Speech production accuracy in children with Down syndrome: relationships with hearing, language, and reading ability and change in speech production accuracy over time.

BACKGROUND: This study examines speech production accuracy in children with Down syndrome and concurrent relationships with hearing, language and reading ability. It also examines change in speech production accuracy over a 21-month period. METHODS: A group of 50 children with Down syndrome (aged 5-10 years) completed measures of speech accuracy, non-verbal IQ, reading (single-word reading, letter-sound knowledge and phoneme blending) and language (expressive and receptive vocabulary and receptive grammar). Hearing was assessed by parental report. Speech accuracy was reassessed 21 months later. RESULTS: Although there was considerable variability in the sample, speech was characterised by high levels of errors. There were no effects of gender, hearing status or non-verbal IQ on speech production accuracy. In contrast, speech production accuracy was significantly related to age and to measures of receptive vocabulary, phoneme blending and word reading. There was no significant improvement in speech production accuracy over time. CONCLUSIONS: Children with Down syndrome experience difficulties producing accurate sounds in speech. These difficulties are related to age and to vocabulary and reading skills and persist over time, highlighting the need for intensive targeted speech intervention in this group of children.

A Study of GP Workload and Satisfaction.

Aims In this novel study in the Irish setting, we quantified the number items managed per General Practitioner (GP) consult, how each item is managed, and impact on a GP's job satisfaction. Methods Participating GPs at two surgeries completed a questionnaire - integrated into the practice management software - after each consultation that satisfied the inclusion criteria during a four-week period. Results Due to feasibility constraints, 500 of 857 (58.3%) completed questionnaires were randomly selected for our sample. GPs manage an average of 1.76 items per consultation. Older patients presented with more items. Greater number of presenting items led to less being managed on the day 71% (n=5) for 5 items vs. 95.2% (n= 246) for 1 item, longer consultation duration (mean = 14.63 minutes (4-45) and decreased GP satisfaction, mean 8/10 (2-10). Conclusion Increasing the number of items in a GP consultation has a statistically significant effect on duration of consultation, how each item is managed, and even GP satisfaction.

Perception of Special Needs Dentistry education and practice amongst Australian dental auxiliary students.

INTRODUCTION: The role of dental auxiliaries in collaborative care of patients with special needs is compelling. This study was undertaken to investigate the perceptions of Special Needs Dentistry (SND) education and practice amongst students enrolled in Australian programmes in dental auxiliary, namely dental hygiene, dental therapy and oral health therapy (DH/DT/OHT). MATERIALS AND METHODS: All Australian institutions offering DH/DT/OHT programmes (n = 14) were invited to participate in a self-administered questionnaire survey, conducted online, involving students across all academic years. Twelve institutions agreed to participate, but only five institutions were included in the final analysis, with a student response rate of 31.1%. Answers to open-ended questions were coded and grouped for measurement of frequencies. Quantitative data were analysed via chi-squared and Fisher's exact tests (significance taken as P < .05). RESULTS: The majority of students could not define SND (87.0%) were not aware of the existence of this specialty (53.5%) and did not have clinical experience treating patients with special needs (68.9%). Nevertheless, they felt comfortable and positive about treating these patients independently. Most agreed that they should receive clinical and didactic education in SND, with many of them expressing interest in pursuing a specialty training in this field. CONCLUSION: DH/DT/OHT students' comfort levels, positive attitudes and supportiveness for SND suggested positive implications for these practitioners to partake in multidisciplinary management of patients with special needs, thus indicating the need for standardised training requirements and practice guidelines in this area of care.

Dodecylmaltoside Modulates Bicellular Tight Junction Contacts To Promote Enhanced Permeability.

Intestinal permeation enhancers are a crucial component of many oral formulations, without which many drugs would show an insufficient absorption in the gut. The present study sought to provide a better understanding of the molecular interaction of such absorption enhancers with the intestine, by investigating the effect of the surfactant-like permeation enhancer dodecylmaltoside (DDM) on Caco-2 cells. The extent to which the action of DDM is apportioned between the para- and transcellular routes was addressed by examining the transport of relevant marker compounds ([3H]-mannitol and [3H]-propranolol, respectively). In the case of [3H]-mannitol, a robust permeation enhancement was achieved with 0.5 mM DDM (∼6-fold), whereas little effect was seen on the permeation of [3H]-propranolol. Concomitantly measured TEER values revealed a rapid onset of action of DDM with a swift recovery and complete restitution (>90%) within 4 h after washout. To localize the site(s) of action of DDM at the absorptive surface of Caco-2 cells, sulfo-NHS-SS-biotin, a membrane-impermeable compound, was applied apically. In the presence of 0.5 mM DDM, translocated biotin was found to be accumulated toward bicellular contacts, whereas no biotin permeation was observed in untreated control cells. Western blot analysis of DDM-treated and untreated Caco-2 cells revealed an interaction of DDM with specific tight junction associated proteins, resulting in a reduction of claudin-3 and -4 and also occludin, as well as a depletion of claudin-2 from lipid rafts. Collectively, the results presented provide a more in depth understanding of the molecular mechanism(s) underlying the permeation-enhancing actions of DDM.

Systemic delivery of scAAV9 in fetal macaques facilitates neuronal transduction of the central and peripheral nervous systems.

Correction of perinatally lethal neurogenetic diseases requires efficient transduction of several cell types within the relatively inaccessible CNS. Intravenous AAV9 delivery in mouse has achieved development stage-specific transduction of neuronal cell types, with superior neuron-targeting efficiency demonstrated in prenatal compared with postnatal recipients. Because of the clinical relevance of the non-human primate (NHP) model, we investigated the ability of AAV9 to transduce the NHP CNS following intrauterine gene therapy (IUGT). We injected two macaque fetuses at 0.9 G with 1 × 10(13) vg scAAV9-CMV-eGFP through the intrahepatic continuation of the umbilical vein. Robust green fluorescent protein (GFP) expression was observed for up to 14 weeks in the majority of neurons (including nestin-positive cells), motor neurons and oligodendrocytes throughout the CNS, with a significantly lower rate of transduction in astrocytes. Photoreceptors and neuronal cell bodies in the plexiform and ganglionic retinal layers were also transduced. In the peripheral nervous system (PNS), widespread transduction of neurons was observed. Tissues harvested at 14 weeks showed substantially lower vector copy number and GFP levels, although the percentage of GFP-expressing cells remained stable. Thus, AAV9-IUGT in late gestation efficiently transduces both the CNS and PNS with neuronal predilection, of translational relevance to hereditary disorders characterized by perinatal onset of neuropathology.

Regular recreational physical activity and risk of hematologic malignancies: results from the prospective VITamins And lifestyle (VITAL) study.

BACKGROUND: Conflicting evidence exists on the relationship between physical activity (PA) and incident hematologic malignancies. Herein, we used a large cohort study to examine this association. PATIENTS AND METHODS: Sixty-five thousand three hundred twenty-two volunteers aged 50-76 years were recruited from 2000 to 2002. Incident hematologic malignancies (n = 666) were identified through 2009 by linkage to the Surveillance, Epidemiology, and End Results cancer registry. Hazard ratios (HRs) for hematologic malignancies associated with PA averaged over 10 years before baseline were estimated with Cox proportional hazards models, adjusting for factors associated with hematologic cancers or PA. RESULTS: There was a decreased risk of hematologic malignancies associated with PA (HR = 0.66 [95% confidence interval, 95% CI 0.51-0.86] for the highest tertile of all PA, P-trend = 0.005, and HR = 0.60 [95% CI 0.44-0.82] for the highest tertile of moderate/high-intensity PA, P-trend = 0.002). These associations were strongest for myeloid neoplasms (HR = 0.48 [95% CI 0.29-0.79] for the highest tertile of all PA, P-trend = 0.013, and HR = 0.40 [95% CI 0.21-0.77] for the highest tertile of moderate/high-intensity PA, P-trend = 0.016). There were also significant associations between PA and chronic lymphocytic leukemia/small lymphocytic lymphoma or other mature B-cell lymphomas except plasma cell disorders. CONCLUSIONS: Our study offers the strongest epidemiological evidence, to date, to suggest an association between regular PA and dose-dependent risk reduction for most hematologic malignancies, particularly myeloid neoplasms.

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression.

The efficient delivery of genetic material to the developing fetal brain represents a powerful research tool and a means to supply therapy in a number of neonatal lethal neurological disorders. In this study, we have delivered vectors based upon adenovirus serotype 5 (Ad5) and adeno-associated virus (AAV) pseudotypes 2/5, 2/8 and 2/9 expressing green fluorescent protein to the E16 fetal mouse brain. One month post injection, widespread caudal to rostral transduction of neural cells was observed. In discrete areas of the brain these vectors produced differential transduction patterns. AAV2/8 and 2/9 produced the most extensive gene delivery and had similar transduction profiles. All AAV pseudotypes preferentially transduced neurons whereas Ad5 transduced both neurons and glial cells. None of the vectors elicited any significant microglia-mediated immune response when compared with control uninjected mice. Whole-body imaging and immunohistological evaluation of brains 9 months post injection revealed long-term expression using these non-integrating vectors. These data will be useful in targeting genetic material to discrete or widespread areas of the fetal brain with the purpose of devising therapies for early neonatal lethal neurodegenerative disease and for studying brain development.

Pelvic girdle pain during pregnancy and puerperium.

Pelvic girdle pain (PGP) is a term used specifically to pregnancy-related pain in the lumbosacral, sacroiliac and symphysis pubis joints. Pregnancy-induced hormonal and physical changes increase the risk of musculoskeletal problems in pregnancy. The severity of these conditions varies from mild self-limiting pain to a severe disabling condition. PGP is common in pregnancy and while most can be managed as outpatients, a few patients require inpatient admission for further investigations and management. Prompt identification of these conditions is essential to avoid serious disability. Lack of awareness and failure of recognition not only results in women feeling isolated, but may also result in long-term morbidity. In this review, we explore the aetiology, presentation, risk factors, risk of recurrence, differential diagnosis and multidisciplinary management of these conditions. We also enclose obstetric guidelines to increase the awareness of the health professionals.

Financial analysis of revision knee surgery at a tertiary referral centre as classified according to the Revision Knee Complexity Classification (RKCC).

BACKGROUND: Revision total knee arthroplasty (rTKA) can be complex, with greater costs to the treating hospital than primary TKA. A rTKA regional network has been proposed in England. The aim of this work was to accurately quantify current costs and reimbursement for the rTKA service and to assess whether costs are proportional to case complexity at a tertiary referral centre within the National Health Service (NHS). METHODS: A review of all rTKA performed at our institution over two consecutive financial years (2017-2019) was performed. Cases were classified according to the Revision Knee Complexity Classification (RKCC) and by mode of failure; "infected" and "non-infected". Financial data was acquired through Patient-Level Information and Costing System (PLICS). The primary outcome was the financial difference between tariff and cost per episode. Comparisons between groups were analysed using analysis of variance and two-tailed unpaired t-test as appropriate. RESULTS: 159 patients underwent 188 rTKA procedures. Length of stay and cost significantly increased between complexity groups (p < 0.0001) and for infected revisions (p < 0.0001). All groups sustained a mean deficit but this significantly increased with revision complexity (from £1,903 to £5,269 per case) and for infected revisions. The total deficit to the Trust for the two-year rTKA service was £667,091. CONCLUSIONS: The current level of NHS reimbursement are inadequate for centres that offer rTKA and should be more closely aligned to case complexity. An increase in the most complex rTKA at major revision centres will undoubtedly place an even greater strain on the finances of these units.

Overexpression of transforming growth factor-beta1 in fetal monkey lung results in prenatal pulmonary fibrosis.

Altered transforming growth factor (TGF)-ß expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-ß in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-ß1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-ß1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-ß1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-ß1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-ß1 overexpression was no longer evident. Therefore, overexpression of TGF-ß1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia.

Synthesis of a Vocal Sound from the 3,000 year old Mummy, Nesyamun 'True of Voice'.

The sound of a 3,000 year old mummified individual has been accurately reproduced as a vowel-like sound based on measurements of the precise dimensions of his extant vocal tract following Computed Tomography (CT) scanning, enabling the creation of a 3-D printed vocal tract. By using the Vocal Tract Organ, which provides a user-controllable artificial larynx sound source, a vowel sound is synthesised which compares favourably with vowels of modern individuals.

Efficient gene delivery to the adult and fetal CNS using pseudotyped non-integrating lentiviral vectors.

Non-integrating lentiviral vectors show considerable promise for gene therapy applications as they persist as long-term episomes in non-dividing cells and diminish risks of insertional mutagenesis. In this study, non-integrating lentiviral vectors were evaluated for their use in the adult and fetal central nervous system of rodents. Vectors differentially pseudotyped with vesicular stomatitis virus, rabies and baculoviral envelope proteins allowed targeting of varied cell populations. Efficient gene delivery to discrete areas of the brain and spinal cord was observed following stereotactic administration. Furthermore, after direct in utero administration (E14), sustained and strong expression was observed 4 months into adulthood. Quantification of transduction and viral copy number was comparable when using non-integrating lentivirus and conventional integrating vector. These data support the use of non-integrating lentiviral vectors as an effective alternative to their integrating counterparts in gene therapy applications, and highlight their potential for treatment of inherited and acquired neurological disorders.

OpenPET: A Flexible Electronics System for Radiotracer Imaging.

We present the design for OpenPET, an electronics readout system designed for prototype radiotracer imaging instruments. The critical requirements are that it has sufficient performance, channel count, channel density, and power consumption to service a complete camera, and yet be simple, flexible, and customizable enough to be used with almost any detector or camera design. An important feature of this system is that each analog input is processed independently. Each input can be configured to accept signals of either polarity as well as either differential or ground referenced signals. Each signal is digitized by a continuously sampled ADC, which is processed by an FPGA to extract pulse height information. A leading edge discriminator creates a timing edge that is "time stamped" by a TDC implemented inside the FPGA. This digital information from each channel is sent to an FPGA that services 16 analog channels, and information from multiple channels is processed by this FPGA to perform logic for crystal lookup, DOI calculation, calibration, etc. As all of this processing is controlled by firmware and software, it can be modified / customized easily. The system is open source, meaning that all technical data (specifications, schematics and board layout files, source code, and instructions) will be publicly available.

Lessons from eleven primary health care nursing innovations in New Zealand.

INTRODUCTION: In New Zealand in 2003, 11 primary health care (PHC) nursing innovation projects and an evaluation of the initiative were funded by the Ministry of Health to develop and explore the ways new models of nursing practice could help address health inequalities and contribute to PHC. DESIGN AND METHODS: A research-and-development approach was used in the evaluation. Data were gathered from interviews with national stakeholders, workshops with personnel from all projects, visits to each project site and case studies of four projects. Analysis involved assessing each project individually as well as the projects as a whole. CONTEXT: The initiative was one of many international and local PHC developments in this period designed to reduce health inequalities and improve patient care and health outcomes. FINDINGS: Each project was developed from a different starting point; was located in different parts of the health system; and had different levels of funding. Some were principally focused on leading nursing development; others focused on developing nursing practice. Each involved influencing or providing nursing services, nurse education, leadership and service integration. Most projects progressed well, but some had limited success. LESSONS: Lessons are on many levels, and include those related to: developing successful innovation; the importance of nursing leadership; developing the nursing workforce; and advancing nursing practice. CONCLUSION: The funding of the innovative projects enabled nurses to pioneer developments. Such funding is important, as it paves the way for change and provides an opportunity for reflection and new learnings.

A superconducting thermal switch with ultrahigh impedance for interfacing superconductors to semiconductors.

A number of current approaches to quantum and neuromorphic computing use superconductors as the basis of their platform or as a measurement component, and will need to operate at cryogenic temperatures. Semiconductor systems are typically proposed as a top-level control in these architectures, with low-temperature passive components and intermediary superconducting electronics acting as the direct interface to the lowest-temperature stages. The architectures, therefore, require a low-power superconductor-semiconductor interface, which is not currently available. Here we report a superconducting switch that is capable of translating low-voltage superconducting inputs directly into semiconductor-compatible (above 1,000 mV) outputs at kelvin-scale temperatures (1K or 4 K). To illustrate the capabilities in interfacing superconductors and semiconductors, we use it to drive a light-emitting diode (LED) in a photonic integrated circuit, generating photons at 1K from a low-voltage input and detecting them with an on-chip superconducting single-photon detector. We also characterize our device's timing response (less than 300 ps turn-on, 15 ns turn-off), output impedance (greater than 1MΩ), and energy requirements (0.18fJ/µm2,3.24mV/nW).

Lentiviral transduction of the murine lung provides efficient pseudotype and developmental stage-dependent cell-specific transgene expression.

Gene transfer for cystic fibrosis (CF) airway disease has been hampered by the lung's innate refractivity to pathogen infection. We hypothesized that early intervention with an integrating gene transfer vector capable of transducing the lung via the lumen may be a successful therapeutic approach. An HIV-based lentiviral vector pseudotyped with the baculovirus gp64 envelope was applied to the fetal, neonatal or adult airways. Fetal intra-amniotic administration resulted in transduction of approximately 14% of airway epithelial cells, including both ciliated and non-ciliated epithelia of the upper, mid and lower airways; there was negligible alveolar or nasal transduction. Following neonatal intra-nasal administration we observed significant transduction of the airway epithelium (approximately 11%), although mainly in the distal lung, and substantial alveolar transduction. This expression was still detectable at 1 year after application. In the adult, the majority of transduction was restricted to the alveoli. In contrast, vesicular stomatitis virus glycoprotein pseudotyped virus transduced only alveoli after adult and neonatal application and no transduction was observed after fetal administration. Repeat administration did not increase transduction levels of the conducting airway epithelia. These data demonstrate that application at early developmental stages in conjunction with an appropriately pseudotyped virus provides efficient, high-level transgene expression in the murine lung. This may provide a modality for treatment for lung disease in CF.

Local delivery of VEGF adenovirus to the uterine artery increases vasorelaxation and uterine blood flow in the pregnant sheep.

Impaired materno-placental perfusion causes two important obstetric complications, fetal growth restriction and preeclampsia. This study investigated whether adenoviral vector-mediated overexpression of vascular endothelial growth factor (VEGF) in the uterine arteries (UtAs) increases uterine artery blood flow (UBF). First-generation adenovirus vectors (5 x 10(11) particles) containing the VEGF gene (Ad.VEGF-A or -D) or the beta-galactosidase reporter gene (Ad.lacZ) were injected into the UtAs of pregnant sheep (n=6) at 88-102 days of gestation (term=145 days). UBF was measured using Doppler sonography before, and 4-7 days after injection. Mean UBF increased significantly from 233+/-156 (s.d.) ml min(-1) to 753+/-415 ml min(-1) following Ad.VEGF-A injection (P=0.005, n=5); Ad.lacZ infection had no significant effect. Organ bath experiments on uterine arterial sections 4-7 days after injection showed that, compared with Ad.lacZ vessels, Ad.VEGF-A-transduced vessels had a reduced contractile response to phenylephrine (E max 148+/-10.9 vs E max 228.2+/-27.5, P<0.05) but increased relaxation with bradykinin (pD2 (-log EC50) values 9.11+/-0.01 vs 8.65+/-0.11, P<0.05). Injection of Ad.VEGF-A into the UtAs increases UBF by enhancing vasodilatation. This may provide the basis for therapy in pregnancies complicated by uteroplacental insufficiency.

A study of complicated grief symptoms in people with intellectual disabilities.

INTRODUCTION: Previous studies have shown a significant association between familial bereavement and the onset of challenging behaviours and psychopathology in people with intellectual disabilities (ID). However, little work has been done to accurately describe the specific symptoms of grief, in particular symptoms of complicated grief in this population. Consensus criteria for the diagnosis of complicated grief have been drawn up and tested for validity in the general population. AIMS: To examine the occurrence of symptoms of complicated grief, and to explore the relationships between complicated grief and bereavement experience. METHOD: A bereavement history questionnaire and a newly developed measure examining for symptoms of complicated grief were administered to a group of carers of people with mild or moderate ID, who had experienced a parental bereavement within the previous 2 years. The questionnaires were also administered to a matched comparison group, who had not been bereaved. RESULTS/CONCLUSIONS: This carer-based comparison study has revealed that bereaved individuals with ID experience complicated grief symptoms following the death of a parent, with one-third of the bereaved group experiencing 10 or more clinically apparent symptoms. In addition, complicated grief symptoms were more likely to occur with higher rates of bereavement ritual involvement. These findings have both clinical and research implications.

Long-term results of acetabular reconstruction using irradiated allograft bone.

AIMS: The management of acetabular defects at the time of revision hip arthroplasty surgery is a challenge. This study presents the results of a long-term follow-up study of the use of irradiated allograft bone in acetabular reconstruction. PATIENTS AND METHODS: Between 1990 and 2000, 123 hips in 110 patients underwent acetabular reconstruction for aseptic loosening, using impaction bone grafting with frozen, irradiated, and morsellized femoral heads and a cemented acetabular component. A total of 55 men and 55 women with a mean age of 64.3 years (26 to 97) at the time of revision surgery are included in this study. RESULTS: At a mean follow-up of 16.9 years, there had been 23 revisions (18.7%), including ten for infection, eight for aseptic loosening, and three for dislocation. Of the 66 surviving hips (58 patients) that could be reassessed, 50 hips (42 patients; 75.6%) were still functioning satisfactorily. Union of the graft had occurred in all hips with a surviving implant. Survival analysis for all indications was 80.6% at 15 years (55 patients at risk, 95% confidence interval (CI) 71.1 to 87.2) and 73.7% at 20 years (eight patients at risk, 95% CI 61.6 to 82.5). CONCLUSION: Acetabular reconstruction using frozen, irradiated, and morsellized allograft bone and a cemented acetabular component is an effective method of treatment. It gives satisfactory long-term results and is comparable to other types of reconstruction. Cite this article: Bone Joint J 2018;100-B:1449-54.

Sorbents can tailor nitrogen release from organic wastes to match the uptake capacity of crops.

Delivering nutrients from mineral or organic fertilizers out of synchrony with crop uptake causes inefficiencies and pollution. We explore methodologies for evaluating sorbents as additives to organic agricultural wastes to retain nitrogen in an exchangeable form and deliver at rates that approximate the uptake capacity of roots. Focussing on ammonium (NH4+) as the main inorganic nitrogen form in the studied wastes (sugarcane mill mud, poultry litter), we tested geo-sorbents and biochar for their ability to retain NH4+. Sorption capacity was ranked palagonite < bentonite, biochar, vermiculite < chabazite, clinoptilolite (5.7 to 24.3 mg NH4+ g-1 sorbent). Sorbent-waste formulations were analysed for sorption capacity, leaching and fluxes of NH4+. Ammonium-sorption capacity broadly translated to sorbent-waste formulations with clinoptilolite conferring the strongest NH4+ attenuation (80%), and palagonite the lowest (7%). A 1:1 ratio of sorbent:waste achieved stronger sorption than a 0.5:1 ratio, and similar sorption as a 1:1.5 ratio. In line with these results, clinoptilolite-amended wastes had the lowest in situ NH4+ fluxes, which exceeded the NH4+ uptake capacity (Imax) of sugarcane and sorghum roots 9 to 84-fold, respectively. Less efficient sorbent-waste formulations and un-amended wastes exceeded Imax of crop roots up to 274-fold. Roots preferentially colonized stronger sorbent-waste formulations and avoided weaker ones, suggesting that lower NH4+ fluxes generate a more favourable growth environment. This study contributes methodologies to identify suitable sorbents to formulate organic wastes as next-generation fertilizers with view of a crop's nutrient physiology. Efficient re-purposing of wastes can improve nutrient use efficiency in agriculture and support the circular nutrient economy.