Early Renal Outcomes Following Heart Transplantation Using Organs Procured After Circulatory Death.

BACKGROUND: Transplantation using hearts obtained through donation after circulatory death (DCD) is increasing, but data on recipient renal outcomes are limited. METHODS AND RESULTS: Patients at a single institution who underwent heart transplantation using organs procured through DCD or donation after brain death (DBD) from April 2016 to August 2022 were included in this retrospective cohort study. Hemodynamic measures were collected via right heart catheterization performed 1 week after transplantation. Posttransplantation renal outcomes included estimated glomerular filtration rate at 1 week, 4 weeks, and 16 weeks, and the incidence of acute kidney injury (AKI) and renal replacement therapy within 1 week. The analysis included 225 patients (55 recipients of DCD). Baseline characteristics were comparable between recipients of DCD and DBD. Renal outcomes within 1 week posttransplantation in recipients of DCD were similar to recipients of DBD, including percent change in estimated glomerular filtration rate (-37.9% [-58.6 to -6.2] versus -31.9% [-52.4 to -9.9]; P=0.91), incidence of AKI (47.3% versus 46.5%; P>0.99) and incidence of renal replacement therapy (3.6% versus 4.7%; P>0.99). Recipients of DCD with AKI within 1 week ("early AKI") did not recover to baseline estimated glomerular filtration rate (75.8 [60.2-91.3] mL/min per 1.73 m2) by week 16 (59.3 [46.9-73.6] mL/min per 1.73 m2; P=0.002), whereas recipients without early AKI exhibited comparable estimated glomerular filtration rate to baseline by week 4 (84.5 [70.8-98.5] mL/min per 1.73 m2; P=0.084). Similar trends were observed in recipients of DBD. CONCLUSIONS: Recipients of DCD demonstrated similar renal outcomes compared with recipients of DBD, supporting the ongoing use of DCD transplantation. Early AKI was associated with persistent renal dysfunction for recipients of both DCD and DBD.

Laminar organization of visual responses in core and parabelt auditory cortex.

Audiovisual (AV) interaction has been shown in many studies of auditory cortex. However, the underlying processes and circuits are unclear because few studies have used methods that delineate the timing and laminar distribution of net excitatory and inhibitory processes within areas, much less across cortical levels. This study examined laminar profiles of neuronal activity in auditory core (AC) and parabelt (PB) cortices recorded from macaques during active discrimination of conspecific faces and vocalizations. We found modulation of multi-unit activity (MUA) in response to isolated visual stimulation, characterized by a brief deep MUA spike, putatively in white matter, followed by mid-layer MUA suppression in core auditory cortex; the later suppressive event had clear current source density concomitants, while the earlier MUA spike did not. We observed a similar facilitation-suppression sequence in the PB, with later onset latency. In combined AV stimulation, there was moderate reduction of responses to sound during the visual-evoked MUA suppression interval in both AC and PB. These data suggest a common sequence of afferent spikes, followed by synaptic inhibition; however, differences in timing and laminar location may reflect distinct visual projections to AC and PB.

Parallel patterns of cognitive aging in marmosets and macaques.

As humans age, some experience cognitive impairment while others do not. When impairment does occur, it is not expressed uniformly across cognitive domains and varies in severity across individuals. Translationally relevant model systems are critical for understanding the neurobiological drivers of this variability, which is essential to uncovering the mechanisms underlying the brain's susceptibility to the effects of aging. As such, non-human primates are particularly important due to shared behavioral, neuroanatomical, and age-related neuropathological features with humans. For many decades, macaque monkeys have served as the primary non-human primate model for studying the neurobiology of cognitive aging. More recently, the common marmoset has emerged as an advantageous model for this work due to its short lifespan that facilitates longitudinal studies. Despite their growing popularity as a model, whether marmosets exhibit patterns of age-related cognitive impairment comparable to those observed in macaques and humans remains unexplored. To address this major limitation for the development and evaluation of the marmoset as a model of cognitive aging, we directly compared working memory ability as a function of age in macaques and marmosets on the identical working memory task. Our results demonstrate that marmosets and macaques exhibit remarkably similar age-related working memory deficits, highlighting the value of the marmoset as a model for cognitive aging research within the neuroscience community.

Oral minoxidil for late alopecia in cancer survivors.

PURPOSE: Late alopecia, defined as incomplete hair regrowth > 6 months following cytotoxic chemotherapy or > 6 months from initiation of endocrine therapy, negatively impacts quality of life and may affect dose intensity of adjuvant therapy. This study investigates the effect of oral minoxidil in women with chemotherapy and/or endocrine therapy-induced late alopecia. METHODS: The rate of clinical response was assessed by standardized photography and quantitated with trichoscopy. RESULTS: Two hundred and sixteen patients (mean age 57.8 ± 13.7) were included. The most common cancer diagnosis was breast, in 170 patients (79.1%). Alopecia developed after chemotherapy in 31 (14.4%) patients, endocrine monotherapy in 65 (30.1%) patients, and chemotherapy followed by endocrine therapy in 120 (55.6%) patients. In 119 patients, standardized photography assessments were used to determine clinical change in alopecia after a median of 105 (IQR = 70) days on oral minoxidil and revealed improvement in 88 (74%) patients. Forty-two patients received quantitative trichoscopic assessments at baseline and at follow-up after a median of 91 (IQR = 126) days on oral minoxidil. Patients had clinically and statistically significant increases in frontal hair shaft density (from 124.2 hairs/cm2 at initial to 153.2 hairs/cm2 at follow-up assessment, p = 0.008) and occipital shaft density (from 100.3 hairs/cm2 at initial to 123.5 hairs/cm2 at follow-up assessment. p = 0.004). No patients discontinued oral minoxidil due to adverse events. CONCLUSIONS: Overall, oral minoxidil was well tolerated by patients and may benefit both frontal and occipital late alopecia in cancer survivors treated with cytotoxic and/or endocrine therapy by increasing hair shaft and follicle density.

IFN Receptor 2 Regulates TNF-α-Mediated Damaging Inflammation during Aspergillus Pulmonary Infection.

The increased incidence of invasive pulmonary aspergillosis, caused by Aspergillus fumigatus, occurring in patients infected with severe influenza or SARS-CoV-2, suggests that antiviral immune responses create an environment permissive to fungal infection. Our recent evidence suggests that absence of the type I IFN receptor 2 subunit (IFNAR2) of the heterodimeric IFNAR1/2 receptor is allowing for this permissive immune environment of the lung through regulation of damage responses. Because damage is associated with poor outcome to invasive pulmonary aspergillosis, this suggested that IFNAR2 may be involved in A. fumigatus susceptibility. In this study, we determined that absence of IFNAR2 resulted in increased inflammation, morbidity, and damage in the lungs in response to A. fumigatus challenge, whereas absence of IFNAR1 did not. Although the Ifnar2-/- mice had increased morbidity, we found that the Ifnar2-/- mice cleared more conidia compared with both wild-type and Ifnar1-/- mice. However, this early clearance did not prevent invasive disease from developing in the Ifnar2-/- mice as infection progressed. Importantly, by altering the inflamed environment of the Ifnar2-/- mice early during A. fumigatus infection, by neutralizing TNF-α, we were able to reduce the morbidity and fungal clearance in these mice back to wild-type levels. Together, our results establish a distinct role for IFNAR2 in regulating host damage responses to A. fumigatus and contributing to an A. fumigatus-permissive environment through regulation of inflammation. Specifically, our data reveal a role for IFNAR2 in regulating TNF-α-mediated damage and morbidity during A. fumigatus infection.

Gastric Emptying Scintigraphy Protocol Optimization Using Machine Learning for the Detection of Delayed Gastric Emptying.

PURPOSE: The purpose of this study is to examine the feasibility of a machine learning (ML) system for optimizing a gastric emptying scintigraphy (GES) protocol for the detection of delayed gastric emptying (GE), which is considered a primary indication for the diagnosis of gastroparesis. METHODS: An ML model was developed using the JADBio AutoML artificial intelligence (AI) platform. This model employs the percent GE at various imaging time points following the ingestion of a standardized radiolabeled meal to predict normal versus delayed GE at the conclusion of the 4 h GES study. The model was trained and tested on a cohort of 1002 patients who underwent GES using a 70/30 stratified split ratio for training vs. testing. The ML software automated the generation of optimal predictive models by employing a combination of data preprocessing, appropriate feature selection, and predictive modeling analysis algorithms. RESULTS: The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was employed to evaluate the predictive modeling performance. Several models were developed using different combinations of imaging time points as input features and methodologies to achieve optimal output. By using GE values at time points 0.5 h, 1 h, 1.5 h, 2 h, and 2.5 h as input predictors of the 4 h outcome, the analysis produced an AUC of 90.7% and a balanced accuracy (BA) of 80.0% on the test set. This performance was comparable to the training set results (AUC = 91.5%, BA = 84.7%) within the 95% confidence interval (CI), demonstrating a robust predictive capability. Through feature selection, it was discovered that the 2.5 h GE value alone was statistically significant enough to predict the 4 h outcome independently, with a slightly increased test set performance (AUC = 92.4%, BA = 83.3%), thus emphasizing its dominance as the primary predictor for delayed GE. ROC analysis was also performed for single time imaging points at 1 h and 2 h to assess their independent predictiveness of the 4 h outcome. Furthermore, the ML model was tested for its ability to predict "flipping" cases with normal GE at 1 h and 2 h that became abnormal with delayed GE at 4 h. CONCLUSIONS: An AI/ML model was designed and trained for predicting delayed GE using a limited number of imaging time points in a 4 h GES clinical protocol. This study demonstrates the feasibility of employing ML for GES optimization in the detection of delayed GE and potentially shortening the protocol's time length without compromising diagnostic power.

Efficacy of laser hair removal in hidradenitis suppurativa: A systematic review and meta-analysis.

OBJECTIVES: Hidradenitis suppurativa (HS) is a chronic inflammatory condition characterized by painful nodules, draining tunnels, and fibrotic scarring in intertriginous, hair-bearing areas. The pathogenesis involves follicular occlusion and subsequent rupture, leading to uncontrolled inflammation. Treatment options for HS are limited and lack universal effectiveness. Laser hair removal (LHR) has been explored as a potential treatment; however, the efficacy and appropriate laser modalities remain unclear. This systematic review examined the efficacy and adverse effects of LHR in HS. METHODS: A comprehensive literature search was conducted from inception to September 2023 in Ovid MEDLINE, Ovid Embase, and The Cochrane Library (Wiley) with predefined inclusion and exclusion criteria, and a meta-analysis was conducted. RESULTS: Ten studies were selected (n = 227 total patients) and included six randomized controlled trials, two nonrandomized experimental studies, and two case series. Various laser modalities, including long-pulsed neodymium-doped yttrium aluminum garnet (Nd:YAG) (n = 115), intense pulsed light (n = 18), Alexandrite (n = 54), intralesional 1064 nm diode (n = 20), and combined fractional CO2 and long-pulsed Nd:YAG laser (n = 20), consistently demonstrated significant improvement in HS disease severity, irrespective of the disease scoring method used. Minimal adverse effects (primarily mild pain and erythema) were reported. A meta-analysis of three studies utilizing long-pulsed Nd:YAG laser demonstrated a standardized mean difference in disease severity of -1.68 (95% confidence interval: -2.99; -0.37), favoring treatment with LHR for HS. CONCLUSIONS: Hair follicles are key in HS pathogenesis and all included studies showed a significant improvement in HS disease severity after LHR regardless of the laser device used, likely related to hair follicle unit destruction. HS is a complex and heterogenous condition, and multiple disease scoring methods complicate outcome comparisons across studies. However, LHR, utilizing various techniques, is an effective treatment option for HS with minimal adverse effects.

A combined cross-sectional analysis and case-control study evaluating tick-borne encephalitis vaccination coverage, disease and vaccine effectiveness in children and adolescents, Switzerland, 2005 to 2022.

BackgroundTick-borne encephalitis (TBE) is a severe, vaccine-preventable viral infection of the central nervous system. Symptoms are generally milder in children and adolescents than in adults, though severe disease does occur. A better understanding of the disease burden and duration of vaccine-mediated protection is important for vaccination recommendations.AimTo estimate TBE vaccination coverage, disease severity and vaccine effectiveness (VE) among individuals aged 0-17 years in Switzerland.MethodsVaccination coverage between 2005 and 2022 was estimated using the Swiss National Vaccination Coverage Survey (SNVCS), a nationwide, repeated cross-sectional study assessing vaccine uptake. Incidence and severity of TBE between 2005 and 2022 were determined using data from the Swiss disease surveillance system and VE was calculated using a case-control analysis, matching TBE cases with SNVCS controls.ResultsOver the study period, vaccination coverage increased substantially, from 4.8% (95% confidence interval (CI): 4.1-5.5%) to 50.1% (95% CI: 48.3-52.0%). Reported clinical symptoms in TBE cases were similar irrespective of age. Neurological involvement was less likely in incompletely (1-2 doses) and completely (≥ 3 doses) vaccinated cases compared with unvaccinated ones. For incomplete vaccination, VE was 66.2% (95% CI: 42.3-80.2), whereas VE for complete vaccination was 90.8% (95% CI: 87.7-96.4). Vaccine effectiveness remained high, 83.9% (95% CI: 69.0-91.7) up to 10 years since last vaccination.ConclusionsEven children younger than 5 years can experience severe TBE. Incomplete and complete vaccination protect against neurological manifestations of the disease. Complete vaccination offers durable protection up to 10 years against TBE.

Battle of the sections: Student outcomes and course feedback support combined prosection and dissection laboratory formats to maximize student success.

Gross anatomy laboratories frequently utilize dissection or prosection formats within medical curricula. Practical examination scores are consistent across the formats, yet these examinations assessed larger anatomical structures. In contrast, a single report noted improved scores when prosection was used in the hand and foot regions, areas that are more difficult to dissect. The incorporation of prosected donors within "Head and Neck" laboratories provided an opportunity to further characterize the impact of prosection in a structurally complex area. Retrospective analysis of 21 Head and Neck practical examination questions was completed to compare scores among cohorts that utilized dissection exclusively or incorporated prosection. Mean scores of practical examination questions were significantly higher in the prosection cohort (84.27% ± 12.69) as compared with the dissection cohort (75.59% ± 12.27) (p < 0.001). Of the 12 questions that performed better in the prosection cohort (88.42% ± 8.21), 10 items mapped to deeper anatomical regions. By comparison, eight of nine questions in the dissection cohort outperformed (88.44% ± 3.34) the prosection cohort (71.74% ± 18.11), and mapped to anatomically superficial regions. Despite the mean score increase with positional location of the questions, this effect was not statically significant across cohorts (p = 1.000), suggesting that structure accessibility in anatomically complex regions impacts performance. Student feedback cited structure preservation (71.5%) and time savings (55.8%) as advantages to prosection; however, dissection was the perceived superior and preferred laboratory format (88.6%). These data support combined prosection and dissection formats for improving student recognition of deeply positioned structures and maximizing student success.

Age-related differences in structural and resting-state functional brain network organization across the adult lifespan: A cross-sectional study.

We investigated age-related trends in the topology and hierarchical organization of brain structural and functional networks using diffusion-weighted imaging and resting-state fMRI data from a large cohort of healthy aging adults. At the cross-modal level, we explored age-related patterns in the RC involvement of different functional subsystems using a high-resolution functional parcellation. We further assessed age-related differences in the structure-function coupling as well as the network vulnerability to damage to rich club connectivity. Regardless of age, the structural and functional brain networks exhibited a rich club organization and small-world topology. In older individuals, we observed reduced integration and segregation within the frontal-occipital regions and the cerebellum along the brain's medial axis. Additionally, functional brain networks displayed decreased integration and increased segregation in the prefrontal, centrotemporal, and occipital regions, and the cerebellum. In older subjects, structural networks also exhibited decreased within-network and increased between-network RC connectivity. Furthermore, both within-network and between-network RC connectivity decreased in functional networks with age. An age-related decline in structure-function coupling was observed within sensory-motor, cognitive, and subcortical networks. The structural network exhibited greater vulnerability to damage to RC connectivity within the language-auditory, visual, and subcortical networks. Similarly, for functional networks, increased vulnerability was observed with damage to RC connectivity in the cerebellum, language-auditory, and sensory-motor networks. Overall, the network vulnerability decreased significantly in subjects older than 70 in both networks. Our findings underscore significant age-related differences in both brain functional and structural RC connectivity, with distinct patterns observed across the adult lifespan.

Prolonged testosterone 17ß-cyclopentylpropionate exposition induces behavioral, ovarian, oviductal, uterine and reproductive disturbances in female mice.

Anabolic-androgenic steroids (AAS) abuse is often associated with metabolic disorders and infertility. However, the current evidence on AAS-induced reproductive toxicity is mainly based on male studies. Thus, AAS repercussions on female reproductive capacity remain poorly understood, despite scarce evidence that fertility determinants may be more severely impaired in females than males exposed to these drugs. Accordingly, this study used an integrated framework to investigate the impact of different testosterone 17ß-cyclopentylpropionate (TC) doses on pain sensitivity, aggressiveness, anxiety, sexual behavior, ovarian, oviductal, uterine and reproductive morphofunctional and molecular outcomes. These parameters were used to explore the reproductive capacity in female mice exposed to this synthetic testosterone ester. The animals were untreated or intraperitoneally treated with 5, 10 and 20 mg/kg TC every 48 h for 12 weeks. Our findings indicated that testosterone was upregulated while the hormones luteinizing, follicle-stimulating, estrogen and progesterone were down-regulated by TC. This AAS also exerted deleterious effects on anxiety, aggressivity, nociception, exploratory and sexual behavior in female mice. Concurrently, TC attenuated ovarian follicle maturation, interrupted the estrous cycle, induced oviductal and uterine hypotrophy. Estrous cyclicity was reestablished 60 days after AAS treatment. However, TC-treated mice still exhibited impaired reproductive capacity, a disturbance potentially related to deficiency in folliculogenesis, sex hormones production, and endometrial receptivity mediate by ER-α, PR, HOXA-10 and LIF down-regulation. Taken together, our findings indicated that in addition to female behavior, reproductive organs microstructure and function are markedly impaired by TC in a dose-dependent manner, whose time-dependent reversibility remains to be clarified.

Adjuvant Trastuzumab Emtansine Versus Paclitaxel and Trastuzumab in Stage I HER2-Positive Breast Cancer: The ATEMPT Trial.

This ASO perspective reviews the findings of a randomized, phase II clinical trial evaluating adjuvant trastuzumab emtansine (T-DM1) compared with paclitaxel and trastuzumab (TH) in stage I human epidermal growth factor receptor 2-positive breast cancer, as reported recently by the ATEMPT trial investigators. Patients treated with T-DM1 had better disease-free survival but did not have fewer treatment toxicities. The T-DM1-treated group had higher rates of treatment discontinuations, therefore long-term follow-up will be required to evaluate survival differences between T-DM1 and TH.

Diet-induced changes in metabolism influence immune response and viral shedding dynamics in Jamaican fruit bats.

Land-use change may drive viral spillover from bats into humans, partly through dietary shifts caused by decreased availability of native foods and increased availability of cultivated foods. We manipulated diets of Jamaican fruit bats to investigate whether diet influences shedding of a virus they naturally host. To reflect dietary changes experienced by wild bats during periods of nutritional stress, bats were fed either standard or putative suboptimal diets which were deprived of protein (suboptimal-sugar) and/or supplemented with fat (suboptimal-fat). Upon H18N11 influenza A-virus infection, bats fed the suboptimal-sugar diet shed the most viral RNA for the longest period, but bats fed the suboptimal-fat diet shed the least viral RNA for the shortest period. Unlike mice and humans, bats fed the suboptimal-fat diet displayed higher pre-infection levels of metabolic markers associated with gut health. Diet-driven heterogeneity in viral shedding may influence population-level viral dynamics in wild bats and alter risk of shedding and spillover to humans.

Optimizing Interprofessional Simulation with Intentional Pre-Briefing and Debriefing.

The use of simulation and interprofessional education (IPE) has been shown to enhance healthcare student and provider confidence, strengthen teamwork, and improve patient outcomes. Although debriefing has been widely practiced and studied, the value of intentional pre-briefing has been recently recognized. At the University of the Incarnate Word (UIW), Doctor of Physical Therapy (DPT) and Bachelor of Science in Nursing (BSN) students engaged in a simulation with multiple acute care scenarios. The goal of this activity was to foster competence and confidence in coordinating care for patients with complex medical conditions while functioning as integral members of a team. Faculty members recognized an opportunity to practice interprofessional care coordination behaviors through this simulation. The activity was intentionally structured with three key components: (1) thorough advanced preparation, (2) a well-organized pre-briefing session encompassing pre-simulation orientation, and (3) a structured debrief that encouraged reflection on patient care prioritization. The simulation addressed the activity goals and provided students with opportunities for growth in the Interprofessional Education Collaborative (IPEC) core competencies.

Data-driven multiscale model of macaque auditory thalamocortical circuits reproduces in vivo dynamics.

We developed a detailed model of macaque auditory thalamocortical circuits, including primary auditory cortex (A1), medial geniculate body (MGB), and thalamic reticular nucleus, utilizing the NEURON simulator and NetPyNE tool. The A1 model simulates a cortical column with over 12,000 neurons and 25 million synapses, incorporating data on cell-type-specific neuron densities, morphology, and connectivity across six cortical layers. It is reciprocally connected to the MGB thalamus, which includes interneurons and core and matrix-layer-specific projections to A1. The model simulates multiscale measures, including physiological firing rates, local field potentials (LFPs), current source densities (CSDs), and electroencephalography (EEG) signals. Laminar CSD patterns, during spontaneous activity and in response to broadband noise stimulus trains, mirror experimental findings. Physiological oscillations emerge spontaneously across frequency bands comparable to those recorded in vivo. We elucidate population-specific contributions to observed oscillation events and relate them to firing and presynaptic input patterns. The model offers a quantitative theoretical framework to integrate and interpret experimental data and predict its underlying cellular and circuit mechanisms.

Genetic variation in environmental enteropathy and stunting in Zambian children: A pilot genome wide association study using the H3Africa chip.

PURPOSE: Stunting is known to be heavily influenced by environmental factors, so the genetic contribution has received little attention. Here we report an exploration of genetic influences in stunted Zambian children with environmental enteropathy. METHOD: Children with stunting (LAZ < -2) were enrolled and given nutritional therapy. Those that were non-responsive to therapy were designated as cases, and children with good growth (LAZ > -1) from the same community as controls. Blood and stool samples were taken to measure biomarkers of intestinal inflammation, epithelial damage, and microbial translocation. Single nucleotide polymorphism array genotyping was carried out on saliva samples using the H3Africa consortium array. RESULTS: Genome wide associations were analysed in 117 cases and 41 controls. While no significant associations with stunting were observed at P<5x10-8, likely due to the small sample size, interesting associations were observed at lower thresholds. SNPs associated with stunting were in genomic regions known to modulate neuronal differentiation and fatty acid biosynthesis. SNPs associated with increased microbial translocation were associated with non-integrin membrane ECM interactions, tight junctions, hemostasis, and G-alpha signalling events. SNPs associated with increased inflammation were associated with, ECM interactions, purine metabolism, axon guidance, and cell motility. SNPs negatively associated with inflammation overlapped genes involved in semaphoring interactions. We explored the existing coeliac disease risk HLA genotypes and found present: DQ2.5 (7.5%), DQ8 (3.5%) and DQ2.2 (3.8%); however, no children were positive for coeliac antibodies. We detected HLA-DRB:1301 and HLA-C:1802 with high odds ratios and P<0.05 in stunted children compared to controls. CONCLUSION: Genetic variations associated with stunting and the enteropathy underlying it, include variants associated with multiple pathways relating to gene expression, glycosylation, nerve signalling, and sensing of the nutritional and microbiological milieu.

Prism adaptation therapy in spatial neglect: The importance of connectional anatomy.

The meta-analysis conducted by Székely et al. described the lack of beneficial effect of prism adaptation in neglect patients. The authors concluded that the results did "not support the routine use of prism adaptation as a therapy for spatial neglect". However, a possible nuance to this conclusion could be that the response (or lack thereof) of neglect patients to prism adaptation may actually depend on the connectional anatomy of their lesion. We develop this idea in our commentary, in order to offer a more balanced perspective on the implications of the findings obtained by Székely et al.

Phosphorylation of spleen tyrosine kinase at Y346 negatively regulates ITAM-mediated signaling and function in platelets.

Spleen tyrosine kinase (Syk) is expressed in a variety of hemopoietic cells. Upon phosphorylation of the platelet immunoreceptor-based activation motif of the glycoprotein VI (GPVI)/Fc receptor gamma chain collagen receptor, both the tyrosine phosphorylation and activity of Syk are increased leading to downstream signaling events. Although it has been established that the activity of Syk is regulated by tyrosine phosphorylation, the specific roles of individual phosphorylation sites remain to be elucidated. We observed that Syk Y346 in mouse platelets was still phosphorylated when GPVI-induced Syk activity was inhibited. We then generated Syk Y346F mice and analyzed the effect this mutation exerts on platelet responses. Syk Y346F mice bred normally, and their blood cell count was unaltered. We did observe potentiation of GPVI-induced platelet aggregation and ATP secretion as well as increased phosphorylation of other tyrosines on Syk in the Syk Y346F mouse platelets when compared to WT littermates. This phenotype was specific for GPVI-dependent activation, since it was not seen when AYPGKF, a PAR4 agonist, or 2-MeSADP, a purinergic receptor agonist, was used to activate platelets. Despite a clear effect of Syk Y346F on GPVI-mediated signaling and cellular responses, there was no effect of this mutation on hemostasis as measured by tail-bleeding times, although the time to thrombus formation determined using the ferric chloride injury model was reduced. Thus, our results indicate a significant effect of Syk Y346F on platelet activation and responses in vitro and reveal its complex nature manifesting itself by the diversified translation of platelet activation into physiological responses.