The relationship between intraoperative surrogates of vascular stiffness, cerebral aneurysms, and surgical outcomes.

OBJECTIVE: Increased arterial stiffness has been linked to aneurysm formation in the systemic and cerebral circulations, though the role played by arterial stiffness in the cerebral vasculature continues to be refined. This study assesses whether intraoperative surrogates of arterial stiffness differ between patients with cerebral aneurysms and controls, and the extend that these indices relate to outcomes following open surgical treatment. METHODS: We evaluated patients in a prospectively maintained database who underwent cerebral aneurysm surgery, and compared them to controls without cerebral aneurysms. Arterial stiffness was estimated using the intraoperative ambulatory arterial stiffness index (AASI) and average pulse pressure (PP). RESULTS: We analyzed 214 cerebral aneurysm patients and 234 controls. Patients in the aneurysm group were predominantly female and had a higher incidence of hypertension, diabetes mellitus, and vascular disease. They also demonstrate elevated AASI and average PP. When stratified by the occurrence of subarachnoid hemorrhage (SAH) or unfavorable neurological outcome, the AASI and average PP were not highly associated with the occurrence of SAH but were highly associated with unfavorable neurological outcomes. After multivariable analysis, both the AASI and average PP were no longer associated with unfavorable neurological outcomes, however elevated age, strongly linked with arterial stiffness, became a key predictive variable. CONCLUSION: Readily obtained intraoperative surrogates of arterial stiffening demonstrates its presence in those with cerebral aneurysm disease and the extent that it does it may meaningfully direct their clinical course. However, multivariable analysis demonstrates limitations of using arterial stiffness measures to predict clinical outcomes.

The Impact of Leg Length and Offset Change on Dislocation Risk Following Primary Total Hip Arthroplasty.

BACKGROUND: Soft tissue management in total hip arthroplasty includes appropriate restoration and/or alteration of leg length (LL) and offset to re-establish natural hip biomechanics. The purpose of this study was to evaluate the effect of LL and offset-derived variables in a multivariable survival model for dislocation. METHODS: Clinical, surgical, and radiographic data was retrospectively acquired for 12,582 patients undergoing primary total hip arthroplasty at a single institution from 1998 to 2018. There were twelve variables derived from preoperative and postoperative radiographs related to LL and offset that were measured using a validated automated algorithm. These measurements, as well as other modifiable and nonmodifiable surgical, clinical, and demographic factors, were used to determine hazard ratios for dislocation risk. RESULTS: None of the LL or offset variables conferred significant risk or protective benefit for dislocation risk. By contrast, all other variables included in the multivariable model demonstrated a statistically significant effect on dislocation risk with a minimum effect size of 28% (range 0.72 to 1.54) (sex, surgical approach, acetabular liner type, femoral head size, neurologic disease, spine disease, and prior spine surgery). CONCLUSIONS: Contrary to traditional teaching and our hypothesis, operative changes in LL and offset did not demonstrate any clinically or statistically significant effect in this large and well-characterized cohort. This does not imply that these variables are not important in individual cases, but rather suggests the overall impact of LL and offset changes is relatively minor for dislocation risk compared to other variables that were found to be highly clinically and statistically significant in this population. These results may also suggest that surgeons do a good job of restoring native LL and offset for patients, which may mitigate their analyzed impact.

Lymphotoxin limits Foxp3+ regulatory T cell development from Foxp3lo precursors via IL-4 signaling.

Regulatory T cells (Treg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25+Foxp3- and CD25-Foxp3lo precursors. However, the mechanisms regulating the recently identified Foxp3lo precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin α1ß2 (LTα1ß2) heterocomplex is upregulated during Treg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of Treg from Foxp3lo precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LTα1ß2-lymphotoxin ß receptor-mediated interactions with mTEC limit Treg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic Treg development that fine-tunes the Foxp3lo Treg precursor pathway by limiting IL-4 availability.

Development and implementation of a roadmap for improving quality of care in prearthritic hip disease: A journey over 20 years.

The understanding and treatment of prearthritic hip disease has evolved remarkably over the past 20 years. The principal investigator and the multicenter Academic Network of Conservational Hip Outcomes Research (ANCHOR) group have had a key role in improving the quality of care for these patients suffering from the three most common prearthritic conditions: femoroacetabular impingement, developmental dysplasia of the hip, and residual Legg-Calve-Perthes Disease. We aim to demonstrate that based on the six quality of care dimensions as defined by Donabedian, our 20-year academic journey has markedly improved the quality of care for young patients with prearthritic hip disease.

No Revisions Attributable to Wear of Highly Cross-Linked Polyethylene Liners: A Long-Term Follow-Up Study.

BACKGROUND: There is a paucity of data beyond 15 years on the survivorship of total hip arthroplasty since the introduction of highly cross-linked polyethylene (HXLPE) liners. Our aim was to evaluate implant survivorship, liner wear rates, and clinical outcomes after primary total hip arthroplasty using HXLPE liners implanted between 1999 and 2002. METHODS: Between 1999 and 2002, 690 primary total hip arthroplasties utilizing 28-mm femoral heads and HXLPE liners of a single design were identified using our institutional total joint registry. Femoral heads were made of metal in 96% of cases and ceramic in 4%. The mean age was 56 years, 48% were women, and the mean body mass index was 30. Survivorship analyses were performed for the outcomes of implant revision, reoperation, and complications for the entire cohort. Linear HXLPE liner wear rates were determined on 197 hips with radiographs with more than 18.5 years of follow-up. RESULTS: At 20 years, survivorship free of revision was 94%, free of reoperation was 92%, and free of any complication was 81%. There were no documented wear-related revisions. The linear wear rate at a mean of 20.3 years postoperatively was 0.02 mm/y. There was no statistically significant difference in measured wear observed between the first available postoperative radiographs and those taken at the final follow-up. The use of elevated liners, patient body mass index, age, preoperative diagnosis, acetabular component inclination, and anteversion angles were not associated with increased wear rates. Mean Harris hip scores improved from 52 preoperatively to 90 at greater than 18.5 years CONCLUSIONS: Primary total hip arthroplasties using a single first-generation HXLPE liner demonstrated excellent survivorship and clinical outcomes at long-term follow-up with no wear-related revisions. Wear rates of HXLPE liners at 20 years are exceedingly low and are not significantly impacted by acetabular component position or patient-dependent variables such as BMI. LEVEL OF EVIDENCE: IV.

Identifying Critical Evidence Gaps in Wound Closure and Incision Management After Total Knee Arthroplasty: Delphi Panel Insights.

BACKGROUND: Effective surgical wound management in total knee arthroplasty (TKA) is crucial for optimal healing and patient outcomes. Despite surgical advances, managing wounds to prevent complications remains challenging. This study aimed to identify and address evidence gaps in TKA wound management, including preoperative optimization, intraoperative options, and postoperative complication avoidance. Addressing these issues is vital for patient recovery and surgical success. METHODS: This study used the Delphi method with 20 experienced orthopedic surgeons from Europe and North America. Conducted from April to September 2023, the process involved three stages: an initial electronic survey, a virtual meeting, and a concluding electronic survey. The panel reviewed and reached a consensus on 26 statements about TKA wound management based on a comprehensive literature review. Additionally, the panel aimed to identify critical evidence gaps in wound management practices. RESULTS: The panel achieved consensus on various wound management practices but highlighted significant evidence gaps. Consensus was reached on wound closure methods, including mesh-adhesive dressings, skin glue, staples, barbed sutures, and negative pressure wound therapy. However, further evidence is needed to address the cost-effectiveness of these methods and develop best practices for patient outcomes. Identifying these gaps highlights the need for more research to improve TKA wound care. CONCLUSIONS: Identifying major evidence gaps underscores the need for targeted research in TKA wound management. Addressing these gaps is crucial for developing effective, efficient, and patient-friendly wound care strategies. Future research should focus on comparative effectiveness studies and developing guidelines for emerging technologies. Bridging these gaps could improve patient outcomes, reduce complications, and enhance TKA surgery success.

Affirming Community Cultural Wealth of Chicana/o and Latina/o Youth in a Community-Based After-School Program.

Racialized, deficit-oriented educational practices and inadequate safe spaces for youth undermine Communities of Color. We discuss our after-school program's framework, strategies, activities, and partnerships with community stakeholders, demonstrating that a collaborative, culturally responsive, strengths-based approach to mitigate trauma and enhance health and educational opportunities is essential for empowering Chicana/o/Latina/o youth and families.

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner.

Epidemiological studies link exposure to viral infection during pregnancy, including influenza A virus (IAV) infection, with increased incidence of neurodevelopmental disorders (NDDs) in offspring. Models of maternal immune activation (MIA) using viral mimetics demonstrate that activation of maternal intestinal T helper 17 (TH17) cells, which produce effector cytokine interleukin (IL)-17, leads to aberrant fetal brain development, such as neocortical malformations. Fetal microglia and border-associated macrophages (BAMs) also serve as potential cellular mediators of MIA-induced cortical abnormalities. However, neither the inflammation-induced TH17 cell pathway nor fetal brain-resident macrophages have been thoroughly examined in models of live viral infection during pregnancy. Here, we inoculated pregnant mice with two infectious doses of IAV and evaluated peak innate and adaptive immune responses in the dam and fetus. While respiratory IAV infection led to dose-dependent maternal colonic shortening and microbial dysregulation, there was no elevation in intestinal TH17 cells nor IL-17. Systemically, IAV resulted in consistent dose- and time-dependent increases in IL-6 and IFN-γ. Fetal cortical abnormalities and global changes in fetal brain transcripts were observable in the high-but not the moderate-dose IAV group. Profiling of fetal microglia and BAMs revealed dose- and time-dependent differences in the numbers of meningeal but not choroid plexus BAMs, while microglial numbers and proliferative capacity of Iba1+ cells remained constant. Fetal brain-resident macrophages increased phagocytic CD68 expression, also in a dose- and time-dependent fashion. Taken together, our findings indicate that certain features of MIA are conserved between mimetic and live virus models, while others are not. Overall, we provide consistent evidence of an infection severity threshold for downstream maternal inflammation and fetal cortical abnormalities, which recapitulates a key feature of the epidemiological data and further underscores the importance of using live pathogens in NDD modeling to better evaluate the complete immune response and to improve translation to the clinic.

TRIM7 ubiquitinates SARS-CoV-2 membrane protein to limit apoptosis and viral replication.

SARS-CoV-2 is a highly transmissible virus that causes COVID-19 disease. Mechanisms of viral pathogenesis include excessive inflammation and viral-induced cell death, resulting in tissue damage. We identified the host E3-ubiquitin ligase TRIM7 as an inhibitor of apoptosis and SARS-CoV-2 replication via ubiquitination of the viral membrane (M) protein. Trim7 -/- mice exhibited increased pathology and virus titers associated with epithelial apoptosis and dysregulated immune responses. Mechanistically, TRIM7 ubiquitinates M on K14, which protects cells from cell death. Longitudinal SARS-CoV-2 sequence analysis from infected patients revealed that mutations on M-K14 appeared in circulating variants during the pandemic. The relevance of these mutations was tested in a mouse model. A recombinant M-K14/K15R virus showed reduced viral replication, consistent with the role of K15 in virus assembly, and increased levels of apoptosis associated with the loss of ubiquitination on K14. TRIM7 antiviral activity requires caspase-6 inhibition, linking apoptosis with viral replication and pathology.

Total knee replacement with an accelerometer-based, hand-held navigation system improves knee alignment: reliable in all patients.

BACKGROUND: Achieving adequate alignment has traditionally been an important goal in total knee arthroplasty to achieve long-term implant survival. While accelerometer-based hand-held navigation systems (ABN) has been introduced as a way to achieve alignment, there is a limited body of evidence on its accuracy, especially in patients under 65 years with differing etiologies for knee arthritis. This study aimed to assess the precision of a specific ABN system in restoring the mechanical axis and report surgical variables and complications, with particular attention to younger patients. METHODS: We conducted a retrospective review of 310 primary TKA performed with ABN from May 2016 to February 2021. The mean patient age was 67.4 (SD 8.9) years, with 43% under 65 years and mean body mass index of 33.2 (SD 6.8). The average surgical time was 96.8 min (57-171) and the average follow-up was 3.3 years (1.9-6.7). Data regarding length of stay, pain, range of motion (ROM), complications, and reinterventions were collected from the institutional joint arthroplasty registry and the medical records. Preoperative mechanical axis measurements and postoperative radiological data, including mechanical axis, component alignment and mechanical alignment outliers were analyzed. RESULTS: The mean preoperative mechanical axis was 175.4° (SD 7.6), with 248 knees (80%) in preoperative varus. The mean postoperative mechanical axis was 179.5° (SD 1.96) with 98% of knees falling within ± 3° of the neutral mechanical axis. Only 6 knees (2 varus, 4 valgus) fell outside the ± 3° range. And 3 knees (1 varus, 2 valgus) fell outside the ± 5° range. In the sagittal plane, 296 knees (95.5%) knees were within ± 3° of goal of 3 degrees of femoral flexion and 302 (97.4%) knees were within ± 2° of goal 1° of slope for tibial component. Far outliers (alignment outside ± 5° of targeted position) were found in 3 knees. Factors such as posttraumatic arthrosis, previous surgery, presence of retained hardware, and age below 65 years were not associated with increase in alignment outliers and far outliers. No complications related to the navigation system were observed. There were 22 complications and 20 reoperations, including 2 revisions for periprosthetic joint infection and 1 revision for flexion instability. Patients that required knee manipulation achieved an ultimate flexion of 110° (SD 14.1). CONCLUSIONS: The ABN system proved to be user-friendly and accurate in reducing alignment outliers in both coronal and sagittal planes in all patient populations. It offers a straightforward navigation solution while preserving surgeon autonomy and the use of traditional surgical tools. These findings advocate for the integration of this navigation system as a valuable tool to enhance the precision of TKA surgery in all patient groups.

Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.

Metabolically active neutrophils represent a permissive niche for Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb)-infected neutrophils are often found in the airways of patients with active tuberculosis (TB), and excessive recruitment of neutrophils to the lung is linked to increased bacterial burden and aggravated pathology in TB. The basis for the permissiveness of neutrophils for Mtb and the ability to be pathogenic in TB has been elusive. Here, we identified metabolic and functional features of neutrophils that contribute to their permissiveness in Mtb infection. Using single-cell metabolic and transcriptional analyses, we found that neutrophils in the Mtb-infected lung displayed elevated mitochondrial metabolism, which was largely attributed to the induction of activated neutrophils with enhanced metabolic activities. The activated neutrophil subpopulation was also identified in the lung granulomas from Mtb-infected non-human primates. Functionally, activated neutrophils harbored more viable bacteria and displayed enhanced lipid uptake and accumulation. Surprisingly, we found that interferon-γ promoted the activation of lung neutrophils during Mtb infection. Lastly, perturbation of lipid uptake pathways selectively compromised Mtb survival in activated neutrophils. These findings suggest that neutrophil heterogeneity and metabolic diversity are key to their permissiveness for Mtb and that metabolic pathways in neutrophils represent potential host-directed therapeutics in TB.

Peri-Operative Management of Periacetabular Osteotomy: A Report of Current Practices from the Anchor Group, Supporting Literature, and Areas for Future Investigation.

Background: Periacetabular osteotomy (PAO) is a well-established surgical treatment for hip dysplasia, but very few studies report the impact of peri-operative management strategies on early pain and function. The purpose of this study is to describe peri-operative management variability among a group of experienced surgeons and review the literature supporting these practice patterns. Methods: We surveyed 16 surgeons that perform PAO to document various aspects of peri-operative management at four stages: pre-operative, intra-operative, post-operative in the hospital, and at discharge. Our goal was to report current surgical pain management strategies, adjunct medications, type of anesthesia, deep venous thrombosis and heterotopic ossification prophylaxis strategies, initiation of physical therapy, and use of continuous passive motion (CPM). We reviewed current literature to identify studies supporting these perioperative strategies and identify knowledge gaps that would benefit from further investigation. Results: Of the 16 surgeons surveyed, 75% had been in practice greater than 10 years and most had not altered their post-operative protocol for more than 3 years. 15/16 surgeons felt that length of stay could be reduced at their institution with improved peri-operative pain management. 6/16 were considering or had already implemented outpatient PAO as a part of their practice. We found significant variability in the pain medications provided at all peri-operative stages. 14/16 utilized general anesthesia, and many utilized epidural or peripheral nerve blocks. 6/16 surgeons utilized surgical field block (also referred to as periarticular block). These surgeons advocated that surgical field block was an effective intervention with no/minimal complication risk. There is very little literature critically evaluating efficacy of these perioperative management strategies for PAO. Conclusion: There is significant practice variability in peri-operative management of PAO surgery. We report various strategies utilized by a group of experienced surgeons and review supporting literature. There are significant knowledge gaps in best surgical pain management strategies, adjunct medications, surgical field blocks, and use of CPM that need further investigation. Level of Evidence: IV.

Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis.

During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with Mycobacterium tuberculosis (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB.

A Randomized Clinical Trial of Direct Anterior Versus Mini-Posterior Total Hip Arthroplasty: Small, Early Functional Differences Did Not Lead to Meaningful Clinical Differences at 7.5 Years.

BACKGROUND: Our previously reported randomized clinical trial of direct anterior approach (DAA) versus mini-posterior approach (MPA) total hip arthroplasty showed slightly faster initial recovery for patients who had a DAA and no differences in complications or clinical or radiographic outcomes beyond 8 weeks. The aims of the current study were to determine if early advantages of DAA led to meaningful clinical differences beyond 5 years and to identify differences in midterm complications. METHODS: Of the 101 original patients, 93 were eligible for follow-up at a mean of 7.5 years (range, 2.1 to 10). Clinical outcomes were compared with Harris Hip, 12-Item Short Form Health Survey, and Hip Disability and Osteoarthritis Outcomes Scores (HOOS) scores and subscores, complications, reoperations, and revisions. RESULTS: Harris Hip scores were similar (95.3 ± 6.0 versus 93.5 ± 10.3 for DAA and MPA, respectively, P = .79). The 12-Item Short Form Health Survey physical and mental scores were similar (46.2 ± 9.3 versus 46.2 ± 10.6, P = .79, and 52.3 ± 7.1 versus 55.2 ± 4.5, P = .07 in the DAA and MPA groups, respectively). The HOOS scores were similar (97.4 ± 7.9 versus 96.3 ± 6.7 for DAA and MPA, respectively, P = .07). The HOOS quality of life subscores were 96.9 ± 10.8 versus 92.3 ± 16.0 for DAA and MPA, respectively (P = .046). No clinical outcome met the minimally clinically important difference. There were 4 surgical complications in the DAA group (1 femoral loosening requiring revision, 1 dislocation treated closed, and 2 wound dehiscences requiring debridement), and 6 surgical complications in the MPA group (3 dislocations, 2 treated closed, and 1 revised to dual mobility; 2 intraoperative fractures treated with a cable; and 1 wound dehiscence treated nonoperatively). CONCLUSIONS: At a mean of 7.5 years, this randomized clinical trial demonstrated no clinically meaningful differences in outcomes, complications, reoperations, or revisions between DAA and MPA total hip arthroplasty. LEVEL OF EVIDENCE: IV.

Diaphyseal Impaction Grafting Combined with Metaphyseal Cones: Outcomes in 88 Revision Total Knee Arthroplasties.

BACKGROUND: Metaphyseal cones with cemented stems can be successfully utilized in most revision total knee arthroplasties (TKAs). However, if the diaphysis has been previously violated, fixation of the cemented stem, which is important for cone ingrowth and construct survival, can be compromised. The initial results of our novel technique combining diaphyseal impaction bone-grafting with a metaphyseal cone were promising but required additional study. The purpose of the present study was to assess results of this technique in a larger cohort. METHODS: A metaphyseal cone combined with diaphyseal impaction grafting and a cemented stem was utilized in 88 revision TKAs at our institution, including 35 from our prior study. The mean age at the time of revision was 67 years, and 67% of patients were male. Patients had had a mean of 4 prior knee arthroplasty procedures. The 2 most common reasons for revision were aseptic loosening (78%) and 2-stage reimplantation for periprosthetic joint infection (PJI) (19%). The mean follow-up was 4 years. RESULTS: At the time of the latest follow-up, no cone-impaction grafting constructs required re-revision for aseptic loosening. Five-year survivorship free from any revision of the cone-impaction grafting construct and free from any reoperation was 95% and 65%, respectively. A total of 25 knees (28%) underwent reoperation, with the 2 most common indications being PJI and periprosthetic fracture. All cones were osseointegrated, and all bone graft appeared stable or incorporated. One patient had radiographic evidence of tibial component loosening despite a well-fixed cone; however, this patient was asymptomatic and had not undergone revision at 9 years. CONCLUSIONS: When presented with a sclerotic, polished diaphyseal canal with deficient cancellous bone and concomitant metaphyseal bone loss, our technique of combining diaphyseal impaction grafting with a metaphyseal cone proved extremely durable in this larger series of patients. No cone-impaction grafting constructs required re-revision for aseptic loosening. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Relevance of individual bronchial symptoms for asthma diagnosis and control in patients with rhinitis: A MASK-air study.

RATIONALE: It is unclear how each individual asthma symptom is associated with asthma diagnosis or control. OBJECTIVES: To assess the performance of individual asthma symptoms in the identification of patients with asthma and their association with asthma control. METHODS: In this cross-sectional study, we assessed real-world data using the MASK-air® app. We compared the frequency of occurrence of five asthma symptoms (dyspnea, wheezing, chest tightness, fatigue and night symptoms, as assessed by the Control of Allergic Rhinitis and Asthma Test [CARAT] questionnaire) in patients with probable, possible or no current asthma. We calculated the sensitivity, specificity and predictive values of each symptom, and assessed the association between each symptom and asthma control (measured using the e-DASTHMA score). Results were validated in a sample of patients with a physician-established diagnosis of asthma. MEASUREMENT AND MAIN RESULTS: We included 951 patients (2153 CARAT assessments), with 468 having probable asthma, 166 possible asthma and 317 no evidence of asthma. Wheezing displayed the highest specificity (90.5%) and positive predictive value (90.8%). In patients with probable asthma, dyspnea and chest tightness were more strongly associated with asthma control than other symptoms. Dyspnea was the symptom with the highest sensitivity (76.1%) and the one consistently associated with the control of asthma as assessed by e-DASTHMA. Consistent results were observed when assessing patients with a physician-made diagnosis of asthma. CONCLUSIONS: Wheezing and chest tightness were the asthma symptoms with the highest specificity for asthma diagnosis, while dyspnea displayed the highest sensitivity and strongest association with asthma control.