Bilinguals' and second language learners' knowledge of Japanese syllable structure

The acquisition of second language phonology has been commanding researchers' attention in recent years. The aim of this thesis is to contribute to this area with a study on Japanese as a second language. The thesis explores both the development of phonological competence by post-puberty second language learners and the end state of pre-puberty bilingual acquisition. Reviewing the literature on the theoretical aspects of mora, syllables and syllable structure, we see that the mora is distinctive and plays vital role in Japanese phonology. We next look at the acquisition theories proposed in recent years, and adopt a Universal Grammar-based approach. Comparing first, bilingual and second language acquisition, three research hypotheses are presented: 1) the Mora Assignment Hypothesis, 2) L2 phonological Acquisition and Age Onset Hypothesis, and the 3) Quality and Quantity of Input Hypothesis. To test these hypotheses, a study was designed involving 24 bilingual children and adults, and 94 adult L2 learners of Japanese at varying levels of proficiency. The results provide evidence to support all three research hypotheses. First the data show that the both English-dominant bilinguals and second language learners at all levels deleted morae and all but the beginning second language learners added morae in oral and written production tasks, indicating non-native competence with respect to morae. In addition, learners attempt to preserve the overall mora count. Since English is not a mora sensitive language, the mora conservation exhibited here is from their Japanese. The learners, including English-dominant bilinguals, first become sensitive to the mora and only at a later stage assign segments to the correct mora slot. The difference in performance between English-dominant bilinguals and Japanese-dominant bilinguals was such that by the age of eight, those who had spent more years in Japan demonstrated native phonological competence, whereas the English-dominant bilinguals' performance pointed to non-native competence. With respect to the second and third hypotheses, results from the bilinguals indicate that in addition to age of onset, the amount of exposure to a second language must be taken into account as a factor influencing ultimate attainment. The study also reveals strong influence of literacy in both oral and written production of Japanese

The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies

The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.Centro de Investigaciones Inmunológicas Básicas y Aplicada

Cohort profile : the Australian genetics of depression study

Purpose Depression is the most common psychiatric disorder and the largest contributor to global disability. The Australian Genetics of Depression study was established to recruit a large cohort of individuals who have been diagnosed with depression at some point in their lifetime. The purpose of establishing this cohort is to investigate genetic and environmental risk factors for depression and response to commonly prescribed antidepressants. Participants A total of 20 689 participants were recruited through the Australian Department of Human Services and a media campaign, 75% of whom were female. The average age of participants was 43 years±15 years. Participants completed an online questionnaire that consisted of a compulsory module that assessed self-reported psychiatric history, clinical depression using the Composite Interview Diagnostic Interview Short Form and experiences of using commonly prescribed antidepressants. Further voluntary modules assessed a wide range of traits of relevance to psychopathology. Participants who reported they were willing to provide a DNA sample (75%) were sent a saliva kit in the mail. Findings to date 95% of participants reported being given a diagnosis of depression by a medical practitioner and 88% met the criteria for a lifetime depressive episode. 68% of the sample report having been diagnosed with another psychiatric disorder in addition to depression. In line with findings from clinical trials, only 33% of the sample report responding well to the first antidepressant they were prescribed. Future plans A number of analyses to investigate the genetic architecture of depression and common comorbidities will be conducted. The cohort will contribute to the global effort to identify genetic variants that increase risk to depression. Furthermore, a thorough investigation of genetic and psychosocial predictors of antidepressant response and side effects is planned. © © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies

The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration.Centro de Investigaciones Inmunológicas Básicas y Aplicada

The outcome of critically ill neonates undergoing laparotomy for necrotising enterocolitis in the neonatal intensive care unit: a 10-year review

Results: 221 infants with NEC were referred for surgical evaluation; 182 (82%) underwent surgery; 15 (8%) required a laparotomy on NICU. Five had NEC totalis, 4 multifocal disease and 6 focal disease. Five had an open and close laparotomy, 8 stoma with/without bowel resection and 2 bowel resection and primary anastomosis. Ten (67%) died at a median of 6.5-hours (2-72) postoperatively; 2 died at 72 and 264-days. The 30-day mortality rate was higher (p = 0.01) among infants undergoing a laparotomy on NICU (10/15; 67%) than in theatre (54/167; 32%). There was no significant difference in mean Paediatric Index of Mortality 2 Scores between survivors and nonsurvivors (p = 0.55). Three (20%) infants remain alive with no or minimal disability at 1.4 (0.5-7.5) years. Conclusion: Laparotomy for NEC on NICU is a treatment option for neonates who are too unstable to transfer to theatre. However, with 67% dying within 6.5-hours and a further 13% after months in hospital, we must consider whether surgery is always in their best interests. Development of a prediction model to help distinguish those at highest risk of long-term morbidity and mortality could help with decision making in this difficult situation

Neurologic phenotypes associated with COL4A1/2 mutations

Objective: To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods: We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results: Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion: COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall

Glastir Monitoring & Evaluation Programme. First year annual report

The Welsh Government has commissioned a comprehensive new ecosystem monitoring and evaluation programme to monitor the effects of Glastir, its new land management scheme, and to monitor progress towards a range of international biodiversity and environmental targets. A random sample of 1 km squares stratified by landcover types will be used both to monitor change at a national level in the wider countryside and to provide a backdrop against which intervention measures are assessed using a second sample of 1 km squares located in areas eligible for enhanced payments for advanced interventions. Modelling in the first year has forecast change based on current understanding, whilst a rolling national monitoring programme based on an ecosystem approach will provide an evidence-base for on-going, adaptive development of the scheme by Welsh Government. To our knowledge, this will constitute the largest and most in-depth ecosystem monitoring and evaluation programme of any member state of the European Union

Infection prevention and care bundles addressing health care-associated infections in neonatal care in low-middle income countries: a scoping review.

BACKGROUND: Health care-associated infections (HCAI) in neonatal units in low- and middle-income countries (LMIC) are a major cause of mortality. This scoping review aimed to synthesise published literature on infection prevention and care bundles addressing neonatal HCAI in LMICs and to construct a Classification Framework for their components (elements). METHODS: Five electronic databases were searched between January 2001 and July 2020. A mixed-methods approach was applied: qualitative content analysis was used to build a classification framework to categorise bundle elements and the contents of the classification groups were then described quantitatively. FINDINGS: 3619 records were screened, with 44 eligible studies identified. The bundle element Classification Framework created involved: (1) Primary prevention, (2) Detection, (3) Case management, and Implementation (3 + I). The 44 studies included 56 care bundles with 295 elements that were then classified. Primary prevention elements (128, 43%) predominated of which 71 (55%) focused on central line catheters and mechanical ventilators. Only 12 elements (4%) were related to detection. A further 75 (25%) elements addressed case management and 66 (88%) of these aimed at outbreak control. INTERPRETATION: The 3 + I Classification Framework was a feasible approach to reporting and synthesising research for infection-relevant bundled interventions in neonatal units. A shift towards the use in infection prevention and care bundles of primary prevention elements focused on the neonate and on commonly used hospital devices in LMIC (e.g., self-inflating bags, suctioning equipment) would be valuable to reduce HCAI transmission. Detection elements were a major gap. FUNDING: This work was made possible in part by the John D. and Catherine T. MacArthur Foundation, the Bill & Melinda Gates Foundation, ELMA Philanthropies, The Children's Investment Fund Foundation UK, The Lemelson Foundation, and the Ting Tsung and Wei Fong Chao Foundation under agreements to William Marsh Rice University. The project leading to these results has also received the support of a fellowship from the "la Caixa" Foundation (ID 100010434). The fellowship code is LCF/BQ/EU19/11710040. EJAF is an Academic Clinical Fellow whose salary is funded by the UK National Institute for Health Research (NIHR). NES receives a Research Training Program Scholarship (Australian Commonwealth Government)

Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens

BACKGROUND: Both infection and vaccination, alone or in combination, generate antibody and T cell responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the maintenance of such responses-and hence protection from disease-requires careful characterization. In a large prospective study of UK healthcare workers (HCWs) (Protective Immunity from T Cells in Healthcare Workers [PITCH], within the larger SARS-CoV-2 Immunity and Reinfection Evaluation [SIREN] study), we previously observed that prior infection strongly affected subsequent cellular and humoral immunity induced after long and short dosing intervals of BNT162b2 (Pfizer/BioNTech) vaccination. METHODS: Here, we report longer follow-up of 684 HCWs in this cohort over 6-9 months following two doses of BNT162b2 or AZD1222 (Oxford/AstraZeneca) vaccination and up to 6 months following a subsequent mRNA booster vaccination. FINDINGS: We make three observations: first, the dynamics of humoral and cellular responses differ; binding and neutralizing antibodies declined, whereas T and memory B cell responses were maintained after the second vaccine dose. Second, vaccine boosting restored immunoglobulin (Ig) G levels; broadened neutralizing activity against variants of concern, including Omicron BA.1, BA.2, and BA.5; and boosted T cell responses above the 6-month level after dose 2. Third, prior infection maintained its impact driving larger and broader T cell responses compared with never-infected people, a feature maintained until 6 months after the third dose. CONCLUSIONS: Broadly cross-reactive T cell responses are well maintained over time-especially in those with combined vaccine and infection-induced immunity ("hybrid" immunity)-and may contribute to continued protection against severe disease