A common tumour in a rare location: a single centre case series of cerebellar glioblastoma.

Although glioblastoma is the commonest primary brain tumour in adults, its location in the cerebellum is extremely rare. We present thirteen cases (3 female, 10 male; median age at presentation 56 [age range 21-77]) of surgically managed, histologically confirmed, primary cerebellar glioblastoma (cGB) over a 17 year period (2005-2022). Pre-operative radiological diagnosis was challenging given cGB rarity, although MRI demonstrated ring enhancement in all cases. Surgical management included posterior fossa craniectomy and debulking in 11 cases and burr hole biopsy in two. CSF diversion was necessary in four cases. No evidence of IDH or ATRX gene mutations was found when tested. Survival ranged from 1 to 22 months after diagnosis (mean 10.9 months). We also seek to understand why glioblastoma is rare in this location and discuss potential reasons for this. We hypothesise that increasing anatomical distance from germinal regions and decreased local endogenous neural stem cell activity (which has been associated with glioblastoma) may explain why glioblastoma is rare in the cerebellum. We hereby seek to add to the limited literature on cGB as this is the largest UK cGB series to date.

Radiological follow-up of endovascularly treated intracranial aneurysms: a survey of current practice in the UK and Ireland.

PURPOSE: Due to the risk of intracranial aneurysm (IA) recurrence and the potential requirement for re-treatment following endovascular treatment (EVT), radiological follow-up of these aneurysms is necessary. There is little evidence to guide the duration and frequency of this follow-up. The aim of this study was to establish the current practice in neurosurgical units in the UK and Ireland. METHODS: A survey was designed with input from interventional neuroradiologists and neurosurgeons. Neurovascular consultants in each of the 30 neurosurgical units providing a neurovascular service in the UK and Ireland were contacted and asked to respond to questions regarding the follow-up practice for IA treated with EVT in their department. RESULTS: Responses were obtained from 28/30 (94%) of departments. There was evidence of wide variations in the duration and frequency of follow-up, with a minimum follow-up duration for ruptured IA that varied from 18 months in 5/28 (18%) units to 5 years in 11/28 (39%) of units. Young patient age, previous subarachnoid haemorrhage and incomplete IA occlusion were cited as factors that would prompt more intensive surveillance, although larger and broad-necked IA were not followed-up more closely in the majority of departments. CONCLUSIONS: There is a wide variation in the radiological follow-up of IA treated with EVT in the UK and Ireland. Further standardisation of this aspect of patient care is likely to be beneficial, but further evidence on the behaviour of IA following EVT is required in order to inform this process.

Coughing on the coil; a case report and literature review of eight cases of endovascularly treated ICA pseudoaneurysms with coil migration into the oropharnyx.

We report a case of coil migration into the oropharynx five years after treatment of a left internal carotid pseudoaneurysm following abandoned transsphenoidal resection of a pituitary macroadenoma. Eight other cases were found on literature review, with coil migration occurring between 2 and 120 months often after a history of transsphenoidal surgery. The majority of these were treated with trimming in a day case setting. This report highlights the need for careful extended follow up when a pseudoaneurysm forms with a concurrent skull base deficit.

A survey of the radiological follow-up of unruptured intracranial aneurysms in the United Kingdom.

OBJECTIVE: Unruptured intracranial aneurysms (UIA) are common. For many the treatment risks outweigh their risk of subarachnoid haemorrhage and patients undergo surveillance imaging. There is little data to inform if and how to monitor UIAs resulting in widely varying practices. This study aimed to determine the current practice of unruptured UIA surveillance in the United Kingdom. METHODS: A questionnaire was designed to address the themes of surveillance protocols for UIA including when surveillance is initiated, how frequently it is performed, and when it is terminated. Additionally, how aneurysm growth is managed and how clinically meaningful growth is defined were explored. The questionnaire was distributed to members of the British Neurovascular Group using probability-based cluster and non-probability purposive sampling methods. RESULTS: Responses were received from 30 of the 30 (100.0%) adult neurosurgical units in the United Kingdom of which 27 (90.0%) routinely perform surveillance for aneurysm growth. Only four units had a unit policy. The mean patient age up to which a unit would initiate follow-up of a low-risk UIA was 65.4 ± 9.0 years. The time points at which imaging is performed varied widely. There was an even split between whether units use a fixed duration of follow-up or an age threshold for terminating surveillance. Forty percent of units will follow-up patients more than 5 years from diagnosis. The magnitude in the change in size that was felt to constitute growth ranged from 1 to 3mm. No units routinely used vessel wall imaging although 27 had access to 3T MRI capable of performing it. CONCLUSIONS: There is marked heterogeneity in surveillance practices between units in the United Kingdom. This study will help units better understand their practice relative to their peers and provide a framework forplanning further research on aneurysm growth.

Excluding subarachnoid haemorrhage within 24 hours: to LP or not to LP?

BACKGROUND AND PURPOSE: Subarachnoid haemorrhage (SAH) is a potentially life-threatening cause of acute headache. Current conventional practice in the United Kingdom (UK) is for head computed tomography (CT) followed by cerebrospinal fluid (CSF) xanthochromia analysis if the head CT is normal. However, with increasing radiological accuracy, head CT alone may be sufficient to exclude SAH without requiring CSF xanthochromia for confirmation. This study aims to determine whether CSF xanthochromia is still required to confirm exclusion of SAH after normal head CT within a tertiary referral centre. METHODS: Data was obtained from Nottingham University Hospitals (NUH) NHS Trust databases on 999 patients presenting with symptoms suspicious of SAH from 2012 to 2015. All patients had CSF xanthochromia analysis when head CT was normal or inconclusive for suspected SAH. RESULTS: A total of 179 patients were diagnosed with SAH (17.9%). 176 patients were diagnosed radiologically and 3 patients required further investigations. The 3 of the 802 patients who underwent lumbar puncture (LP) and were identified as having had SAH presented more than 24 hours after ictus. When stratified according to the time of presentation, a normal CT head was observed in those who presented within 24 hours from ictus (sensitivity of 100% [95% CI 92.5-100] and negative predictive value of 100% [97.2-100]). CONCLUSION: Within a tertiary referral centre for SAH, a normal head CT has a very high negative predictive value to exclude SAH when carried out within 24 hours from ictus provided a 3rd generation CT scanner is utilised, and the scan is reported by a neuroradiologist. CSF xanthochromia analysis in this cohort may still be indicated in those presenting with a high clinical suspicion of SAH and in hospital settings where neuroradiologists or 3rd generation CT scanners are not easily accessible.

CSF rhinorrhoea after endonasal intervention to the anterior skull base (CRANIAL): proposal for a prospective multicentre observational cohort study.

BACKGROUND: The endonasal transsphenoidal approach (TSA) has emerged as the preferred approach in order to treat pituitary adenoma and related sellar pathologies. The recently adopted expanded endonasal approach (EEA) has improved access to the ventral skull base whilst retaining the principles of minimally invasive surgery. Despite the advantages these approaches offer, cerebrospinal fluid (CSF) rhinorrhoea remains a common complication. There is currently a lack of comparative evidence to guide the best choice of skull base reconstruction, resulting in considerable heterogeneity of current practice. This study aims to determine: (1) the scope of the methods of skull base repair; and (2) the corresponding rates of postoperative CSF rhinorrhoea in contemporary neurosurgical practice in the UK and Ireland. METHODS: We will adopt a multicentre, prospective, observational cohort design. All neurosurgical units in the UK and Ireland performing the relevant surgeries (TSA and EEA) will be eligible to participate. Eligible cases will be prospectively recruited over 6 months with 6 months of postoperative follow-up. Data points collected will include: demographics, tumour characteristics, operative data), and postoperative outcomes. Primary outcomes include skull base repair technique and CSF rhinorrhoea (biochemically confirmed and/or requiring intervention) rates. Pooled data will be analysed using descriptive statistics. All skull base repair methods used and CSF leak rates for TSA and EEA will be compared against rates listed in the literature. ETHICS AND DISSEMINATION: Formal institutional ethical board review was not required owing to the nature of the study - this was confirmed with the Health Research Authority, UK. CONCLUSIONS: The need for this multicentre, prospective, observational study is highlighted by the relative paucity of literature and the resultant lack of consensus on the topic. It is hoped that the results will give insight into contemporary practice in the UK and Ireland and will inform future studies.

Disruption of stomatal lineage signaling or transcriptional regulators has differential effects on mesophyll development, but maintains coordination of gas exchange.

Stomata are simultaneously tasked with permitting the uptake of carbon dioxide for photosynthesis while limiting water loss from the plant. This process is mainly regulated by guard cell control of the stomatal aperture, but recent advancements have highlighted the importance of several genes that control stomatal development. Using targeted genetic manipulations of the stomatal lineage and a combination of gas exchange and microscopy techniques, we show that changes in stomatal development of the epidermal layer lead to coupled changes in the underlying mesophyll tissues. This coordinated response tends to match leaf photosynthetic potential (Vcmax ) with gas-exchange capacity (gsmax ), and hence the uptake of carbon dioxide for water lost. We found that different genetic regulators systematically altered tissue coordination in separate ways: the transcription factor SPEECHLESS (SPCH) primarily affected leaf size and thickness, whereas peptides in the EPIDERMAL PATTERNING FACTOR (EPF) family altered cell density in the mesophyll. It was also determined that interlayer coordination required the cell-surface receptor TOO MANY MOUTHS (TMM). These results demonstrate that stomata-specific regulators can alter mesophyll properties, which provides insight into how molecular pathways can organize leaf tissues to coordinate gas exchange and suggests new strategies for improving plant water-use efficiency.

Flying saucer1 is a transmembrane RING E3 ubiquitin ligase that regulates the degree of pectin methylesterification in Arabidopsis seed mucilage.

Pectins are complex polysaccharides that form the gel matrix of the primary cell wall and are abundant in the middle lamella that holds plant cells together. Their degree of methylesterification (DM) impacts wall strength and cell adhesion since unesterified pectin regions can cross-link via Ca(2+) ions to form stronger gels. Here, we characterize flying saucer1 (fly1), a novel Arabidopsis thaliana seed coat mutant, which displays primary wall detachment, reduced mucilage extrusion, and increased mucilage adherence. These defects appear to result from a lower DM in mucilage and are enhanced by the addition of Ca(2+) or completely rescued using alkaline Ca(2+) chelators. FLY1 encodes a transmembrane protein with a RING-H2 domain that has in vitro E3 ubiquitin ligase activity. FLY1 is orthologous to TRANSMEMBRANE UBIQUITIN LIGASE1, a Golgi-localized E3 ligase involved in the quality control of membrane proteins in yeast. However, FLY1-yellow fluorescent protein (YFP) fusions are localized in punctae that are predominantly distinct from the Golgi and the trans-Golgi network/early endosome in the seed coat epidermis. Wortmannin treatment, which induces the fusion of late endosomes in plants, resulted in enlarged FLY1-YFP bodies. We propose that FLY1 regulates the DM of pectin in mucilage, potentially by recycling pectin methylesterase enzymes in the endomembrane system of seed coat epidermal cells.

Therapeutic antibody targeting of individual Notch receptors.

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.

An integrated model of stomatal development and leaf physiology.

• Stomatal conductance (g(s)) is constrained by the size and number of stomata on the plant epidermis, and the potential maximum rate of g(s) can be calculated based on these stomatal traits (Anatomical g(smax)). However, the relationship between Anatomical g(smax) and operational g(s) under atmospheric conditions remains undefined. • Leaf-level gas-exchange measurements were performed for six Arabidopsis thaliana genotypes that have different Anatomical g(smax) profiles resulting from mutations or transgene activity in stomatal development. • We found that Anatomical g(smax) was an accurate prediction of g(s) under gas-exchange conditions that maximized stomatal opening, namely high-intensity light, low [CO2], and high relative humidity. Plants with different Anatomical g(smax) had quantitatively similar responses to increasing [CO2] when g(s) was scaled to Anatomical g(smax). This latter relationship allowed us to produce and test an empirical model derived from the Ball-Woodrow-Berry equation that estimates g(s) as a function of Anatomical g(smax), relative humidity, and [CO2] at the leaf. • The capacity to predict operational g(s) via Anatomical g(smax) and the pore-specific short-term response to [CO2] demonstrates a precise link between stomatal development and leaf physiology. This connection should be useful to quantify the gas flux of plants in past, present, and future CO2 regimes based upon the anatomical features of stomata.

The physiological importance of developmental mechanisms that enforce proper stomatal spacing in Arabidopsis thaliana.

• Genetic and cell biological mechanisms that regulate stomatal development are necessary to generate an appropriate number of stomata and enforce a minimum spacing of one epidermal cell between stomata. The ability to manipulate these processes in a model plant system allows us to investigate the physiological importance of stomatal patterning and changes in density, therein testing underlying theories about stomatal biology. • Twelve Arabidopsis thaliana genotypes that have varied stomatal characteristics as a result of mutations or transgenes were analyzed in this study. Stomatal traits were used to categorize the genotypes and predict maximum stomatal conductance to water vapor (Anatomical g(smax)) for individuals. Leaf-level gas-exchange measurements determined Diffusive g(smax), net carbon assimilation (A), water-use efficiency (WUE), and stomatal responses to increasing CO2 concentration. Genotypes with proper spacing (< 5% of stomata in clusters) achieved Diffusive g(smax) values comparable to Anatomical g(smax) across a 10-fold increase in stomatal density, while lines with patterning defects (> 19% clustering) did not. • Genotypes with clustering also had reduced A and impaired stomatal responses, while WUE was generally unaffected by patterning. • Consequently, optimal function per stoma was dependent on maintaining one epidermal cell spacing and the physiological parameters controlled by stomata were strongly correlated with Anatomical g(smax).

A Reappraisal of the Pathophysiology of Cushing Ulcer: A Narrative Review.

In 1932, Harvey Cushing described peptic ulceration secondary to raised intracranial pressure and attributed this to vagal overactivity, causing excess gastric acid secretion. Cushing ulcer remains a cause of morbidity in patients, albeit one that is preventable. This narrative review evaluates the evidence pertaining to the pathophysiology of neurogenic peptic ulceration. Review of the literature suggests that the pathophysiology of Cushing ulcer may extend beyond vagal mechanisms for several reasons: (1) clinical and experimental studies have shown only a modest increase in gastric acid secretion in head-injured patients; (2) increased vagal tone is found in only a minority of cases of intracranial hypertension, most of which are related to catastrophic, nonsurvivable brain injury; (3) direct stimulation of the vagus nerve does not cause peptic ulceration, and; (4) Cushing ulcer can occur after acute ischemic stroke, but only a minority of strokes are associated with raised intracranial pressure and/or increased vagal tone. The 2005 Nobel Prize in Medicine honored the discovery that bacteria play key roles in the pathogenesis of peptic ulcer disease. Brain injury results in widespread changes in the gut microbiome in addition to gastrointestinal inflammation, including systemic upregulation of proinflammatory cytokines. Alternations in the gut microbiome in patients with severe traumatic brain injury include colonization with commensal flora associated with peptic ulceration. The brain-gut-microbiome axis integrates the central nervous system, the enteric nervous system, and the immune system. Following the review of the literature, we propose a novel hypothesis that neurogenic peptic ulcer may be associated with alterations in the gut microbiome, resulting in gastrointestinal inflammation leading to ulceration.

Risk of Aneurysm Rupture (ROAR) study: protocol for a long-term, longitudinal, UK multicentre study of unruptured intracranial aneurysms.

INTRODUCTION: Unruptured intracranial aneurysms (UIA) are common in the adult population, but only a relatively small proportion will rupture. It is therefore essential to have accurate estimates of rupture risk to target treatment towards those who stand to benefit and avoid exposing patients to the risks of unnecessary treatment. The best available UIA natural history data are the PHASES study. However, this has never been validated and given the known heterogeneity in the populations, methods and biases of the constituent studies, there is a need to do so. There are also many potential predictors not considered in PHASES that require evaluation, and the estimated rupture risk is largely based on short-term follow-up (mostly 1 year). The aims of this study are to: (1) test the accuracy of PHASES in a UK population, (2) evaluate additional predictors of rupture and (3) assess long-term UIA rupture rates. METHODS AND ANALYSIS: The Risk of Aneurysm Rupture study is a longitudinal multicentre study that will identify patients with known UIA seen in neurosurgery units. Patients will have baseline demographics and aneurysm characteristics collected by their neurosurgery unit and then a single aggregated national cohort will be linked to databases of hospital admissions and deaths to identify all patients who may have subsequently suffered a subarachnoid haemorrhage. All matched admissions and deaths will be checked against medical records to confirm the diagnosis of aneurysmal subarachnoid haemorrhage. The target sample size is 20 000 patients. The primary outcome will be aneurysm rupture resulting in hospital admission or death. Cox regression models will be built to test each of the study's aims. ETHICS AND DISSEMINATION: Ethical approval has been given by South Central Hampshire A Research Ethics Committee (21SC0064) and Confidentiality Advisory Group support (21CAG0033) provided under Section 251 of the NHS Act 2006. The results will be disseminated in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN17658526.

An explanation for Terson syndrome at last: the glymphatic reflux theory.

Terson Syndrome (TS) describes the presence of intraocular hemorrhage in patients with intracranial hemorrhage, typically subarachnoid hemorrhage. Despite TS being a well-defined and frequently occurring phenomenon, its pathophysiology remains controversial. This review will present the current understanding of TS, with view to describing a contemporary and more plausible pathomechanism of TS, given recent advances in ophthalmic science and neurobiology. Previously proposed theories include a sudden rise in intracranial pressure (ICP) transmitted to the optic nerve sheath leading to rupture of retinal vessels; or intracranial blood extending to the orbit via the optic nerve sheath. The origin of blood in TS is uncertain, but retinal vessels appear to be an unlikely source. In addition, an anatomical pathway for blood to enter the eye from the intracranial space remains poorly defined. An ocular glymphatic system has recently been described, drainage of which from the globe into intracranial glymphatics is reliant on the pressure gradient between intraocular pressure and intracranial pressure. The glymphatic pathway is the only extravascular anatomical conduit between the subarachnoid space and the retina. We propose that subarachnoid blood in skull base cisterns near the optic nerve is the substrate of blood in TS. Raised ICP causes it to be refluxed through glymphatic channels into the globe, resulting in intraocular hemorrhage. We herewith present glymphatic reflux as an alternative theory to explain the phenomenon of Terson Syndrome.

Retrospective Review of Surgical Site Infections after Endoscopic Endonasal Sellar and Parasellar Surgery: Multicenter Quality Data from the North American Skull Base Society.

Introduction Transnasal access to the anterior skull base provides a minimally invasive approach for sellar and parasellar masses compared with its open counterparts. The unique microbiome of the sinonasal mucosa provides distinct challenges not encountered with other cranial approaches. The use of antibiotics in these cases has not been standardized, and data remain scarce regarding infectious outcomes. Methods We conducted a multicenter retrospective analysis of shared quality data points for the endoscopic endonasal approach (EEA) for pituitary adenomas, along with other sellar and parasellar region masses that were included by participating institutions. Patient and operative characteristics, perioperative and postoperative antibiotic regimens and their durations, intraoperative and postoperative cerebrospinal fluid leak, and onset of postoperative meningitis and sinusitis were compared. Results Fifteen institutions participated and provided 6 consecutive months' worth of case data. Five hundred ninety-three cases were included in the study, of which 564 were pituitary adenomectomies. The incidences of postoperative meningitis and sinusitis were low (0.67 and 2.87% for all pathologies, respectively; 0.35% meningitis for pituitary adenomas) and did not correlate with any specific antibiotic regimen. Immunocompromised status posed an increased odds of meningitis in pituitary adenomectomies (28.6, 95% confidence interval [1.72-474.4]). Conclusions The results show no clear benefit to postoperative antimicrobial use in EEA, with further larger studies needed.

Plant Biology: Rethinking Structure-Function Relationships in Guard Cells.

Recent findings highlight the role of polar reinforcement in guard cell function, which simultaneously improves our understanding of stomatal mechanics and questions our long-standing beliefs about structurally important factors.

Vein density is independent of epidermal cell size in Arabidopsis mutants.

Densities of leaf minor veins and stomata are co-ordinated within and across vascular plants. This maximises the benefit-to-cost ratio of leaf construction by ensuring stomata receive the minimum amount of water required to maintain optimal aperture. A 'passive dilution' mechanism in which densities of veins and stomata are co-regulated by epidermal cell size is thought to facilitate this co-ordination. However, unlike stomata, veins are spatially isolated from the epidermis and thus may not be directly regulated by epidermal cell expansion. Here, we use mutant genotypes of Arabidopsis thaliana (L.) Heynh. with altered stomatal and epidermal cell development to test this mechanism. To do this we compared observed relationships between vein density and epidermal cell size with modelled relationships that assume veins and stomata are passively diluted by epidermal cell expansion. Data from wild-type plants were consistent with the 'passive dilution' mechanism, but in mutant genotypes vein density was independent of epidermal cell size. Hence, vein density is not causally linked to epidermal cell expansion. This suggests that adaptation favours synchronised changes to the cell size of different leaf tissues to coordinate veins and stomata, and thus balance water supply with transpirational demand.

Spinal tumors in neurofibromatosis type 2. Is emerging knowledge of genotype predictive of natural history?

OBJECT: The authors conducted a study to examine the incidence, classification, and progression of spinal tumors in patients with neurofibromatosis Type 2 (NF2) treated at a single center, and to examine relationships with the known mutational subtypes of NF2. METHODS: They performed a retrospective review of clinical records, neuroimaging studies, and genetic data obtained in 61 patients with NF2. Forty-one (67%) of 61 patients harbored one or more spinal tumors. Thirty-four patients had undergone serial spinal magnetic resonance imaging during a mean follow-up period of 52 months (range 10-103 months; median 53 months). In 16 patients there were multiple extramedullary tumors smaller than 5 mm, which did not progress. Fourteen patients harbored at least one extramedullary tumor that was greater than 5 mm; of these, radiological progression was demonstrated or spinal tumor excision was performed during the follow-up period in eight cases (57%). Eleven patients harbored intramedullary cord tumors in addition to small and large extramedullary tumors, three (27%) of which exhibited radiological progression. In cases in which genotypes were known, protein-truncating mutations were significantly more likely to be associated with the presence of spinal tumors than in other types (p = 0.03, Fisher exact test). No associations between clinical behavior of spinal tumors and genotype, however, could be demonstrated. CONCLUSIONS: Spinal tumors in cases involving NF2 are heterogeneous in type, distribution, and behavior but larger-size tumors are more likely to progress significantly. Intramedullary tumors usually accompany multiple extramedullary tumors. In the authors' experience subtyping of the NF2 mutation has not yet influenced management. Protein-truncating mutations are associated with an increased prevalence of spinal tumors.

Patterning and processes: how stomatal development defines physiological potential.

Stomata present an excellent opportunity for connecting scientific disciplines: they are governed by complex genetic controls and unique cell biology, while also possessing a large influence over plant productivity and relationships with the environment. For this reason, stomata have engaged scientists for many centuries and continue to be a central interest for many fields of research. Recent technological advances have enabled interdisciplinary studies of stomata that were previously out of reach, and as a result, we are beginning to realize new insights about stomatal biology that place them at the intersection of our changing world. This review is intended to describe these interdisciplinary connections, discuss the relevant scales at which they are having an influence, and highlight ways we can capitalize on such novel approaches. While we incorporate knowledge about molecular advances, this is not intended to be an extensive review of that field, but rather, we focus on how those systems inform plant physiology and are connected to global scales.