To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure email@example.com
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
A 2-year fertilization experiment was conducted to study the effect of different ratios of organic (pig) manure on wheat yield and nitrogen use efficiency (NUE). The four treatments were no nitrogen (N) (CK); 100% chemical fertilizer N (urea; T1); 70% chemical fertilizer N + 30% organic manure N (T2) and 50% chemical fertilizer N + 50% organic manure N (T3), with the same amount of applied nitrogen (120 kg/ha). The results showed the maximum grain yield (3049 kg/ha), crop nitrogen uptake (216 kg/ha), NUE (65.4%) and accumulated nitrate nitrogen (NO3−-N in 0–200 cm, 142 kg/ha) were observed in the T1 among all treatments in the first year. However, the largest grain yield (5074 kg/ha), crop nitrogen uptake (244 kg/ha) and NUE (82.5%) were under T2 treatment in the second year. Furthermore, T2 had the maximum NO3−-N content in 0–100 cm layer (116 kg/ha), especially 0–40 cm layer, and the lowest NO3−-N content in 100–200 cm (58.8 kg/ha). However, 50% organic manure N in T3 increased apparent nitrogen loss by 39.0% compared to that in T2. Therefore, 30% organic manure N application was more conducive for enhancing wheat yield and NUE and promoting environmental safety after 1-year fertilization time.
Toxoplasma gondii infections are common in humans and animals worldwide. Domestic free-range chickens (Gallus domesticus) are excellent sentinels of environmental contamination with T. gondii oocysts because they feed on the ground. Chickens can be easily infected with T. gondii; however, clinical toxoplasmosis is rare in these hosts. Chickens are comparatively inexpensive and thus are good sentinel animals for T. gondii infections on the farms. Here, the authors reviewed prevalence, the persistence of infection, clinical disease, epidemiology and genetic diversity of T. gondii strains isolated from chickens worldwide for the past decade. Data on phenotypic and molecular characteristics of 794 viable T. gondii strains from chickens are discussed, including new data on T. gondii isolates from chickens in Brazil. This paper will be of interest to biologists, epidemiologists, veterinarians and parasitologists.
Robust personal protective equipment is essential in preventing the transmission of coronavirus disease 2019 to head and neck surgeons who are routinely involved in aerosol generating procedures.
This paper describes the collective experience, across 3 institutes, of using a reusable half-face respirator in 72 head and neck surgery cases.
Cost analysis was performed to demonstrate the financial implications of using a reusable respirator compared to single-use filtering facepiece code 3 masks.
The reusable respirator is a cost-effective alternative to disposable filtering facepiece code 3 respirators. Supplying reusable respirators to individual staff members may increase the likelihood of them having appropriate personal protective equipment during their clinical duties.
Previous work led to the proposal that the precision feeding of a high-concentrate diet may represent a potential method with which to enhance feed efficiency (FE) when rearing dairy heifers. However, the physiological and metabolic mechanisms underlying this approach remain unclear. This study used metabolomics analysis to investigate the changes in plasma metabolites of heifers precision-fed diets containing a wide range of forage to concentrate ratios. Twenty-four half-sib Holstein heifers, with a similar body condition, were randomly assigned into four groups and precision fed with diets containing different proportions of concentrate (20%, 40%, 60% and 80% based on DM). After 28 days of feeding, blood samples were collected 6 h after morning feeding and gas chromatography time-of-ﬂight/MS was used to analyze the plasma samples. Parameters of oxidative status were also determined in the plasma. The FE (after being corrected for gut fill) increased linearly (P < 0.01) with increasing level of dietary concentrate. Significant changes were identified for 38 different metabolites in the plasma of heifers fed different dietary forage to concentrate ratios. The main pathways showing alterations were clustered into those relating to carbohydrate and amino acid metabolism; all of which have been previously associated with FE changes in ruminants. Heifers fed with a high-concentrate diet had higher (P < 0.01) plasma total antioxidant capacity and superoxide dismutase but lower (P ≤ 0.02) hydroxyl radical and hydrogen peroxide than heifers fed with a low-concentrate diet, which might indicate a lower plasma oxidative status in the heifers fed a high-concentrate diet. Thus, heifers fed with a high-concentrate diet had higher FE and antioxidant capacity but a lower plasma oxidative status as well as changed carbohydrate and amino acid metabolism. Our findings provide a better understanding of how forage to concentrate ratios affect FE and metabolism in the precision-fed growing heifers.
While genome-wide association analysis and related multi-omic strategies have in recent years dominated the field of complex disorders including mental health and addictions, in pharmacogenomics, drug metabolizing enzymes show Mendelian patterns of inheritance with correspondingly large effect sizes. Consistent with this, genes encoding these enzymes make up the majority of the genes for which the strength of the association with clinical effect of psychiatric medications is sufficient to recommend clinical utility (Bousman et al., 2018). Moreover, such enzymes are expressed in the brain (Aitchison et al., 2010; Kalow & Tyndale, 1992). We herein provide a comprehensive review of the relevance of drug metabolizing enzyme and transporter genes to mental health and addictions.
Antibiotics are designed to affect gut microbiota and subsequently gut homeostasis. However, limited information exists about short- and long-term effects of early antibiotic intervention (EAI) on gut homeostasis (especially for the small intestine) of pigs following antibiotic withdrawal. We investigated the impact of EAI on specific bacterial communities, microbial metabolites and mucosal immune parameters in the small intestine of later-growth-stage pigs fed with diets differing in CP levels. Eighteen litters of piglets were fed creep feed with or without antibiotics from day 7 to day 42. At day 42, pigs within each group were offered a normal- or low-CP diet. Five pigs per group were slaughtered at days 77 and 120. At day 77, EAI increased Enterobacteriaceae counts in the jejunum and ileum and decreased Bifidobacterium counts in the jejunum and ileum (P < 0.05). Moreover, tryptamine, putrescine, secretory immunoglobulin (Ig) A and IgG concentrations in the ileum and interleukin-10 (IL-10) mRNA and protein levels in the jejunum and ileum were decreased in pigs with EAI (P < 0.05). At day 120, EAI only suppressed Clostridium cluster XIVa counts in the jejunum and ileum (P < 0.05). These results suggest that EAI has a short-term effect on specific bacterial communities, amino acid decarboxylation and mucosal immune parameters in the small intestine (particularly in the ileum). At days 77 and 120, feeding a low-CP diet affected Bifidobacterium, Clostridium cluster IV, Clostridium cluster XIVa and Enterobacteriaceae counts in the jejunum or ileum (P < 0.05). Moreover, feeding a low-CP diet increased the concentrations of Igs in the jejunum and decreased pro-inflammatory cytokines levels in the jejunum and ileum (P < 0.05). At day 120, feeding a low-CP diet increased short-chain fatty acid concentrations, reduced ammonia and spermidine concentrations and up-regulated genes related to barrier function in the jejunum and ileum (P < 0.05). These results suggest that feeding a low-CP diet changes specific bacterial communities and intestinal metabolite concentrations and modifies mucosal immune parameters. These findings contribute to our understanding on the duration of the impact of EAI on gut homeostasis and may provide basis data for nutritional modification in young pigs after antibiotic treatment.
The aim of this study was to examine whether the presence of risk alleles of the norepinephrine transporter gene (SLC6A2) polymorphisms is associated with differences in regional cerebral blood flow (rCBF) measured by 99mTc-HMPAO single photon emission computerized tomography in a Korean sample of ADHD.
The present study included 24 children with ADHD (9.5±2.4 years), consisting of 20 boys and 4 girls, aged 6-16 years. We investigated the G1287A and -3081(A/T) polymorphisms of the SLC6A2. The rCBF was compared between the ADHD subjects with and without risk alleles at the G1287A polymorphism and at the -3081(A/T) polymorphism. Image analyses were performed with voxelwise t-statistics using SPM2.
1) The ADHD subjects with the A allele (risk allele) at the G1287A polymorphism showed reduced perfusion in the left middle frontal gyrus, left inferior parietal lobule, precuneus, right superior frontal gyrus, and right superior parietal lobule as compared with ADHD subjects without the A allele (p< 0.001).
2) The ADHD subjects with the A allele at the G1287A polymorphism showed increased perfusion in the right middle frontal gyrus, right middle temporal gyrus, right superior temporal gyrus, right fusiform gyrus, right precentral gyrus, and right anterior lobe of cerebellum as compared with ADHD subjects without the A allele (p< 0.001).
3) No significant perfusion differences were found between ADHD subjects with and without the T allele (risk allele) at the -3081(A/T) polymorphism.
Our findings suggest that the SLC6A2 G1287A polymorphism might exert differential effects on rCBF in children with ADHD.
Menopausal syndrome has been reported to be a worldwide women's mental health problem. Aborigines in rural areas have poorer access to mental health services. Thus, it is important to evaluate such symptoms of female aborigines with different menopausal statuses and their association with depression.
The aim of the study is to evaluate the association between physiological menopausal symptoms and depression during different menopausal period among female Taiwanese aborigines.
A total of 672 Taiwanese aboriginal women, aged 40–60, were recruited in the interviewing study and classified as pre-, peri-, and postmenopausal according to menstrual bleeding patterns in the previous 12 months. Then, the postmenopausal symptoms, depression, self-perceived health, family support, and associated demographic variables were assessed by questionnaire based on the results of interviewing by research assistants.
The results revealed that perimenopausal statuses were associated with depression and women with a perimenopausal status had a higher prevalence of depression than those with a premenopausal status. A higher score on physiological postmenopausal symptoms was found to be significantly associated with depression. Furthermore, somatic symptoms were associated with depression for pre-, peri-, and postmenopausal statuses. Moreover, sexual dysfunction and vasomotor symptoms were associated with depression only in the premenopausal status and postmenopausal status, respectively.
Depression should be routinely evaluated for female Taiwanese aborigines consulting with physicians for menopause symptoms, especially for somatic symptoms. Furthermore, attention should be provided to premenopausal women with sexual dysfunction and postmenopausal women with vasomotor symptoms for depression.
Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression.
Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects.
The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes – apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG) – were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control > PSD > stroke subjects; haptoglobin, stroke > PSD > healthy control.
Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.
We hypothesized an increase in dorsolateral prefrontal cortex (DLPFC) glutamate levels would occur after three weeks of repetitve transcranial magnetic stimulation (rTMS) treatment and a decrease in major depressive disorder (MDD) symptoms.
We report six cases (four females) 15–21 years of age with treatment-resistant MDD. Participants had a mean age of 18.7 years and a mean IQ of 102.3. Short echo proton magnetic resonance spectroscopy (H-MRS) was used to quantify glutamate levels in the left DLPFC (4.5cc) before and after rTMS treatment. rTMS was localized to the left DLPFC and applied for 15 consecutive weekdays. Treatment response was defined as a greater than 50% reduction in Hamilton Depression Rating Scale scores (Ham-D).1H-MRS data was analyzed with LCModel to determine glutamate concentration.
Following rTMS, treatment responders (N=4) showed an increase (relative to baseline) in left DLPFC glutamate levels (11%), which corresponded to an improvement in depressive symptom severity (68% Ham-D score reduction). Treatment non-responders (N=2) had elevated baseline glutamate levels compared to responders in that same region, which decreased with rTMS (−10%). Procedures were generally well tolerated with no adverse events.
rTMS is feasible and possibly efficacious in adolescents with MDD. In responders, rTMS may act by Induced elevations in elevating DFPLC glutamate levels in the left DLPFC, thereby leading to symptom improvement. Transcranial Magnetic Stimulation for Adolescent Depression (TMSAD)
Ketamine exerts fast acting, robust, and lasting antidepressant effects in a sub-anesthetic dose, however, the underlying mechanisms are still not fully elucidated. Recent studies have suggested that ketamine's antidepressant effects are probably attributed to the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The present study aimed to observe the effects of AMPA receptor modulators on mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) expression during the procedure of ketamine exerting antidepressant effects. Therefore, we pretreated rats with NBQX, an AMPA receptor antagonist, or CX546, an AMPA receptor agonist, and subsequently observed the immobility time during the forced swimming test (FST) and the hippocampal and prefrontal cortical levels of mTOR and BDNF. The results showed ketamine decreased the immobility time of rats during the FST and increased the hippocampal and prefrontal cortical mTOR and BDNF. NBQX pretreatment significantly increased the immobility time and decreased the levels of mTOR and BDNF when compared with vehicle 1 (DMSO) pretreatment. CX546 pretreatment significantly decreased the immobility time and increased the levels of mTOR and BDNF when compared with vehicle 2 (DMSO + ethanol) pretreatment. Our results suggest ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex.
Recently, a triple-network model suggested the abnormal interactions between the executive-control network (ECN), default-mode network (DMN) and salience network (SN) are important characteristics of addiction, in which the SN plays a critical role in allocating attentional resources toward the ECN and DMN. Although increasing studies have reported dysfunctions in these brain networks in Internet gaming disorder (IGD), interactions between these networks, particularly in the context of the triple-network model, have not been investigated in IGD. Thus, we aimed to assess alterations in the inter-network interactions of these large-scale networks in IGD, and to associate the alterations with IGD-related behaviors.
DMN, ECN and SN were identified using group-level independent component analysis (gICA) in 39 individuals with IGD and 34 age and gender matched healthy controls (HCs). Then alterations in the SN-ECN and SN-DMN connectivity, as well as in the modulation of ECN versus DMN by SN, using a resource allocation index (RAI) developed and validated previously in nicotine addiction, were assessed. Further, associations between these altered network coupling and clinical assessments were also examined.
Compared with HCs, IGD had significantly increased SN-DMN connectivity and decreased RAI in right hemisphere (rRAI), and the rRAI in IGD was negatively associated with their scores of craving.
These findings suggest that the deficient modulation of ECN versus DMN by SN might provide a mechanistic framework to better understand the neural basis of IGD and might provide novel evidence for the triple-network model in IGD.
Large prospective observational studies have cast doubt on the common assumption that endovascular thrombectomy (EVT) is superior to intravenous thrombolysis for patients with acute basilar artery occlusion (BAO). The purpose of this study was to retrospectively review our experience for patients with BAO undergoing EVT with modern endovascular devices.
All consecutive patients undergoing EVT with either a second-generation stent retriever or direct aspiration thrombectomy for BAO at our regional stroke center from January 1, 2013 to March 1, 2019 were included. The primary outcome measure was functional outcome at 1 month using the modified Rankin Scale (mRS) score. Multivariable logistic regression was used to assess the association between patient characteristics and dichotomized mRS.
A total of 43 consecutive patients underwent EVT for BAO. The average age was 67 years with 61% male patients. Overall, 37% (16/43) of patients achieved good functional outcome. Successful reperfusion was achieved in 72% (31/43) of cases. The median (interquartile range) stroke onset to treatment time was 420 (270–639) minutes (7 hours) for all patients. The procedure-related complication rate was 9% (4/43). On multivariate analysis, posterior circulation Alberta stroke program early computed tomography score and Basilar Artery on Computed Tomography Angiography score were associated with improved functional outcome.
EVT appears to be safe and feasible in patients with BAO. Our finding that time to treatment and successful reperfusion were not associated with improved outcome is likely due to including patients with established infarcts. Given the variability of collaterals in the posterior circulation, the paradigm of utilizing a tissue window may assist in patient selection for EVT. Magnetic resonance imaging may be a reasonable option to determine the extent of ischemia in certain situations.
In China, one percent of the richest population holds more than one-third of the wealth, while the poorest 25% shares no more than two percent of the total. The country’s rapid economic development has resulted in increasing socio-economic disparities, and a rapidly deteriorating environment. This puts the Chinese citizens, especially the most vulnerable and deprived socio-economic status (SES) groups, at high risks of environmental inequality (EI). In most SES-based EI studies conducted in China, household wealth has often been overlooked, though it potentially serves a good economic indicator to capture the socio-economic effect of environmental change in China. Nevertheless, existing SES databases in China are of low spatial resolution and are insufficient to support fine-grained EI studies at the intra-city level in China. The core research challenge is to develop a representative household wealth proxy in high-spatial resolution for China. This study highlights the research gaps and proposes a new household wealth proxy, which integrates both fine-grained data/features such as daytime satellite imagery and easily accessible wealth indicators such as house prices. We also capitalize on everyday economic activity data retrieved from personal mobile phones and online transaction/social platforms in the composition of our wealth proxy to achieve a higher accuracy in estimating household wealth at fine-grained resolution via machine learning. Finally, we summarize the challenges in improving both the quality and the availability of Chinese socio-economic datasets, while protecting personal privacy and information security during the data collection process for household wealth proxy development in China.
Chinese men who have sex with men (MSM) are at high risk for depression, anxiety and suicide. The estimated prevalence of these problems is essential to guide public health policy, but published results vary. This meta-analysis aimed to estimate the prevalence of depressive symptoms, anxiety symptoms and suicide among Chinese MSM.
Systematic searches of EMBASE, MEDLINE, PsycINFO, PubMed, CNKI and Wanfang databases with languages restricted to Chinese and English for studies published before 10 September 2019 on the prevalence of depressive symptoms, anxiety symptoms, suicidal ideation, suicide plans and suicide attempts among Chinese MSM. Studies that were published in the peer-reviewed journals and used validated instruments to assess depression and anxiety were included. The characteristics of studies and the prevalence of depression and anxiety symptoms, suicidal ideation, suicide plans and suicide attempts were independently extracted by authors. Random-effects modelling was used to estimate the pooled rates. Subgroup analysis and univariate meta-regression were conducted to explore potential sources of heterogeneity. This study followed the PRISMA and MOOSE.
Sixty-seven studies were included. Fifty-two studies reported the prevalence of depressive symptoms, with a combined sample of 37 376 people, of whom 12 887 [43.2%; 95% confidence interval (CI), 38.9–47.5] reported depressive symptoms. Twenty-seven studies reported the prevalence of anxiety symptoms, with a combined sample of 10 531 people, of whom 3187 (32.2%; 95% CI, 28.3–36.6) reported anxiety symptoms. Twenty-three studies reported the prevalence of suicidal ideation, with a combined sample of 15 034 people, of whom 3416 (21.2%; 95% CI, 18.3–24.5) had suicidal ideation. Nine studies reported the prevalence of suicide plans, with a combined sample of 5271 people, of whom 401 (6.2%; 95% CI, 3.9–8.6) had suicide plans. Finally, 19 studies reported the prevalence of suicide attempts, with a combined sample of 27 936 people, of whom 1829 (7.3%; 95% CI, 5.6–9.0) had attempted suicide.
The mental health of Chinese MSM is poor compared with the general population. Efforts are warranted to develop interventions to prevent and alleviate mental health problems among this vulnerable population.
The small intestine is an important digestive organ and plays a vital role in the life of a pig. We tested the hypothesis that the length of the small intestine is related to growth performance and intestinal functions of piglets. A total of 60 piglets (Duroc × Landrace × Yorkshire), weaned at day 21, were fed an identical diet during a 28-day trial. At the end of the study, all piglets were sacrificed, dissected and grouped according to small intestine lengths (SILs), either short small intestine (SSI), middle small intestine (MSI) or long small intestine (LSI), respectively. Positive relationships between SIL and BW, average daily gain (ADG), average daily feed intake (ADFI) and gain-to-feed ratios (G : F) were observed. Final BW, ADG, ADFI and G : F significantly increased (P < 0.05) in MSI and LSI piglets compared with SSI piglets. Short small intestine and MSI had greater jejunal mucosa sucrase and alkaline phosphatase activities (P < 0.05) than LSI piglets. The mRNA level of solute carrier family 2 member 2 (Slc2a2) in the jejunal mucosa of SSI piglets was the greatest. The MSI piglets had a greater (P < 0.05) ileal villus height than other piglets and greater (P < 0.05) villus height-to-crypt depth ratios than LSI piglets. However, the LSI piglets had a greater (P < 0.05) ileal crypt depth than SSI piglets. No significant differences in duodenal, jejunal, caecal and colonic morphologies were detected among the groups. Moreover, luminal acetate, propionate, butyrate and total short-chain fatty acid contents were greater (P < 0.05) in SSI and MSI piglets than those in LSI piglets. In addition, there was greater serum glucose concentration in MSI piglets than other piglets. Serum albumin concentration in SSI piglets was the lowest. In conclusion, these results indicate that SIL was significantly positively associated with growth performance, and in terms of intestinal morphology and mucosal digestive enzyme activity, the piglets with a medium length of small intestine have better digestion and absorption properties.
Precise bone cut is fundamental in total knee arthroplasty. However, notching of anterior femoral is not uncommon in clinical practice. Reviewing the article, notching and its complication may reach up to 30% and 2.5%, and there is scanty study of notching on the femoral strength. We therefore conduct the finite element analysis to elucidate the effect of notching on femoral mechanical strength. The computerized tomography images were used as the basis to develop the knee model, which was assumed mainly to consist of cortical and cancellous bones. For the implant joint, Zimmer data was considered partly as the basis to develop the model. This study investigated the femoral improper cut effect on the surgery with a static standing condition. The results show that the anterior femoral cut should be undercut 2 mm to overcut 1 mm during the surgery, in order to prevent bone materials from yielding. The exposure of the cancellous bone may cause bone materials to yield when the femur overcut was 2 mm; the cancellous bone may load too much and result in a fracture when the undercut was 3 mm. The effect of undercut, which was rarely discussed, was particularly addressed in our study. Precise femoral cut is crucial for the longevity of total knee arthroplasty.
In this study, the thermal deformation of a machine tool structure due to the heat generated during operation was analyzed, and embedded cooling channels were applied to exchange the heat generated during the operation to achieve thermal error suppression. Then, the finite volume method was used to simulate the effect of cooling oil temperature on thermal deformation, and the effect of thermal suppression was experimentally studied using a feed system combined with a cooler to improve the positioning accuracy of the machine tool. In this study, the supply oil temperature in the structural cooling channels was found to significantly affect the position accuracy of the moving table and moving carrier. If the supply oil temperature in the cooling channels is consistent with the operational ambient temperature, the position accuracy of the moving table in the Y direction and the moving carrier in the X and Z directions has the best performance under different feed rates. From the thermal suppression experiments of the embedded cooling channels, the positioning accuracy of the feed system can be improved by approximately 25.5 % during the dynamic feeding process. Furthermore, when the hydrostatic guideway is cooled and dynamic feeding is conducted, positioning accuracy can be improved by up to 47.8 %. The machining accuracy can be improved by approximately 60 % on average by using the embedded cooling channels in this study. Therefore, thermal suppression by the cooling channels in this study can not only effectively improve the positioning accuracy but also enhance machining accuracy, proving that the method is effective for enhancing machine tool accuracy.