Functional connectivity of the sensorimotor cerebellum in autism: associations with sensory over-responsivity.

The cerebellum has been consistently shown to be atypical in autism spectrum disorder (ASD). However, despite its known role in sensorimotor function, there is limited research on its association with sensory over-responsivity (SOR), a common and impairing feature of ASD. Thus, this study sought to examine functional connectivity of the sensorimotor cerebellum in ASD compared to typically developing (TD) youth and investigate whether cerebellar connectivity is associated with SOR. Resting-state functional connectivity of the sensorimotor cerebellum was examined in 54 ASD and 43 TD youth aged 8-18 years. Using a seed-based approach, connectivity of each sensorimotor cerebellar region (defined as lobules I-IV, V-VI and VIIIA&B) with the whole brain was examined in ASD compared to TD youth, and correlated with parent-reported SOR severity. Across all participants, the sensorimotor cerebellum was functionally connected with sensorimotor and visual regions, though the three seed regions showed distinct connectivity with limbic and higher-order sensory regions. ASD youth showed differences in connectivity including atypical connectivity within the cerebellum and increased connectivity with hippocampus and thalamus compared to TD youth. More severe SOR was associated with stronger connectivity with cortical regions involved in sensory and motor processes and weaker connectivity with cognitive and socio-emotional regions, particularly prefrontal cortex. These results suggest that atypical cerebellum function in ASD may play a role in sensory challenges in autism.

Age-related changes in neural responses to sensory stimulation in autism: a cross-sectional study.

BACKGROUND: Sensory over-responsivity (SOR) is an impairing sensory processing challenge in autism spectrum disorder (ASD) which shows heterogenous developmental trajectories and appears to improve into adulthood in some but not all autistic individuals. However, the neural mechanisms underlying interindividual differences in these trajectories are currently unknown. METHODS: Here, we used functional magnetic resonance imaging (fMRI) to investigate the association between age and neural activity linearly and nonlinearly in response to mildly aversive sensory stimulation as well as how SOR severity moderates this association. Participants included 52 ASD (14F) and 41 (13F) typically developing (TD) youth, aged 8.6-18.0 years. RESULTS: We found that in pre-teens, ASD children showed widespread activation differences in sensorimotor, frontal and cerebellar regions compared to TD children, while there were fewer differences between ASD and TD teens. In TD youth, older age was associated with less activation in the prefrontal cortex. In contrast, in ASD youth, older age was associated with more engagement of sensory integration and emotion regulation regions. In particular, orbitofrontal and medial prefrontal cortices showed a nonlinear relationship with age in ASD, with an especially steep increase in sensory-evoked neural activity during the mid-to-late teen years. There was also an interaction between age and SOR severity in ASD youth such that these age-related trends were more apparent in youth with higher SOR. LIMITATIONS: The cross-sectional design limits causal interpretations of the data. Future longitudinal studies will be instrumental in determining how prefrontal engagement and SOR co-develop across adolescence. CONCLUSIONS: Our results suggest that enhanced recruitment of prefrontal regions may underlie age-related decreases in SOR for a subgroup of ASD youth.

Prospective analysis of the physiological changes caused by prolonged use of N95-type masks.

INTRODUCTION: The clinical and physiological effects of long-duration use of N95-type masks without ventilation valves, on health-care workers during the coronavirus disease-2019 (COVID-19) pandemic, were evaluated. METHODS: All volunteering personnel working in operating theater or intensive care unit, using nonventilated N95 type respiratory masks, minimum for a 2-h noninterrupted duration were observed. The partial oxygen saturation (SpO2) and heart rate (HR) were recorded before wearing the N95 mask and at 1st and 2nd h. Volunteers were then questioned for any symptoms. RESULTS: A total of 210 measurements were completed in 42 (24 males and 18 females) eligible volunteers, each having 5 measurements, on different days. The median age was 32.7. Premask, 1st h, and 2nd h median values for SpO2 were 99%, 97%, and 96%, respectively (P < 0.001). The median HR was 75 premask, 79 at 1st h, and 84/min at 2nd h (P < 0.001). A significant difference between all three consecutive measurements of HR was achieved. Statistical difference was only reached between premask and other SpO2 measurements (1st and 2nd h). Complaints seen in the group were head ache (36%), shortness of breath (27%), palpitation (18%), and nausea feeling (2%). Two individuals took off their masks to breathe, on 87th and 105th min, respectively. CONCLUSIONS: Long duration (>1 h) use of N95-type masks causes a significant reduction in SpO2 measurements and increase in HR. Despite being an essential personal protective equipment in COVID-19 pandemic, it should be used with short intermittent time periods in health-care providers with known heart disease, pulmonary insufficiency, or psychiatric disorders.

KRAS G12C mutation and risk of disease recurrence in stage I surgically resected lung adenocarcinoma.

KRAS G12C mutations are found in about 12-13% of LUAD samples and it is unclear whether they are associated with worse survival outcomes in resected, stage I LUAD. We assessed whether KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours and to KRAS wild-type tumours in a cohort of resected, stage I LUAD (IRE cohort). We then leveraged on publicly available datasets (TCGA-LUAD, MSK-LUAD604) to further test the hypothesis in external cohorts. In the stage I IRE cohort we found a significant association between the KRAS-G12C mutation and worse DFS in multivariable analysis (HR: 2.47). In the TCGA-LUAD stage I cohort we did not find statistically significant associations between the KRAS-G12C mutation and DFS. In the MSK-LUAD604 stage I cohort we found that KRAS-G12C mutated tumours had worse RFS when compared to KRAS-nonG12C mutated tumours in univariable analysis (HR 3.5). In the pooled stage I cohort we found that KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours (HR 2.6), to KRAS wild-type tumours (HR 1.6) and to any other tumours (HR 1.8); in multivariable analysis, the KRAS-G12C mutation was associated with worse DFS (HR 1.61). Our results suggest that patients with resected, stage I LUAD with a KRAS-G12C mutation may have inferior survival outcomes..

The association of allergic rhinitis severity with neutrophil-lymphocyte and platelet-lymphocyte ratio in adults.

OBJECTIVE: To investigate the association of allergic rhinitis (AR) severity with neutrophil-lymphocyte and platelet-lymphocyte ratios in adult patients. METHODS: The study design was prospective observational study and the study included 209 AR patients and 243 healthy individuals. The patient group comprised 38.2% males with a mean age of 31.8 years. All patients who were diagnosed with persistent AR were included. The healthy control group comprised 52.7% males with a mean age of 32.3 years. The blood examination results of patients and healthy individuals were compared in terms of neutrophil-lymphocyte and platelet-lymphocyte ratios. The values were further compared within the patient group, according to AR severity. RESULTS: The neutrophil-lymphocyte ratio was 1.70 ± 0.65 in the healthy group and 2.02 ± 1.24 in the patient group. The platelet-lymphocyte ratio result was 100.85 ± 25.33 in the healthy group and 120.67 ± 40.59 in the patient group. When we compared the neutrophil-lymphocyte and platelet-lymphocyte ratios between the groups, we found statistically significant differences in both ratios (p = 0.003, p = 0.000, respectively). Both the neutrophil-lymphocyte and the platelet-lymphocyte ratios were higher in patients with moderate-severe AR. CONCLUSION: Both neutrophil-lymphocyte and platelet-lymphocyte ratios are useful markers for diagnosis of persistent AR. Specialists may benefit from these markers to assess the severity of the disease at the beginning of the diagnostic process.

Quantity and economic value of unused oral anti-cancer and biological disease-modifying anti-rheumatic drugs among outpatient pharmacy patients who discontinue therapy.

BACKGROUND: Patients sometimes discontinue the use of expensive oral anti-cancer drug (OACD) or biological disease-modifying anti-rheumatic drug (bDMARD) therapies early, leading to medication waste if the patient has not used all dispensed medication. OBJECTIVE: To determine the proportion of patients who have unused OACDs or bDMARDs after therapy discontinuation, and the quantity and economic value of these unused medications. Furthermore, patients' reasons for therapy discontinuation and their disposal method for unused medications were determined. METHODS: In a retrospective follow-up study using a Dutch outpatient pharmacy database, patients (≥18 years) who did not refill an OACD or bDMARD prescription, dispensed between November 2015 and February 2016, within two weeks of the prescription end date were contacted by phone and asked about their unused medication and reasons thereof. The economic value was calculated using Dutch medication prices. Data were descriptively analyzed in STATA13. RESULTS: The database included 1173 patients, of whom 159 likely had discontinued therapy and were contacted. Of these, 88 patients were excluded (39 refilled, 47 missing, and 2 other). Of the 71 patients who had discontinued therapy, 39 (54.9%) had unused medications, comprising 22 OACD users (mean age 63.0 (SD ±â€¯15.9) years, 50.0% female) and 17 bDMARD users (mean age 50.7 (SD ±â€¯13.5) years, 47.1% female). A total of 59 packages were unused, with a total value of €60,341. Unused OACD packages and bDMARD packages had median values of €179 (IQR €24-2487) and €992 (IQR €681-1093), respectively. Patients primarily discontinued therapy due to adverse or insufficient effects. CONCLUSIONS: This study illustrates that more than half of patients discontinuing OACD or bDMARD therapies have unused medication. This emphasizes the need for waste-reducing interventions.

Endoparasites detected in faecal samples from dogs and cats referred for routine clinical visit in Sardinia, Italy.

This study aimed to update data on the prevalence of intestinal and lung parasitic infections in owned dogs and cats in Sardinia, Italy. Examinations on faecal samples from 619 dogs and 343 cats routinely referred to the Veterinary Teaching Hospital of the University of Sassari were performed between the years of 2011 and 2015. Individual faecal samples were analysed using the Wisconsin technique for copro-microscopic examination and the Baermann technique for the presence of lungworm larvae. Endoparasites were found in 34.9% and 43.4% of examined dogs and cats, respectively. Helminthic infections (21.2% in dogs and 32.6% in cats) occurred more frequently than protozoan infections (17.9% in dogs and 17.8% in cats). In both dogs and cats, the most common parasites were ascarids (12.1% and 15.7%), Cystoisospora spp. (10.2% and 10.8%), Giardia duodenalis (9.4% and 8.5%), and hookworms (7.9% and 5.5%). Evidence of bronchopulmonary nematode infections were found in 0.8% of examined dogs and in 15.8% of examined cats. Age was identified as a risk factor, with animals younger than 6months more frequently infected than older animals, while no significant association was observed for gender. This study demonstrated that endoparasites in owned dogs and cats of Sardinia have considerably high prevalence. Veterinary practitioners and pet owners should be more aware of these infections and should adopt more effective and standardized control practices.

Spondylodiscitis after bilateral sequential lung transplantation in a patient with cystic fibrosis.

We report the case of a 24-year-old woman with cystic fibrosis in whom spondylodiscitis developed after bilateral sequential transplantation. The diagnostic work-up included magnetic resonance imaging, computed tomography-guided disk biopsy, histological examination, and cultures of disk specimens. The infective organism was D group Streptococcus and the patient was successfully treated with intravenous piperacillin followed by oral ampicillin. To our knowledge, this is the first reported case of spondylodiscitis after lung transplantation.

alphaIIbbeta3 antagonism vs. antiadhesive treatment to prevent platelet interactions with vascular subendothelium.

Platelets adhering to blood vessels promote coagulation and inflammation, and release growth factors that trigger smooth muscle cell activation. We have therefore studied the pharmacological modification of platelet deposition quantitatively by comparing adhesion of flowing platelets to various subendothelial ligands in the absence or presence of an antialpha(IIb)beta(3) antagonist with the effects of antiadhesive treatment consisting of von Willebrand factor (VWF) and fibronectin neutralization or of the combined inhibition of platelet adhesion and aggregation. In vitro, perfusion of anticoagulated human blood over calf skin collagen reiterated that alpha(IIb)beta(3) antagonism prevents platelet aggregation, but not adhesion per se: single platelets strongly bound to collagen at wall shear rates of both 1300 and 2700 s(-1), largely VWF-independent. When perfused over a human umbilical vein endothelial cell-derived extracellular matrix, single alpha(IIb)beta(3)-antagonized platelets primarily adhered to matrix-bound VWF when perfused at 2700 s(-1), but at 1300 s(-1) they also adhered significantly to fibronectin. During perfusion of anticoagulated rabbit blood over de-endothelialized rabbit aorta at a wall shear rate of 1100 s(-1), alpha(IIb)beta(3) antagonism even increased the absolute numbers of adhering platelets and VWF neutralization redirected alpha(IIb)beta(3)-antagonized platelets towards other vascular ligands. Finally, in vivo, following photochemically induced blood vessel injury in mice, alpha(IIb)beta(3) antagonism inhibited platelet-rich thrombus formation, but platelet adhesion was only significantly inhibited when associated with fibronectin neutralization. In conclusion, antiadhesive platelet treatment more potently interferes with platelet deposition on injured blood vessels than alpha(IIb)beta(3) antagonism, but abrogating platelet adhesion can only be achieved by carefully selected antiplatelet drug combinations.

Tissue factor deficiency causes cardiac fibrosis and left ventricular dysfunction.

Exposure of blood to tissue factor (TF) activates the extrinsic (TF:FVIIa) and intrinsic (FVIIIa:FIXa) pathways of coagulation. In this study, we found that mice expressing low levels of human TF ( approximately 1% of wild-type levels) in an mTF(-/-) background had significantly shorter lifespans than wild-type mice, in part, because of spontaneous fatal hemorrhages. All low-TF mice exhibited a selective heart defect that consisted of hemosiderin deposition and fibrosis. Direct intracardiac measurement demonstrated a 30% reduction (P < 0.001) in left ventricular function in 8-month-old low-TF mice compared with age-matched wild-type mice. Mice expressing low levels of murine FVII ( approximately 1% of wild-type levels) exhibited a similar pattern of hemosiderin deposition and fibrosis in their hearts. In contrast, FIX(-/-) mice, a model of hemophilia B, had normal hearts. Cardiac fibrosis in low-TF and low-FVII mice appears to be caused by hemorrhage from cardiac vessels due to impaired hemostasis. We propose that TF expression by cardiac myocytes provides a secondary hemostatic barrier to protect the heart from hemorrhage.

Targeted deletion of the cytosolic domain of tissue factor in mice does not affect development.

The role of the cytosolic domain of tissue factor (TF) in signal transduction and gene regulation was studied in mice with a targeted deletion of the 18 carboxy-terminal intracellular amino acids. This deletion was introduced in exon 6 along with a floxed neo(R) selection cassette in intron 5 using homologous recombination in embryonic stem cells. Removal of the floxed neo(R) cassette by in vivo Cre-mediated loxP recombination yielded TF(+/deltaCT) and TF(deltaCT/deltaCT) mice. In contrast to TF(-/-) mice, TF(+/deltaCT) and TF(deltaCT/deltaCT) mice displayed normal embryonic development, survival, fertility, and blood coagulation. Factor VIIa or factor Xa stimulation produced similar p44/42 MAPK activation in TF(+/+) and TF(deltaCT/deltaCT) fibroblasts. These data, based on expression of a TF(deltaCT) molecule from the endogenous TF locus, provide conclusive proof that the cytosolic domain of TF is not essential for signal transduction in embryogenesis and in physiological postnatal processes.

Tissue factor is not involved in the mitogenic activity of factor VIIa.

The present study was undertaken to evaluate in vitro the importance of tissue factor in the mitogenic effect of factor VIIa for embryonic fibroblasts. For that purpose, embryonic fibroblasts were isolated from either wild-type or transgenic mice showing a single inactivation of the tissue factor gene or expressing a truncated form (lacking the cytosolic domain) of this protein. Factor VIIa stimulated in a dose-dependent manner the growth of the 3 types of fibroblasts, thus showing that TF is not involved in the mitogenic activity of factor VIIa. The mitogenic activity of factor VIIa disappeared in serum immunopurified in factor X and was almost totally inhibited by DX9065, a selective factor Xa inhibitor, showing that this effect of factor VIIa occurred via factor Xa generated during the incubation period. Hirudin did not show any significant effect on factor VIIa-induced fibroblast proliferation, thus showing that the effect observed for factor VIIa was selectively mediated by factor Xa and was not due to thrombin formation. Our results therefore represent the first evidence for the possible importance of factor Xa in the mitogenic effect of factor VIIa and show the negligible role of tissue factor in this process.

Deficiency or inhibition of Gas6 causes platelet dysfunction and protects mice against thrombosis.

The growth arrest-specific gene 6 product (Gas6) is a secreted protein related to the anticoagulant protein S but its role in hemostasis is unknown. Here we show that inactivation of the Gas6 gene prevented venous and arterial thrombosis in mice, and protected against fatal collagen/epinephrine-induced thrombo embolism. Gas6-/- mice did not, however, suffer spontaneous bleeding and had normal bleeding after tail clipping. In addition, we found that Gas6 antibodies inhibited platelet aggregation in vitro and protected mice against fatal thrombo embolism without causing bleeding in vivo. Gas6 amplified platelet aggregation and secretion in response to known agonists. Platelet dysfunction in Gas6-/- mice resembled that of patients with platelet signaling transduction defects. Thus, Gas6 is a platelet-response amplifier that plays a significant role in thrombosis. These findings warrant further evaluation of the possible therapeutic use of Gas6 inhibition for prevention of thrombosis.

Analysis of assisted-gait characteristics in persons with incomplete spinal cord injury.

UNLABELLED: Ambulatory assistive device use can improve functional independence following spinal cord injury and, potentially, quality of life. However, the interaction between aids and user in this population is poorly understood. OBJECTIVES: To determine the influence of walkers, crutches and canes on assisted-gait following incomplete spinal cord injury. STUDY DESIGN/METHODS: Outcome parameters evaluated in ten individuals included orthogonal forces exerted on instrumented assistive devices, walking speed, cadence, step length, trunk and thigh angles, as well as knee and ankle joint angles. Kinetic data included axial compressive force, and medio/lateral and antero/posterior bending forces. SETTING: Canada. RESULTS: Results indicated that walkers (n= 5) provided the greatest vertical support (up to 100% body weight), but resulted in slow gait with a forward flexed posture. Elbow crutch users (n = 3) walked faster (greater step length and cadence) and had a more upright posture than the walker users. Crutches supported up to 50% of the subject's body weight, granted lateral stability, and provided restraint in the antero/posterior direction. Canes (n = 2) offered restraining and propulsive assistance, some lateral stability, and the least amount of vertical support. CONCLUSION: Ambulatory devices affected posture and walking speed while fulfilling various assistive functions during locomotion. The conclusion drawn is that rehabilitation specialists are advised to match device characteristics to user needs when prescribing walking aids. SPONSORSHIP: Natural Sciences and Engineering Research Council of Canada (NSERC).