Prolonged cytopenias after immune effector cell therapy and lymphodepletion in patients with leukemia, lymphoma and solid tumors.

BACKGROUND AIMS: The success of chimeric antigen receptor (CAR) T-cell therapy in treating B-cell malignancies has led to the evaluation of CAR T-cells targeting a variety of other malignancies. Although the efficacy of CAR T-cells is enhanced when administered post-lymphodepleting chemotherapy, this can trigger bone marrow suppression and sustained cytopenia after CD19.CAR T-cell therapy. Additionally, systemic inflammation associated with CAR T-cell activity may contribute to myelosuppression. Cytopenias, such as neutropenia and thrombocytopenia, elevate the risk of severe infections and bleeding, respectively. However, data on the incidence of prolonged cytopenias after immune effector therapy in the solid tumor context remain limited. OBJECTIVE: We compared the incidence of prolonged cytopenias after immune effector therapy including genetically modified T-cells, virus-specific T-cells (VSTs) and NKT-cells, as well non-gene-modified VSTs for leukemia, lymphoma, and solid tumors (ST) to identify associated risk factors. METHODS: A retrospective analysis was conducted of 112 pediatric and adult patients with relapsed and/or refractory cancers who received lymphodepleting chemotherapy followed by immune effector therapy. Patients treated with 13 distinct immune effector cell therapies through 11 single-center clinical trials and 2 commercial products over a 6-year period were categorized into 3 types of malignancies: leukemia, lymphoma and ST. We obtained baseline patient characteristics and adverse events data for each participant, and tracked neutrophil and platelet counts following lymphodepletion. RESULTS: Of 112 patients, 104 (92.9%) experienced cytopenias and 88 (79%) experienced severe cytopenias. Patients with leukemia experienced significantly longer durations of severe neutropenia (median duration of 14 days) compared with patients with lymphoma (7 days) or ST (11 days) (P = 0.002). Patients with leukemia also had a higher incidence of severe thrombocytopenia (74.1%), compared with lymphoma (46%, P = 0.03) and ST (14.3%, P < 0.0001). Prolonged cytopenias were significantly associated with disease type (63% of patients with leukemia, 44% of patients with lymphoma, and 22.9% of patients with ST, P = 0.006), prior hematopoietic stem cell transplant (HSCT) (66.7% with prior HSCT versus 38.3% without prior HSCT, P = 0.039), and development of immune effector cell-associated neurotoxicity syndrome (ICANS) (75% with ICANS versus 38% without ICANS, P = 0.027). There was no significant association between prolonged cytopenias and cytokine release syndrome. CONCLUSIONS: Immune effector recipients often experience significant cytopenias due to marrow suppression following lymphodepletion regardless of disease, but prolonged severe cytopenias are significantly less common after treatment of patients with lymphoma and solid tumors.

Epidemiology of Injuries in Olympic Sports.

Injuries effect the performance of athletes. Severity of injuries is determined by time loss and sporting performance reduction. To treat injuries adequately, it is necessary to get an overview of varied injuries types in different sports disciplines. In a retrospective study 7.809 athletes from Germany, Switzerland and Austria competing in competitive or recreational levels of sports were included. Injury prevalence was highest in team sports (75 %), followed by combat (64 %), racquet (54 %) and track and field (51 %). Knee (28 %) and shoulder (14 %) were the most at risk joints. Time loss in sporting activity after injury was longest in the region of knee (26 weeks). Of all reported injuries, 48 % were accompanied by a reduced level of performance. The highest injury prevalence occurred in the year 2016 (45 %). More injuries occurred during training (58 %) compared to competition (42 %). Across Olympic disciplines, a large number of injuries occurred during training sessions. Injury frequency increased as the Olympic games drew closer. Knee and shoulder injuries were the most severe injuries with respect to time loss and reduction sporting performance.

Virus-Specific T Cells for the Treatment of Systemic Infections Following Allogeneic Hematopoietic Cell and Solid Organ Transplantation.

Viral infections are a major source of morbidity and mortality in the context of immune deficiency and immunosuppression following allogeneic hematopoietic cell (allo-HCT) and solid organ transplantation (SOT). The pharmacological treatment of viral infections is challenging and often complicated by limited efficacy, the development of resistance, and intolerable side effects. A promising strategy to rapidly restore antiviral immunity is the adoptive transfer of virus-specific T cells (VST). This therapy involves the isolation and ex vivo expansion or direct selection of antigen-specific T cells from healthy seropositive donors, followed by infusion into the patient. This article provides a practical guide to VST therapy by reviewing manufacturing techniques, donor selection, and treatment indications. The safety and efficacy data of VSTs gathered in clinical trials over nearly 30 years is summarized. Current challenges and limitations are discussed, as well as opportunities for further research and development.

Management after acute injury of the anterior cruciate ligament (ACL). Part 3: Recommendation on surgical treatment.

PURPOSE: The aim of this consensus project was to give recommendations regarding surgical treatment of the anterior cruciate ligament (ACL) injured patient. METHODS: For this consensus process, an expert, steering and rating group was formed. In an initial online meeting, the steering group, together with the expert group, formed various key topic complexes for which multiple questions were formulated. For each key topic, a structured literature search was performed by the steering group. The results of the literature review were sent to the rating group with the option to give anonymous comments until a final consensus voting was performed. Sufficient consensus was defined as 80% agreement. RESULTS: During this consensus process, 30 topics regarding the surgical management and technique of ACL reconstruction were identified. The literature search for each key question resulted in 30 final statements. Of these 30 final statements, all achieved consensus. CONCLUSIONS: This consensus process has shown that surgical treatment of ACL injury is a complex process. Various surgical factors influence patient outcomes. The proposed treatment algorithm can be used as a decision aid for the surgeon. LEVEL OF EVIDENCE: Level V.

[Treatment of acute knee dislocations]. / Behandlung der akuten Knieluxation.

A knee dislocation is a serious injury involving at least two of the four major ligamentous stabilizers of the knee. This injury results in multidirectional knee instability. In dislocation of the knee the popliteal artery and the peroneal nerve can also be damaged. Dislocations with vascular involvement are potentially threatening injuries of the lower extremities. The diagnosis of knee dislocation can be difficult due to a high rate of spontaneous reduction at the initial examination. Knee dislocations are rare and mainly occur in young men. They are mostly caused by high-energy trauma; however, they can also be caused by low-energy injuries. Obesity increases the risk of knee dislocations. The classification of a knee dislocation is based on the anatomical structures involved and the direction of dislocation. The acute treatment includes reduction and stabilization measures. Associated injuries, such as vascular, nerve, extensor mechanism and cartilage injuries as well as fractures and meniscal injuries can influence the treatment approach and the outcome. The definitive surgical treatment depends on the severity of the injury and can include ligament reconstruction or repair with bracing. The aftercare should be individually adapted with the aim to restore knee joint stability and function. Complications such as arthrofibrosis, peroneal nerve palsy, compartment syndrome, postoperative infection and recurrent instability can occur. In the long term, patients have an increased risk for the development of symptomatic osteoarthritis.

Mediport use as an acceptable standard for CAR T cell infusion.

Introduction: Mediport use as a clinical option for the administration of chimeric antigen receptor T cell (CAR T cell) therapy in patients with B-cell malignancies has yet to be standardized. Concern for mediport dislodgement, cell infiltration, and ineffective therapy delivery to systemic circulation has resulted in variable practice with intravenous administration of CAR T cell therapy. With CAR T cell commercialization, it is important to establish practice standards for CAR T cell delivery. We conducted a study to establish usage patterns of mediports in the clinical setting and provide a standard of care recommendation for mediport use as an acceptable form of access for CAR T cell infusions. Methods: In this retrospective cohort study, data on mediport use and infiltration rate was collected from a survey across 34 medical centers in the Pediatric Real-World CAR Consortium, capturing 504 CAR T cell infusion routes across 489 patients. Data represents the largest, and to our knowledge sole, report on clinical CAR T cell infusion practice patterns since FDA approval and CAR T cell commercialization in 2017. Results: Across 34 sites, all reported tunneled central venous catheters, including Broviac® and Hickman® catheters, as accepted standard venous options for CAR T cell infusion. Use of mediports as a standard clinical practice was reported in 29 of 34 sites (85%). Of 489 evaluable patients with reported route of CAR T cell infusion, 184 patients were infused using mediports, with no reported incidences of CAR T cell infiltration. Discussion/Conclusion: Based on current clinical practice, mediports are a commonly utilized form of access for CAR T cell therapy administration. These findings support the safe practice of mediport usage as an accepted standard line option for CAR T cell infusion.

Shadow imaging for panoptical visualization of brain tissue in vivo.

Progress in neuroscience research hinges on technical advances in visualizing living brain tissue with high fidelity and facility. Current neuroanatomical imaging approaches either require tissue fixation (electron microscopy), do not have cellular resolution (magnetic resonance imaging) or only give a fragmented view (fluorescence microscopy). Here, we show how regular light microscopy together with fluorescence labeling of the interstitial fluid in the extracellular space provide comprehensive optical access in real-time to the anatomical complexity and dynamics of living brain tissue at submicron scale. Using several common fluorescence microscopy modalities (confocal, light-sheet and 2-photon microscopy) in mouse organotypic and acute brain slices and the intact mouse brain in vivo, we demonstrate the value of this straightforward 'shadow imaging' approach by revealing neurons, microglia, tumor cells and blood capillaries together with their complete anatomical tissue contexts. In addition, we provide quantifications of perivascular spaces and the volume fraction of the extracellular space of brain tissue in vivo.

Vancomycin Concentrations in Synovial Fluid Do Not Reach Chondrotoxic Thresholds After Anterior Cruciate Ligament Reconstruction With Vancomycin-Soaked Autologous Soft Tissue Grafts: An In Vivo Prospective Observational Study in Humans.

BACKGROUND: Studies have revealed that vancomycin soaking of the anterior cruciate ligament (ACL) graft can drastically reduce the incidence of postoperative infections after ACL reconstruction. However, it remains unknown whether the chondrotoxic threshold of vancomycin in synovial fluid is exceeded during this process. Several studies investigated the chondrotoxic properties of vancomycin in in vitro experiments and described a concentration of 1000 µg/mL as the critical threshold. PURPOSE/HYPOTHESIS: The purpose of the study was to measure the vancomycin concentration in synovial fluid after ACL reconstruction with vancomycin-soaked autografts. It was hypothesized that intra-articular vancomycin concentrations in the synovial fluid would not reach the chondrotoxic threshold of 1000 µg/mL after vancomycin soaking of autologous semitendinosus tendon and soft tissue quadriceps tendon grafts for ACL reconstruction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The study enrolled 10 patients undergoing ACL reconstruction using 4-strand semitendinosus tendon autografts and 10 patients undergoing ACL reconstruction using soft tissue quadriceps tendon autografts. Before implantation, each harvested graft was intraoperatively wrapped in gauze swabs that had been soaked in a 5-mg/mL vancomycin solution. After wound closure, an aspirate of 5 mL of synovial fluid was taken from each patient. The vancomycin concentration of the aspirate was analyzed using high-performance liquid chromatography-tandem mass spectrometry. Spearman rho correlation coefficients were used to identify relationships between the parameters, and the t test was used to test for differences between graft types. A P value of <.05 was considered statistically significant. RESULTS: The study included 20 patients (14 women and 6 men; age, 29.35 ± 11.3 years). The mean vancomycin concentration measured in the synovial fluid was 23.23 ± 21.68 µg/mL, with a minimum concentration of 2.32 µg/mL and a maximum concentration of 71.56 µg/mL. No significant difference was found between the 2 graft types (P = .911). Significant positive correlation (r = 0.644; P < .05) was observed only between the vancomycin concentration and the mean duration from initiation of vancomycin soaking of semitendinosus tendon grafts to implantation (13.4 ± 6 minutes). No correlations were observed between the vancomycin concentration and the duration from implantation to fluid aspiration or between the vancomycin concentration and the graft diameter (median, 8.5 mm; range, 6.0-10.0 mm) for both graft types. CONCLUSION: Chondrotoxic vancomycin concentrations ≥1000 µg/mL were not reached in any aspiration of synovial fluid after ACL reconstruction using soft tissue autografts that were intraoperatively soaked in a 5-mg/mL vancomycin solution. Against the backdrop of multiple studies that showed significantly reduced infection rates after ACL reconstruction when vancomycin soaking was used, this study suggests that the chondrotoxic properties of this method are negligible because of its submarginal intra-articular concentrations.

Imaging dendritic spines in the hippocampus of a living mouse by 3D-stimulated emission depletion microscopy.

Significance: Stimulated emission depletion (STED) microscopy has been used to address a wide range of neurobiological questions in optically well-accessible samples, such as cell culture or brain slices. However, the application of STED to deeply embedded structures in the brain of living animals remains technically challenging. Aim: In previous work, we established chronic STED imaging in the hippocampus in vivo but the gain in spatial resolution was restricted to the lateral plane. In our study, we report on extending the gain in STED resolution into the optical axis to visualize dendritic spines in the hippocampus in vivo. Approach: Our approach is based on a spatial light modulator to shape the focal STED light intensity in all three dimensions and a conically shaped window that is compatible with an objective that has a long working distance and a high numerical aperture. We corrected distortions of the laser wavefront to optimize the shape of the bottle beam of the STED laser. Results: We show how the new window design improves the STED point spread function and the spatial resolution using nanobeads. We then demonstrate the beneficial effects for 3D-STED microscopy of dendritic spines, visualized with an unprecedented level of detail in the hippocampus of a living mouse. Conclusions: We present a methodology to improve the axial resolution for STED microscopy in the deeply embedded hippocampus in vivo, facilitating longitudinal studies of neuroanatomical plasticity at the nanoscale in a wide range of (patho-)physiological contexts.

Editorial Commentary: Bony Morphology Determines the Extent of Concomitant Injuries in Anterior Cruciate Ligament Injured Knees.

The bony morphology of both tibia and femur has been found to influence the risk of anterior cruciate ligament (ACL) injuries. Quantifying the femoral condylar's sagittal morphology, the lateral femoral condyle ratio (LFCR) has been associated with injuries to the anterolateral knee joint capsule, including the anterolateral ligament in ACL-injured knees. Rotational instability may be in part attributable to femoral anisometry with an increase of the LFCR contributing to increased laxity and risk for ACL ruptures as well as concomitant injuries. While there is currently no surgical treatment available to change the bony morphology of the femur, possibilities such as the addition of a lateral extra-articular tenodesis, adjustment of graft selection, or modification of surgical techniques may mitigate the risk of ACL rerupture in patients with a high LFCR.

Posoleucel, an Allogeneic, Off-the-Shelf Multivirus-Specific T-Cell Therapy, for the Treatment of Refractory Viral Infections in the Post-HCT Setting.

PURPOSE: Viral infections are a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). In the absence of safe and effective antiviral treatments, virus-specific T cells have emerged as a promising therapeutic option. Posoleucel is a multivirus-specific T-cell therapy for off-the-shelf use against six viral infections that commonly occur in allo-HCT recipients: adenovirus, BK virus (BKV), cytomegalovirus, Epstein-Barr virus, human herpes virus-6, and JC virus. PATIENTS AND METHODS: We conducted an open-label, phase II trial to determine the feasibility and safety of posoleucel in allo-HCT recipients infected with one or more of these viruses. Infections were either unresponsive to or patients were unable to tolerate standard antiviral therapies. Fifty-eight adult and pediatric patients were enrolled and treated. RESULTS: Posoleucel was well tolerated, with no cytokine release syndrome or other infusion-related toxicities; two patients (3.4%) developed Grade 2 and one patient (1.7%) Grade 3 GvHD during the trial. The overall response rate 6 weeks after the first posoleucel infusion was 95%, with a median plasma viral load reduction of 97%. Of the 12 patients who had two or more target viral infections identified at study entry, 10 (83%) had a clinical response for all evaluable viruses. Of the 23 patients treated for refractory BKV-associated hemorrhagic cystitis, 74% had resolution of symptoms and macroscopic hematuria by 6 weeks post-infusion. CONCLUSIONS: In this open-label trial, treatment of refractory viral infections/disease in allo-HCT recipients with posoleucel was feasible, safe, and effective.

Management of nutritional iron deficiency anemia for young children in the emergency department.

BACKGROUND: Guidelines for young children with nutritional iron deficiency anemia (IDA) presenting to the emergency department (ED) are lacking, leading to variability in care. We aimed to standardize management of these patients through the development and implementation of an evidence-based algorithm using quality improvement methodology. PROCEDURE: Baseline data of the target population (n = 42; 60% male; median age 22.5 months, median hemoglobin 5.3 g/dl) identified variability across four key measures of clinical management: laboratory evaluation, therapy choice, therapy administration, and patient disposition. Literature review and consensus from pediatric hematology providers informed a draft algorithm that was refined in an iterative multidisciplinary process. From September 2020 to June 2021, we aimed to increase IDA management per the algorithm by ≥20% relative to baseline for the four key outcome measures using sequential Plan-Do-Study-Act (PDSA) cycles. Process measures focusing on provider communication/documentation and balancing measures involving efficiency and therapy-related adverse events were assessed concurrently. RESULTS: Thirty-five patients were evaluated among four PDSA cycles and shared similar characteristics as the baseline population. Improvements of ≥20% above baseline adherence levels or 100% adherence were achieved for all outcome measure across four PDSA cycles. Adherence to recommended laboratory evaluation improved from 43 (baseline) to 71%, therapy choice from 78 to 100%, therapy administration from 50 to 83%, and disposition from 85 to 100%. ED length of stay remained stable. CONCLUSIONS: Implementation of a standardized algorithm for young children with nutritional IDA in the ED increased adherence to evidence-based patient care.

Current status of the management of isolated syndesmotic injuries in Germany.

INTRODUCTION: Although non-fracture-related syndesmotic injuries of the ankle are relatively rare, they may lead to poor clinical outcome if initially undiagnosed or managed improperly. Despite a variety of literature regarding possibilities for treatment of isolated syndesmotic injuries, little is known about effective applications of different therapeutic methods in day-to-day work. The aim of this study was to assess the current status of the treatment of isolated syndesmotic injuries in Germany. MATERIALS AND METHODS: An online-questionnaire, capturing the routine diagnostic workup including clinical examination, radiologic assessment and treatment strategies, was sent to all members of the German Society of Orthopedic Surgery and Traumatology (DGOU) and Association of Arthroscopic and Joint Surgery (AGA). Statistical analysis was performed using Microsoft excel and SPSS. RESULTS: Each question of the questionnaire was on average answered by 431 ± 113 respondents. External rotation stress test (66%), squeeze test (61%) and forced dorsiflexion test (40%) were most commonly used for the clinical examination. In the diagnostic workup, most clinicians relied on MRI (83%) and conventional X-ray analysis (anterior-posterior 58%, lateral 41%, mortise view 38%). Only 15% of the respondents stated that there is a role for arthroscopic evaluation for the assessment of isolated syndesmotic injuries. Most frequently used fixation techniques included syndesmotic screw fixation (80%, 42% one syndesmotic screw, 38% two syndesmotic screws), followed by suture-button devices in 13%. Syndesmotic screw fixation was mainly performed tricortically (78%). While 50% of the respondents stated that syndesmotic screw fixation and suture-button devices are equivalent in the treatment of isolated syndesmotic injuries with respect to clinical outcome, 36% answered that syndesmotic screw fixation is superior compared to suture-button devices. CONCLUSIONS: While arthroscopy and suture-button devices do not appear to be widely used, syndesmotic screw fixation after diagnostic work-up by MRI seems to be the common treatment algorithm for non-fracture-related syndesmotic injuries in Germany.

Forecasting the publication and citation outcomes of COVID-19 preprints.

Many publications on COVID-19 were released on preprint servers such as medRxiv and bioRxiv. It is unknown how reliable these preprints are, and which ones will eventually be published in scientific journals. In this study, we use crowdsourced human forecasts to predict publication outcomes and future citation counts for a sample of 400 preprints with high Altmetric score. Most of these preprints were published within 1 year of upload on a preprint server (70%), with a considerable fraction (45%) appearing in a high-impact journal with a journal impact factor of at least 10. On average, the preprints received 162 citations within the first year. We found that forecasters can predict if preprints will be published after 1 year and if the publishing journal has high impact. Forecasts are also informative with respect to Google Scholar citations within 1 year of upload on a preprint server. For both types of assessment, we found statistically significant positive correlations between forecasts and observed outcomes. While the forecasts can help to provide a preliminary assessment of preprints at a faster pace than traditional peer-review, it remains to be investigated if such an assessment is suited to identify methodological problems in preprints.

[Future implications of navigation in total knee arthroplasty]. / Gibt es noch Gründe für die Navigation in der Knieendoprothetik?

BACKGROUND: After more than two decades of experience with computer-assisted knee arthroplasty, extensive experience and study data are available, allowing a profound evaluation. Undoubtedly, computer-assisted knee arthroplasty has been proven to achieve excellent results for implant positioning and long-leg axis reconstruction. Thus, computer-assisted knee arthroplasty represents the current gold standard to avoid unintended malpositioning of total knee components for neutrally aligned implants and individualized implant alignment (kinematic alignment, adjusted mechanical alignment, and others). Previous studies could not show significant differences in functional outcomes and patient satisfaction. However, recent meta-analyses showed relevant advantages of computer-assisted knee arthroplasty. These results could be based on further developments in software-assisted soft tissue balancing and more sensitive evaluation methods of follow-up examinations. LONG-TERM OUTCOME: Further, international registries show advantages of computer-assisted knee arthroplasty regarding long-term outcomes. In particular, the Australian arthroplasty registry describes a significantly lower revision rate due to aseptic loosening/osteolysis in the computer-assisted knee arthroplasty group, analyzing a period of up to 17 years. These positive effects can already be proven six months following surgery. FUTURE PROSPECTS: However, despite demonstrated benefits, computer-assisted knee arthroplasty has not yet become established in daily routine, and wide regional variations in its use are observed. Newer developments such as robotic-assisted knee arthroplasty, primarily based on navigation techniques, are currently being heavily promoted. However, this new technology must justify its enormous additional costs and prove its advantages compared to computer-assisted knee arthroplasty. In the backdrop of the development of computer-assisted knee arthroplasty, this might be a difficult task.

Hyperoxia evokes pericyte-mediated capillary constriction.

Oxygen supplementation is regularly prescribed to patients to treat or prevent hypoxia. However, excess oxygenation can lead to reduced cerebral blood flow (CBF) in healthy subjects and worsen the neurological outcome of critically ill patients. Most studies on the vascular effects of hyperoxia focus on arteries but there is no research on the effects on cerebral capillary pericytes, which are major regulators of CBF. Here, we used bright-field imaging of cerebral capillaries and modeling of CBF to show that hyperoxia (95% superfused O2) led to an increase in intracellular calcium level in pericytes and a significant capillary constriction, sufficient to cause an estimated 25% decrease in CBF. Although hyperoxia is reported to cause vascular smooth muscle cell contraction via generation of reactive oxygen species (ROS), endothelin-1 and 20-HETE, we found that increased cytosolic and mitochondrial ROS levels and endothelin release were not involved in the pericyte-mediated capillary constriction. However, a 20-HETE synthesis blocker greatly reduced the hyperoxia-evoked capillary constriction. Our findings establish pericytes as regulators of CBF in hyperoxia and 20-HETE synthesis as an oxygen sensor in CBF regulation. The results also provide a mechanism by which clinically administered oxygen can lead to a worse neurological outcome.

Examining the generalizability of research findings from archival data.

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability-for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples.

The Ca2+-gated channel TMEM16A amplifies capillary pericyte contraction and reduces cerebral blood flow after ischemia.

Pericyte-mediated capillary constriction decreases cerebral blood flow in stroke after an occluded artery is unblocked. The determinants of pericyte tone are poorly understood. We show that a small rise in cytoplasmic Ca2+ concentration ([Ca2+]i) in pericytes activated chloride efflux through the Ca2+-gated anion channel TMEM16A, thus depolarizing the cell and opening voltage-gated calcium channels. This mechanism strongly amplified the pericyte [Ca2+]i rise and capillary constriction evoked by contractile agonists and ischemia. In a rodent stroke model, TMEM16A inhibition slowed the ischemia-evoked pericyte [Ca2+]i rise, capillary constriction, and pericyte death; reduced neutrophil stalling; and improved cerebrovascular reperfusion. Genetic analysis implicated altered TMEM16A expression in poor patient recovery from ischemic stroke. Thus, pericyte TMEM16A is a crucial regulator of cerebral capillary function and a potential therapeutic target for stroke and possibly other disorders of impaired microvascular flow, such as Alzheimer's disease and vascular dementia.