impaired dCA. We thus present here a simple framework for modelling a vessel-driven network model of dCA in the microvasculature, as opposed to the conventional compartmental modelling approach. Network models incorporate the actual connectivity and anatomy of the vasculature, thereby allowing us to include and trace changes in the calibre and morphology of individual vessels, investigate the spatial specificity and heterogeneity of the various control mechanisms to help disentangle their contributions, and link the model parameters to the actual network physiology. The proposed control feedback mechanisms are incorporated at the level of the individual vessel, and the dynamic pressure and flow fields are solved for here within a simple vessel network. In response to an upstream pressure drop, the network is found to be able to recover cerebral blood flow (CBF) while exhibiting the characteristic autoregulatory behaviour in terms of changes in vessel calibre and the biphasic flow response. We assess the feasibility of our formulation in larger networks by comparing the simulation results to those obtained using a one-dimensional (1D) model of CBF applied to the same microvasculature network and find that our model results are in very good agreement with the 1D solution, while significantly reducing the computational cost, thus enabling more detailed models of network behaviour to be adopted in the future. Accurate and computationally feasible models of dCA that are more representative of the vasculature can help increase the translatability of haemodynamic models into the clinical environment, which would help develop more informed treatment guidelines for patients with cerebrovascular diseases.

Quantification of hypoxic regions distant from occlusions in cerebral penetrating arteriole trees.

The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 µm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green's function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli.

Regional Cerebral Blood Flow Changes in Healthy Ageing and Alzheimer's Disease: A Narrative Review.

BACKGROUND: Cerebral blood flow is known to decline with increasing age and is a potential biomarker to distinguish between healthy and unhealthy ageing, where healthy ageing is defined as an absence of comorbidities in senescence. This review aims to synthesize evidence of cerebral blood flow changes over multiple brain regions, for use as a clinical reference or for in silico modelling. SUMMARY: The search identified 1,087 studies, of which 33 met the inclusion criteria to map the difference in cerebral blood flow reduction between healthy ageing and Alzheimer's disease. Analysis was also performed on the effect of imaging modality and brain region functionality as potential confounding factors. KEY MESSAGES: No significant difference was found between the specific functionality of a brain region and cerebral blood flow in healthy ageing (p = 0.65) or Alzheimer's disease (p = 0.42). Arterial spin labelling MRI imaging was shown to measure statistically larger decreases in flow in both healthy ageing (p = 0.0001) and Alzheimer's disease (p = 0.0465). Cerebral blood flow was shown to decrease 0.3-0.5% per year in healthy ageing, which increased to a decline of 2-5% per year in Alzheimer's disease. There was large variability both between and within individual brain regions, and this variability increased greatly in Alzheimer's disease. Future studies would add value by taking more cerebral blood flow measurements during Alzheimer's disease progression and by investigating ageing with comorbidities such as hypertension.

The need for a course to complete urological education for consultant practice using a simulated 'boot camp' structure at the end of specialist training: A survey-based study.

BACKGROUND AND AIMS: To obtain opinions from urology trainees and consultants regarding the need for, and structure of, a post-specialty training Urology Simulation Boot Camp (USBC) for consultant practice. METHODS AND RESULTS: A survey-based study was conducted, and 'Google Forms' were distributed electronically via social media. Urology specialist trainees (ST) in years 5-7 (ST5-ST7), post-certification of completion of training (CCT) fellows and ST3 boot camp faculty consultants in practice for ≤5 years and >5 years were included. One hundred and seven responses were received. 97.2% of responders thought a pre-consultant USBC was worthwhile; 55.1% selected the course duration to be 2 days. 47.7% felt that the USBC should be delivered post-exam in ST7. 91.6%, 43.9%, 73.8%, 87.9% and 74.8% considered that modules in emergency operative procedures, novel uro-technologies, delivering multidisciplinary team (MDT) meetings, non-clinical consultant roles and responsibilities, stress and burnout to be important, respectively. 62.6% and 31.8% felt that the course should be wholly or part-funded by Health Education England (HEE). CONCLUSIONS: A post-specialty training, pre-consultant, USBC delivered post-exam in ST7, is worthwhile and should include modules on emergency operative procedures, leading MDTs, non-clinical roles and responsibilities and managing stress and burnout in consultant careers. Ideally, it should be fully/part-funded by HEE.

Understanding the needs of low-income countries: how urologists can help.

Delivering urological humanitarian aid to countries with greater need has been provided by urologists associated with British Association of Urological Surgeons (BAUS) Urolink over the last 30 years. Urolink has realised the need to understand where that need is geographically, what tangible help is required, and how assistance can be delivered in the most ethically appropriate way. The World Bank stratification of countries by per capita gross national income has helped in the identification of low-come countries or lower-middle-income countries (LMICs), the vast majority of which are in sub-Saharan Africa. The medical and socioeconomic needs of those country's populations, which constitute 17% of the global community, are substantially different from that required in higher income countries. More than 40% of sub-Saharan Africa's population is aged <14 years, it has a substantially reduced life expectancy, which influences the type of pathologies seen, and perinatal complications are a major cause of morbidity for both mother and child. There is a significant problem with the availability of medical care in these countries and almost a third of global deaths have been attributed to the lack of access to emergency and elective surgery. Urologically, the main conditions demanding the attention of the very few available urologists are congenital anomalies, benign prostatic hypertrophy, urolithiasis, urethral stricture, and pelvic cancer. The management of these conditions is often substantially different from that in the UK, being limited by a lack of personnel, equipment, and access to geographically relevant guidelines appropriate to the healthcare environment. Assisting LMICs to develop sustainable urological services can be helped by understanding the local needs of linked institutions, establishing trusting and durable relationships with partner centres and by providing appropriate education that can be perpetuated, and disseminated, across a region of need.

The feasibility of endourological surgery in low-resource settings.

One of the widest variations in contemporary surgical practice between high and low, or low-middle, income countries is the utilisation of endoscopy as a means of treating urological pathology. The endoscopic management of lower urinary tract problems such as benign prostatic hypertrophy, bladder cancer and urethral strictures was established in the UK in the late 1970s, whilst its adoption into everyday practice in sub-Saharan Africa (SSA) has been significantly retarded. It is still neither a major feature of urological training in those countries nor widely available to the patients that established consultants treat. Likewise, the explosion of less invasive technologies for treating upper tract stone disease in the 1980s, particularly the management of renal stone disease, has also lagged behind practice established in the UK over the last 40 years. This is not due to a lack of patients who could be treated endoscopically or restricted by the abilities of the surgeons in SSA. The restraint in assumption of these less-invasive management options is rather due to the physical availability of trained specialist surgeons, their access to basic infrastructure such as electricity and water, access to endoscopes and the peripheral equipment necessary to successfully deploy them, and the ability of patients to afford the disposable items required for less-invasive forms of management. Some endoscopic procedures are viable in resource-poor settings. However, they are largely dependent upon the supply of equipment from non-governmental organisations in high-income countries, frugal innovation to reduce individual procedure costs, adequately skilled mentors, and maintenance and supply chains to make them a durable option in patient management. Urolink and the Medi Tech Trust present their experience of how endoscopic surgery can be taught, and used sustainably, in a resource-poor healthcare environment.

Paediatric urology in Sub-Saharan Africa: challenges and opportunities.

The need for paediatric urological care in low- and middle-income countries in sub-Saharan Africa (SSA) is enormous due to a burgeoning paediatric-aged population and a disproportionate burden of congenital malformations. There are formidable challenges in the provision of a skilled workforce and appropriate infrastructure, resulting in a huge unmet need with consequent effects on the long-term health and prosperity of the population. Constraints of funding, geography, culture, surgical and anaesthetic skills, and instrumentation means that many conditions present late and with complications that could have been avoided by an earlier attendance. It also means that the management of congenital malformations, e.g., bladder exstrophy and congenital obstructive posterior urethral membrane, differ substantially from that seen in the developed world, with the outlook for children with renal failure being particularly bleak. Collaborations between paediatric urologists from high- and low-income countries are beginning to help with the development of a surgical infrastructure customised to paediatric care, and with the training of specific paediatric urological knowledge and skills. These collaborations, whilst welcome, still require substantial expansion to achieve more equitable access to appropriate paediatric urological care for children in SSA. Future efforts have to focus on the creation of sustainable and equal partnerships between urologists from low- and high-income healthcare environments, with an emphasis on providing sustainable management, appropriate to local need and available resources. The provision of shared learning, utilising the benefits of global digital communication, will improve mutual understanding of needs in a resource-poor environment and the involvement of trainees from both income settings can help perpetuate long-term collaborations.

Understanding cultural and logistical contexts for urologists in low-income countries.

The provision of effective urological management in low- and middle-income countries requires the delivery of appropriate and effective care adapted to the needs, capability and resources of the host country. However, a deeper cognisance of the culture, the religious practices and the logistics of healthcare in that environment determines the ability to effectively to 'twin', that is, to provide a long-term healthcare partnership. Patient beliefs can have profound effects on the understanding of the aetiology of illness, its relevance to their long-term health and the stigmatization of their family's social status. Consequently, individuals may have a greater willingness to seek help from practitioners of traditional medicine due to its availability as well as the lower costs of such medicine by comparison to those of medicine from high-income countries (HICs). This can influence the treatment of many urological conditions and lead to late-presenting states such as malignant ureteric obstruction. Social mores, such as cultural paternalism, can also influence many practices that are assumed by HICs to be part of normal healthcare provision, including the delivery of patient information and provision of informed consent to treatment. Doctor's status and dress have greater importance in many countries in sub-Saharan Africa (sSA) than in the UK and the modes of greeting and addressing colleagues and patients can affect the fluency and effectiveness of clinical interactions. A local cultural and religious knowledge is essential, therefore, to optimize the assimilation of external help. Logistics are perhaps the most important factor that needs to be grasped to provide a sustainable healthcare environment. Limitations in resource allocation are a major factor in planning effective urological treatment in many countries in sSA, whether this is the provision of trained personnel, basic infrastructure, a tenable workspace, equipment or drugs. This paper explores all of these factors, and looks at how their recognition assists urologists in providing a twinning process.

The benefits of virtual learning webinars to both low- and high-income countries.

The coronavirus disease 2019 (COVID-19) pandemic has brought about many changes in the relationships between high-income countries and partner organisations in low- or low-middle-income countries, such as predominate in sub-Saharan Africa. Medicine, surgery and in particular urology is no exception to the changes that COVID-19 has demanded. Urolink represents the British Association of Urological Surgeons (BAUS) on the global urology stage and has been deleteriously impacted by the pandemic. Education, one of the pillars of Urolink's founding philosophies, has conventionally been delivered by face-to face teaching, training, or mentoring by UK urologists at their host's site outside of the UK. As a consequence of the inability to travel due to the pandemic, BAUS Urolink has evolved a virtual on-line webinar package evolved by, and delivered between, urologists in Lusaka, Zambia, and various centres in the UK. The aim was to deliver curricular-based educational topics to trainees in both countries. This programme has generated a number of live webinars and archived recordings during the pandemic that has proven accessible and educationally acceptable to trainees in the UK and Zambia. This webinar series has also generated relationships between young urologists on different continents, given each a different view of healthcare delivery outside of their country of origin at no appreciable cost, and would appear to be an educational mechanism that is durable for, and applicable to, a wider participation in the post-pandemic world.

Adaptations in models of urological regulation and their application to sub-Saharan Africa.

Regulation of medical care is something that has grown from humble roots in professional craft groups to huge establishment in well-resourced, high-income countries. Self-regulation was the preferred method of determining appropriate behaviour initially, but a lack of public trust in this, and the desire of patients to contribute to the establishment of the standard of care that they receive, has meant that most Anglophone countries have adopted some form of independent regulation. Regulators are responsible for the registration of doctor's qualifications, licensing them to practise, accrediting institutions to provide undergraduate and postgraduate education and certifying the attainment of accepted standards of achievement by some form of assessment process. Regulators also have powers to sanction individuals whose practice falls outside expected levels of competence. Both centralized and devolved models of regulation have evolved. Much of the accreditation for postgraduate education and training has been handed down to collegiate bodies, or non-governmental organizations, who can also certify completion of training. Evidence-based medicine and clinical practice guidelines have enforced an informal tier of regulation in high-income countries; guideline-derived practice is now widely regarded as an accepted standard of care. In low- and middle-income countries in sub-Saharan Africa the governmental and legislative structures and finance available to provide the regulation espoused in more privileged environments is rarely available. The workforce is structured in a completely different way and some care groups are totally unregulated. Medical councils in sub-Saharan Africa fulfil a registration and licensing function but surgical collegiate bodies provide the structure for postgraduate training. The East and West African Colleges of Surgeons have developed into robust organizations, who have verifiable, quality-assured, accreditation systems that have helped improve standards of care for the large populations for which their member surgeons are responsible. Formal regulation of continuing practice and sanctions are challenges that are, at present, largely unaddressed.

Female urinary incontinence in sub-Saharan Africa.

Urinary incontinence (UI) is highly prevalent amongst women around the world. In this review article we explore UI, its consequences and treatment in sub-Saharan Africa, providing specific examples from Uganda and Malawi. In sub-Saharan Africa the prevalence of UI is difficult to assess because of the wide variation in reporting resulting from patients hiding their condition due to the associated stigma in many communities. Whilst much of the literature from low- or low-middle-income countries focuses on UI from pelvic floor fistula, recent evidence demonstrates that non-fistulous stress, urgency and mixed UI are highly prevalent in sub-Saharan Africa. Incontinence secondary to vesico-vaginal fistula can be related to obstetric causes, mainly obstructed labour. The risk factors for non-fistulous incontinence are similar to those identified in high-income countries, including high parity, vaginal and assisted delivery, gestational age, constipation, obesity, chronic cough and ageing. Urinary incontinence has significant social and emotional consequences, with a high proportion of women in African countries reporting relationship problems, depression and suicidal ideation. There is poor understanding of the perceived aetiology of incontinence in sub-Saharan Africa, which may, in part, act as a barrier for women to seek medical advice. Innovative solutions have been found to manage the large number of obstetric fistulas that are prevalent across Africa, but a lack of capacity in specialists trained to treat women with UI means that more doctors, medical officers and better resource prioritization will be required to help the, as yet unquantified, number of women with non-fistulous leakage. Better patient peri-natal education may reduce the incidence of fistula still further, especially if the stigma felt by women with incontinence is overcome and they are encouraged to seek treatment.

Male urethral stricture disease: why management guidelines are challenging in low-income countries.

Urethral stricture disease (USD) is one of the commonest urological pathologies in adult men in low- or low-middle-income countries, providing a significant work burden for the small number of specialist surgeons who are able to provide appropriate treatment. The underlying causes of anterior urethral stricture relate to urethral fibrosis from sexually transmitted infection, with posterior urethral disruption secondary to pelvic trauma being an equally common cause of USD in many countries in sub-Saharan Africa. Anterior urethral strictures are often long, and multifocal, and bulbo-prostatic disruptions are usually due to relatively low-velocity pelvic trauma. The management options available in resource-poor settings are often severely limited by the individual's ability to pay for care, the availability of a specialist surgeon and, importantly, a shortage of functioning endoscopic equipment for less-invasive treatments. Consequently, reconstructive surgery is often regarded by the patient, and surgeon, as the most cost-effective and, therefore, primary means of treating a urethral stricture once urethral dilatation has failed. Regional anaesthetic techniques have limited the adoption of free-graft augmentation as an alternative to pedicled flaps of locally available skin for reconstruction, whilst an inability to provide tension-free bulbo-prostatic anastomoses has negatively impacted the outcome from the treatment of pelvic fracture disruption injuries in much of sub-Saharan Africa. However, Urolink has found that local surgeons can be taught sustainable skills required for successful complex urethroplasty when supported by longitudinal mentorship in the management of difficult clinical issues. Evidence-based practice is known to improve the standard of care in specific conditions in high-income countries, including the management of male USD. However, guidelines developed in high-income countries are not necessarily appropriate for stricture management in less well-resourced healthcare environments but could be adapted to help improve the delivery of stricture care for men in low- or low-middle income countries.

Stone disease in low- and middle-income countries: could augmented reality have a role in its management?

Urolithiasis is a global phenomenon. Cystolithiasis is common in parts of Africa due to low protein intake and dehydration from endemic diarrhoeal illnesses. Nephrolithiasis is less prevalent than in high-income countries, probably due to a variety of lifestyle issues, such as a more elemental diet, higher physical activity, and less obesity. Although renal stones are less common in low- and middle-income countries (LMICs), the social and economic impacts of nephrolithiasis are still considerable; many stones present late or with complications such as upper urinary tract obstruction or urosepsis. These may lead to the development of chronic kidney disease, or end-stage renal failure in a small proportion of cases, conditions for which there is very poor provision in most LMICs. Early treatment of nephrolithiasis by the least invasive method possible can, however, reduce the functional consequences of urinary stone disease. Although extracorporeal lithotripsy is uncommon, and endoscopic interventions for stone are not widespread in most of Africa, percutaneous nephrolithotomy and ureteroscopic renal surgery are viable techniques in those regional centres with infrastructure to support them. Longitudinal mentoring has been shown to be a key step in the adoption of these minimally invasive procedures by local surgeons, something that has been difficult during the coronavirus disease 2019 (COVID-19) pandemic due to travel restriction. Augmented reality (AR) technology is an alternative means of providing remote mentoring, something that has been trialled by Urolink, the MediTech Trust and other global non-governmental organisations during this period. Our preliminary experience suggests that this is a viable technique for promulgating skills in LMICs where appropriate connectivity exists to support remote communication. AR may also have long-term promise for decreasing the reliance upon short-term surgical visits to consolidate competence, thereby reducing the carbon footprint of global surgical education.

Modelling the impact of clot fragmentation on the microcirculation after thrombectomy.

Many ischaemic stroke patients who have a mechanical removal of their clot (thrombectomy) do not get reperfusion of tissue despite the thrombus being removed. One hypothesis for this 'no-reperfusion' phenomenon is micro-emboli fragmenting off the large clot during thrombectomy and occluding smaller blood vessels downstream of the clot location. This is impossible to observe in-vivo and so we here develop an in-silico model based on in-vitro experiments to model the effect of micro-emboli on brain tissue. Through in-vitro experiments we obtain, under a variety of clot consistencies and thrombectomy techniques, micro-emboli distributions post-thrombectomy. Blood flow through the microcirculation is modelled for statistically accurate voxels of brain microvasculature including penetrating arterioles and capillary beds. A novel micro-emboli algorithm, informed by the experimental data, is used to simulate the impact of micro-emboli successively entering the penetrating arterioles and the capillary bed. Scaled-up blood flow parameters-permeability and coupling coefficients-are calculated under various conditions. We find that capillary beds are more susceptible to occlusions than the penetrating arterioles with a 4x greater drop in permeability per volume of vessel occluded. Individual microvascular geometries determine robustness to micro-emboli. Hard clot fragmentation leads to larger micro-emboli and larger drops in blood flow for a given number of micro-emboli. Thrombectomy technique has a large impact on clot fragmentation and hence occlusions in the microvasculature. As such, in-silico modelling of mechanical thrombectomy predicts that clot specific factors, interventional technique, and microvascular geometry strongly influence reperfusion of the brain. Micro-emboli are likely contributory to the phenomenon of no-reperfusion following successful removal of a major clot.

Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.

Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.