Validity of the MoCA as a cognitive screening tool in epilepsy: Are there implications for global care and research?

OBJECTIVE: This study evaluated the diagnostic performance of a widely available cognitive screener, the Montreal cognitive assessment (MoCA), to detect cognitive impairment in older patients (age ≥ 55) with epilepsy residing in the US, using the International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) as the gold standard. METHODS: Fifty older adults with focal epilepsy completed the MoCA and neuropsychological measures of memory, language, executive function, and processing speed/attention. The IC-CoDE taxonomy divided participants into IC-CoDE Impaired and Intact groups. Sensitivity and specificity across several MoCA cutoffs were examined. Spearman correlations examined relationships between the MoCA total score and clinical and demographic variables and MoCA domain scores and individual neuropsychological tests. RESULTS: IC-CoDE impaired patients demonstrated significantly lower scores on the MoCA total, visuospatial/executive, naming, language, delayed recall, and orientation domain scores (Cohen's d range: 0.336-2.77). The recommended MoCA cutoff score < 26 had an overall accuracy of 72%, 88.2% sensitivity, and 63.6% specificity. A MoCA cutoff score < 24 yielded optimal sensitivity (70.6%) and specificity (78.8%), with overall accuracy of 76%. Higher MoCA total scores were associated with greater years of education (p = 0.016) and fewer antiseizure medications (p = 0.049). The MoCA memory domain was associated with several standardized measures of memory, MoCA language domain with category fluency, and MoCA abstraction domain with letter fluency. SIGNIFICANCE: This study provides initial validation of the MoCA as a useful screening tool for older adults with epilepsy that can be used to identify patients who may benefit from comprehensive neuropsychological testing. Further, we demonstrate that a lower cutoff (i.e., <24) better captures cognitive impairment in older adults with epilepsy than the generally recommended cutoff and provides evidence for construct overlap between MoCA domains and standard neuropsychological tests. Critically, similar efforts in other regions of the world are needed. PLAIN LANGUAGE SUMMARY: The Montreal cognitive assessment (MoCA) can be a helpful tool to screen for cognitive impairment in older adults with epilepsy. We recommend that adults 55 or older with epilepsy who score less than 24 on the MoCA are referred to a neuropsychologist for a comprehensive evaluation to assess any changes in cognitive abilities and mood.

Autonomy support in an exercise intervention with colorectal cancer patients during chemotherapy: a qualitative perspective.

OBJECTIVE: Physical activity (PA) has emerged as an important element of supportive care for cancer patients, but few patients engage with exercise. Considering that autonomy support is associated with healthy lifestyles, it would be useful to know the specific autonomy-supportive techniques that can help to encourage PA in colorectal cancer (CRC) patients. This study aims to qualitatively explore autonomy support perceptions through a self-determination-theory-based exercise program (FIT-CANCER) with CRC patients during chemotherapy treatment. METHODS AND MEASURES: A total of 27 participants were included, 16 CRC patients, six relatives, and five healthcare professionals. Qualitative data from semi-structured interviews and observational field notes were analyzed with thematic analysis. RESULTS: Three main themes were identified: Healthcare professionals encouraging enrollment in the exercise program, Relatives supporting attendance to the exercise sessions, Exercise instructor favoring adherence to the exercise program. The different subthemes showed autonomy-supportive techniques from these social agents to promote CRC patients' participation in the exercise program. CONCLUSION: The present research showed the importance of autonomy support from healthcare professionals, relatives and the exercise instructor to promote the initiation and maintenance of CRC patients' PA behavior and improve their quality of life, health and well-being.

Increased plasma levels of N-terminal pro-B-type natriuretic peptide as biomarker for the diagnosis of cardioembolic ischaemic stroke.

BACKGROUND: Despite comprehensive study, the aetiology of stroke is not identified in 35% of cases. AIMS: We conducted a study to assess the diagnostic capacity of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the identification of ischaemic stroke of cardioembolic origin. The secondary purpose of the study was to evaluate the prognostic value of NT-proBNP for predicting 90-day all-cause mortality. METHODS: We designed a prospective observational study including patients hospitalised due to stroke between March 2019 and March 2020. Blood samples were collected on admission to the emergency department and serum NT-proBNP levels were determined. Statistical analysis was performed using a bivariate logistic regression model and receiver operating characteristic (ROC) and Kaplan-Meier curves. Statistical significance was established at p<.05. RESULTS: The study included 207 patients with first ischaemic stroke. Plasma NT-proBNP levels were significantly higher (p<.001) in the cardioembolic stroke group (2069pg/mL±488.5). ROC curves showed that NT-proBNP>499pg/mL was the optimum value for diagnosing cardioembolic ischaemic stroke (sensitivity, 82%; specificity, 80%). Moreover, plasma NT-proBNP levels>499pg/mL were independently associated with cardioembolic stroke (OR: 9.881; p=.001). Finally, NT-proBNP>1500pg/mL was useful for predicting 90-day mortality (sensitivity, 70%; specificity, 93%). CONCLUSIONS: NT-proBNP was independently associated with cardioembolic stroke and should be quantified in blood tests within 24h of stroke onset. High plasma levels (>499pg/mL) may indicate an underlying cardioembolic cause, which should be further studied, while NT-proBNP >1500pg/mL was associated with increased 90-day mortality.

Maintaining the Physiological Lateral Flexion Gap in the Kinematically Aligned TKA Does Not Compromise Clinical Outcomes at One-Year Follow-Up.

Background: Instability is a common cause of (total knee arthroplasty) TKA failure, which can be prevented by achieving proper gap balance during surgery. There is no consensus on the ideal gap balance in TKA, and different alignment philosophies result in varying soft-tissue tightness. Traditional TKA aims for symmetric compartment balance, while kinematic alignment (KA) restores anatomy and accepts asymmetric flexion gaps. This study evaluated the impact of these philosophies on the flexion gap balance and clinical outcomes. Methods: A retrospective review of 167 patients who received true or restricted KA robotic-assisted TKA with at least one year of follow-up was conducted. The groups were based on intraoperative flexion gap differences: symmetric (0-1 mm) (n = 94) and asymmetric (2-5 mm) (n = 73). Results: Preoperative demographics and postoperative clinical and functional scores were compared. Both groups were similar in demographics and preoperative scores. True KA alignment was more likely to result in an asymmetric flexion gap, while restricted KA produced symmetric gaps. Conclusions: The study found no adverse effects from the physiological asymmetric flexion gap, with clinical and functional outcomes comparable to symmetric gaps. A 5 mm difference between the medial and lateral gap width did not negatively impact the outcomes. True KA more frequently results in a physiological asymmetric flexion gap.

In Vitro Identification of Phosphorylation Sites on TcPolß by Protein Kinases TcCK1, TcCK2, TcAUK1, and TcPKC1 and Effect of Phorbol Ester on Activation by TcPKC of TcPolß in Trypanosoma cruzi Epimastigotes.

Chagas disease is caused by the single-flagellated protozoan Trypanosoma cruzi, which affects several million people worldwide. Understanding the signal transduction pathways involved in this parasite's growth, adaptation, and differentiation is crucial. Understanding the basic mechanisms of signal transduction in T. cruzi could help to develop new drugs to treat the disease caused by these protozoa. In the present work, we have demonstrated that Fetal Calf Serum (FCS) can quickly increase the levels of both phosphorylated and unphosphorylated forms of T. cruzi DNA polymerase beta (TcPolß) in tissue-cultured trypomastigotes. The in vitro phosphorylation sites on TcPolß by protein kinases TcCK1, TcCK2, TcAUK1, and TcPKC1 have been identified by Mass Spectrometry (MS) analysis and with antibodies against phosphor Ser-Thr-Tyr. MS analysis indicated that these protein kinases can phosphorylate Ser and Thr residues on several sites on TcPolß. Unexpectedly, it was found that TcCK1 and TcPKC1 can phosphorylate a different Tyr residue on TcPolß. By using a specific anti-phosphor Tyr monoclonal antibody, it was determined that TcCK1 can be in vitro autophosphorylated on Tyr residues. In vitro and in vivo studies showed that phorbol 12-myristate 13-acetate (PMA) can activate the PKC to stimulate the TcPolß phosphorylation and enzymatic activity in T. cruzi epimastigotes.

Do caring teachers protect African American youth with adverse adolescent experiences from risky behaviors?

The current study aims to fill the existing research gaps by investigating the role of teacher care in protecting African American adolescents in under-resourced neighborhoods from negative outcomes of adverse life events. The study included 638 adolescents from four under-resourced neighborhoods in Chicago's Southside who were assessed to determine the moderating role of caring teachers on the relationship between adverse adolescent experiences and risky sexual behaviors, substance use, bullying perpetration, and violent behaviors. Caring teachers had a significant moderating effect on the association between adverse experiences and both bullying perpetration and violent behaviors. Adolescents who perceived their teachers as caring showed lower tendencies towards bullying and violence, even if they had adverse experiences. These results highlight the crucial role of teacher care in supporting African American adolescents from under-resourced neighborhoods who have experienced adverse life events. It emphasizes educators' role in shaping our youth's future, especially those facing adversity and at a crossroads in their lives.

Despite adverse life events, adolescents who perceived their teachers as caring were less at risk of engaging in bullying and violence. Caring teachers are especially important for African American adolescents in under-resourced neighborhoods.

Optogenetic control of Nodal signaling patterns.

A crucial step in early embryogenesis is the establishment of spatial patterns of signaling activity. Tools to perturb morphogen signals with high resolution in space and time can help reveal how embryonic cells decode these signals to make appropriate fate decisions. Here, we present new optogenetic reagents and an experimental pipeline for creaHng designer Nodal signaling patterns in live zebrafish embryos. Nodal receptors were fused to the light-sensitive heterodimerizing pair Cry2/CIB1N, and the Type II receptor was sequestered to the cytosol. The improved optoNodal2 reagents eliminate dark activity and improve response kinetics, without sacrificing dynamic range. We adapted an ultra-widefield microscopy platform for parallel light patterning in up to 36 embryos and demonstrated precise spatial control over Nodal signaling activity and downstream gene expression. Patterned Nodal activation drove precisely controlled internalization of endodermal precursors. Further, we used patterned illumination to generate synthetic signaling patterns in Nodal signaling mutants, rescuing several characteristic developmental defects. This study establishes an experimental toolkit for systematic exploration of Nodal signaling patterns in live embryos.

Aortic thrombosis and acute kidney injury due to atherosclerosis in a dog.

OBJECTIVE: Atherosclerosis is a chronic lipid-driven inflammatory disease of the arterial wall. Due to its cardiovascular ischemic complications, it is one of the most common causes of death in people. However, atherosclerosis is seldomly reported in dogs. ANIMAL: A 10-year-old male mixed-breed dog. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: Severe acute kidney injury associated with thrombosis of the abdominal aorta. TREATMENT AND OUTCOME: Treatment included renal replacement therapy, antithrombotic therapy, and supportive care. However, the dog developed neurological and respiratory complications and was euthanized due to worsening kidney function and lack of improvement of the thrombosis. Postmortem examination confirmed the presence of aortic thromboembolism and renal infarcts. Histology revealed severe chronic-active atherosclerosis of the distal aorta and renal arteries. CLINICAL RELEVANCE: Aortic thrombosis is uncommon in dogs, and it is often associated with underlying conditions such as protein-losing nephropathy, endocrine disorders, cardiac disease, or hypercoagulability. In this case, no specific underlying cause was identified and atherosclerosis was considered the primary cause of the thrombosis.

Changes in the Serum Metabolome in an Inflammatory Model of Osteoarthritis in Rats.

Osteoarthritis (OA) is a pathology of great impact worldwide. Its physiopathology is not completely known, and it is usually diagnosed by imaging techniques performed at advanced stages of the disease. The aim of this study was to evaluate early serum metabolome changes and identify the main metabolites involved in an inflammatory OA animal model. This study was performed on thirty rats. OA was induced in all animals by intra-articular injection of monoiodoacetate into the knee joint. Blood samples were taken from all animals and analyzed by mass spectrometry before OA induction and 28, 56, and 84 days following induction. Histological evaluation confirmed OA in all samples. The results of this study allow the identification of several changes in 18 metabolites over time, including organic acids, benzenoids, heterocyclic compounds, and lipids after 28 days, organic acids after 56 days, and lipid classes after 84 days. We conclude that OA induces serological changes in the serum metabolome, which could serve as potential biomarkers. However, it was not possible to establish a relationship between the identified metabolites and the time at which the samples were taken. Therefore, these findings should be confirmed in future OA studies.

Valor pronóstico de los parámetros hematológicos y los parámetros metabólicos de la PET/TC con [18F]FDG en el cáncer de cabeza y cuello / Prognostic value of haematological parameters and [18F]FDG PET/CT metabolic parameters in head and neck cancer

Objetivo Determinar la utilidad de los cocientes neutrófilos/linfocitos (N/L) y plaquetas/linfocitos (P/L), así como de parámetros cuantitativos de la PET/TC con [18F]FDG, como factores pronósticos para la supervivencia global (SG), la supervivencia cáncer específica (SCE) y la supervivencia libre de progresión (SLP) en pacientes con carcinoma escamoso de cabeza y cuello (CyC) Material y métodos Se valoraron retrospectivamente 66 pacientes (56 hombres) diagnosticados de CyC durante un intervalo de 8años. Se determinaron los parámetros SUV máximo (SUVmax), volumen metabólico tumoral (MTV) y glucólisis tumoral total (TLG) del estudio PET/TC al diagnóstico. Tras tratamiento con quimiorradioterapia, se valoró la supervivencia de los pacientes. El modelo de regresión de Cox y el método de Kaplan-Meier se utilizaron para analizar factores pronósticos y curvas de supervivencia. Resultados El seguimiento medio fue de 50,4meses, produciéndose 39 recurrencias-progresiones y 39 fallecimientos. En el análisis univariante los parámetros metabólicos, excepto el SUVmax, fueron factores predictivos para las tres supervivencias, y los dos parámetros sanguíneos lo fueron para la SG y la SCE. La TLG fue el único factor predictivo en el análisis multivariante. Las tres curvas de supervivencias fueron significativamente diferentes para los parámetros metabólicos y la curva de SG para el cociente N/L. Se apreciaron correlaciones entre el cociente N/L, el MTV y la TLG. No se demostraron correlaciones entre el cociente P/L y los parámetros metabólicos. Conclusión El uso de marcadores hematológicos y metabólicos permitiría identificar pacientes con un alto riesgo de recurrencias y pobre supervivencia e individualizar el tratamiento aplicando terapias más agresivas (AU)

Aim To determine the usefulness of neutrophil/lymphocyte (N/L) and platelet/lymphocyte (P/L) ratios as well as quantitative [18F]FDG PET/CT parameters as prognostic factors for overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) in patients with head and neck squamous cell carcinoma (HyN). Material and methods Sixty-six patients (56 men) diagnosed with HyN carcinoma were retrospectively assessed over an 8-year interval. Maximum SUV (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) parameters were determined from the PET/CT study at diagnosis. After treatment with chemoradiotherapy, patient survival was assessed. The Cox regression model and the Kaplan-Meier method were used to analyse prognostic factors and survival curves. Results Median follow-up was 50.4months, with 39 recurrences-progressions and 39 deaths. In the univariate analysis, metabolic parameters, except SUVmax, were predictive factors for all three survivals and the two blood parameters were predictive for OS and EFS. TLG was the only predictive factor in the multivariate analysis. The three survival curves were significantly different for the metabolic parameters and the OS curve for the N/L ratio. Correlations were seen between N/L ratio, MTV and TLG. No correlations were demonstrated between P/L ratio and metabolic parameters. Conclusion The use of haematological and metabolic markers would allow to identify patients with a high risk of recurrences and poor survival and to individualise treatment by applying more aggressive therapies (AU)

Genetic determinants of micronucleus formation in vivo.

Genomic instability arising from defective responses to DNA damage1 or mitotic chromosomal imbalances2 can lead to the sequestration of DNA in aberrant extranuclear structures called micronuclei (MN). Although MN are a hallmark of ageing and diseases associated with genomic instability, the catalogue of genetic players that regulate the generation of MN remains to be determined. Here we analyse 997 mouse mutant lines, revealing 145 genes whose loss significantly increases (n = 71) or decreases (n = 74) MN formation, including many genes whose orthologues are linked to human disease. We found that mice null for Dscc1, which showed the most significant increase in MN, also displayed a range of phenotypes characteristic of patients with cohesinopathy disorders. After validating the DSCC1-associated MN instability phenotype in human cells, we used genome-wide CRISPR-Cas9 screening to define synthetic lethal and synthetic rescue interactors. We found that the loss of SIRT1 can rescue phenotypes associated with DSCC1 loss in a manner paralleling restoration of protein acetylation of SMC3. Our study reveals factors involved in maintaining genomic stability and shows how this information can be used to identify mechanisms that are relevant to human disease biology1.

International Physical Activity Questionnaire Short Form and accelerometer-assessed physical activity: concurrent validity using six cut-points in HF patients.

AIMS: Physical activity (PA) is an important target for improving clinical outcomes in heart failure (HF) patients. Nonetheless, assessing the daily PA profile in this population is a challenging task, traditionally performed using self-report questionnaires such as the International PA Questionnaire Short Form (IPAQ-SF). This study aimed to evaluate the concurrent validity of the IPAQ-SF and accelerometer-assessed PA using six published cut-points in patients with HF and reduced or mildly reduced ejection fraction. METHODS AND RESULTS: The concordance between the IPAQ-SF and a hip-worn accelerometer regarding daily time spent performing moderate to vigorous PA in bouts of at least 10 min was assessed in 53 participants for seven consecutive days using six different cut-points (Barnett, Dibben, Mark, Sanders, Troiano, and Vaha-Ypya). Spearman's correlation and Bland-Altman plots were used to evaluate concurrent validity between methods. Regressions were used to study the association between patient variables, wear protocol (waking hour or 24 h), and absolute bias. The kappa index was used to evaluate the concordance between IPAQ-SF and accelerometry for classifying patients as active or non-active. All analyses were re-run using non-bouted metrics to investigate the effect of bouted versus non-bouted analysis. The IPAQ-SF and accelerometry showed low to negligible correlation (ρ = 0.12 to 0.37), depending on the cut-point used. The regression analysis showed that the absolute bias was higher in participants following the waking-hour protocol at all cut-points except Dibben's (P ≤ 0.007). The concordance between the two methods to classify patients as active and non-active was low when using Mark (κ = 0.23) and Barnett (κ = 0.34) cut-points and poor for the remaining cut-points (κ = 0.03 to 0.18). The results of the sensitivity analysis showed negligible to low correlation using non-bouted metrics (ρ = 0.27 to 0.33). CONCLUSIONS: Moderate to vigorous PA measures using IPAQ-SF and accelerometers are not equivalent, and we do not encourage researchers to use IPAQ-SF alone when assessing PA in HF patients. Moreover, applying personalized collection and processing criteria is important when assessing PA in HF patients. We recommend following the 24 h protocol and selecting cut-points calibrated in patients with cardiovascular diseases. Finally, it is necessary to develop a new tailored questionnaire that considers walking intensity and is adjusted to the current World Health Organisation recommendations, which use non-bouted metrics.

Retrospective evaluation of hematological ratios in canine parvovirosis: 401 cases.

BACKGROUND: The utility of neutrophil-to-lymphocyte ratio (NLR), platelet to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) as prognostic indicators has not been investigated in canine parvovirosis (CPV). HYPOTHESIS: To evaluate whether these hematological ratios obtained at hospital admission in CPV are associated with outcome or duration of hospitalization. ANIMALS: Four hundred one client-owned dogs presented with CPV. Methods-Retrospective multicenter cohort study. Medical records were reviewed to identify dogs with CPV. Data regarding signalment, complete blood count at admission, duration of hospitalization and outcome were collected. RESULTS: Of the 401 dogs included in the study, 336 (83.8%) survived to discharge. The median (25th and 75th percentiles) PLR in nonsurvivors (336.56 [159.84-635.77]) was significantly higher than in survivors (217.65 [117.67-389.65]) (P = .003). The area under the receiver-operating characteristic curve for nonsurvival was 0.615 (95% CI [0.593-0.691], P = .003). A cut off of 700 showed a 21.5% sensitivity and 90% specificity for nonsurvival. No association was observed between hospitalization duration and either hematological ratios or total WBC counts. The median (25th and 75th percentiles) lymphocyte count was below reference interval in all dogs and was significantly lower in the dogs which died (0.82 × 109 /L [0.5-1.87]) than in survivors (1.27 × 109 /L [0.73-2.22]) (P = .005). The median (25th and 75th percentiles) monocyte count however was lower in survivors (0.38 × 109 /L [0.29-1.59]), than in nonsurvivors (0.73 × 109 /L [0.1-2]) (P = .002). CONCLUSIONS: Evaluation of PLR at hospital admission might be a useful marker of disease severity and could have prognostic value in dogs with CPV.

Interactions between functional networks in Parkinson's disease mild cognitive impairment.

The study of mild cognitive impairment (MCI) is critical to understand the underlying processes of cognitive decline in Parkinson's disease (PD). Functional connectivity (FC) disruptions in PD-MCI patients have been observed in several networks. However, the functional and cognitive changes associated with the disruptions observed in these networks are still unclear. Using a data-driven methodology based on independent component analysis, we examined differences in FC RSNs among PD-MCI, PD cognitively normal patients (PD-CN) and healthy controls (HC) and studied their associations with cognitive and motor variables. A significant difference was found between PD-MCI vs PD-CN and HC in a FC-trait comprising sensorimotor (SMN), dorsal attention (DAN), ventral attention (VAN) and frontoparietal (FPN) networks. This FC-trait was associated with working memory, memory and the UPDRS motor scale. SMN involvement in verbal memory recall may be related with the FC-trait correlation with memory deficits. Meanwhile, working memory impairment may be reflected in the DAN, VAN and FPN interconnectivity disruptions with the SMN. Furthermore, interactions between the SMN and the DAN, VAN and FPN network reflect the intertwined decline of motor and cognitive abilities in PD-MCI. Our findings suggest that the memory impairments observed in PD-MCI are associated with reduced FC within the SMN and between SMN and attention networks.

Acute Dislocation of the Elbow: An All-Arthroscopic Repair of the Lateral Ligament Complex.

The elbow is one of the most commonly dislocated joints. While conservative management is frequently performed for simple elbow dislocations, the importance of primary surgical treatment is still undetermined. However, promising results have been reached after surgical repair. We propose an arthroscopic surgical repair of the lateral ligament complex (LCL), performed with a horizontal suture and 2 Fibertak Knotless implants (Arthrex) placed on the LCL origin, one anterior and the other posterior. Operative treatment should be performed in patients with moderate and gross elbow laxity to avoid post-traumatic sequelae and decrease revision rates. Arthroscopic techniques create fewer complications. This procedure allows one to address intra-articular elbow joint pathology with less chance of wound complications and the ability to use bone anchors if desired.

The Accuracy and Absolute Reliability of a Knee Surgery Assistance System Based on ArUco-Type Sensors.

Recent advances allow the use of Augmented Reality (AR) for many medical procedures. AR via optical navigators to aid various knee surgery techniques (e.g., femoral and tibial osteotomies, ligament reconstructions or menisci transplants) is becoming increasingly frequent. Accuracy in these procedures is essential, but evaluations of this technology still need to be made. Our study aimed to evaluate the system's accuracy using an in vitro protocol. We hypothesised that the system's accuracy was equal to or less than 1 mm and 1° for distance and angular measurements, respectively. Our research was an in vitro laboratory with a 316 L steel model. Absolute reliability was assessed according to the Hopkins criteria by seven independent evaluators. Each observer measured the thirty palpation points and the trademarks to acquire direct angular measurements on three occasions separated by at least two weeks. The system's accuracy in assessing distances had a mean error of 1.203 mm and an uncertainty of 2.062, and for the angular values, a mean error of 0.778° and an uncertainty of 1.438. The intraclass correlation coefficient was for all intra-observer and inter-observers, almost perfect or perfect. The mean error for the distance's determination was statistically larger than 1 mm (1.203 mm) but with a trivial effect size. The mean error assessing angular values was statistically less than 1°. Our results are similar to those published by other authors in accuracy analyses of AR systems.

How myosin VI traps its off-state, is activated and dimerizes.

Myosin VI (Myo6) is the only minus-end directed nanomotor on actin, allowing it to uniquely contribute to numerous cellular functions. As for other nanomotors, the proper functioning of Myo6 relies on precise spatiotemporal control of motor activity via a poorly defined off-state and interactions with partners. Our structural, functional, and cellular studies reveal key features of myosin regulation and indicate that not all partners can activate Myo6. TOM1 and Dab2 cannot bind the off-state, while GIPC1 binds Myo6, releases its auto-inhibition and triggers proximal dimerization. Myo6 partners thus differentially recruit Myo6. We solved a crystal structure of the proximal dimerization domain, and show that its disruption compromises endocytosis in HeLa cells, emphasizing the importance of Myo6 dimerization. Finally, we show that the L926Q deafness mutation disrupts Myo6 auto-inhibition and indirectly impairs proximal dimerization. Our study thus demonstrates the importance of partners in the control of Myo6 auto-inhibition, localization, and activation.