RAB1A haploinsufficiency phenocopies the 2p14-p15 microdeletion and is associated with impaired neuronal differentiation.

Hereditary spastic parapareses (HSPs) are clinically heterogeneous motor neuron diseases with variable age of onset and severity. Although variants in dozens of genes are implicated in HSPs, much of the genetic basis for pediatric-onset HSP remains unexplained. Here, we re-analyzed clinical exome-sequencing data from siblings with HSP of unknown genetic etiology and identified an inherited nonsense mutation (c.523C>T [p.Arg175Ter]) in the highly conserved RAB1A. The mutation is predicted to produce a truncated protein with an intact RAB GTPase domain but without two C-terminal cysteine residues required for proper subcellular protein localization. Additional RAB1A mutations, including two frameshift mutations and a mosaic missense mutation (c.83T>C [p.Leu28Pro]), were identified in three individuals with similar neurodevelopmental presentations. In rescue experiments, production of the full-length, but not the truncated, RAB1a rescued Golgi structure and cell proliferation in Rab1-depleted cells. In contrast, the missense-variant RAB1a disrupted Golgi structure despite intact Rab1 expression, suggesting a dominant-negative function of the mosaic missense mutation. Knock-down of RAB1A in cultured human embryonic stem cell-derived neurons resulted in impaired neuronal arborization. Finally, RAB1A is located within the 2p14-p15 microdeletion syndrome locus. The similar clinical presentations of individuals with RAB1A loss-of-function mutations and the 2p14-p15 microdeletion syndrome implicate loss of RAB1A in the pathogenesis of neurodevelopmental manifestations of this microdeletion syndrome. Our study identifies a RAB1A-related neurocognitive disorder with speech and motor delay, demonstrates an essential role for RAB1a in neuronal differentiation, and implicates RAB1A in the etiology of the neurodevelopmental sequelae associated with the 2p14-p15 microdeletion syndrome.

Moving beyond symptom reduction: A meta-analysis on the effect of exposure therapy for PTSD on quality of life.

OBJECTIVES: Quality of life (QOL) is a multidimensional construct including emotional well-being, life satisfaction, and physical health. Individuals with posttraumatic stress disorder (PTSD) consistently report low QOL, highlighting the importance of assessing the effectiveness of first-line PTSD treatments (e.g., exposure-based therapies) on QOL. This meta-analysis examined the efficacy of exposure therapy for PTSD on QOL compared to control conditions (e.g., waitlist, medication, treatment-as-usual) at posttreatment and follow-up (ranging from 1 month to 2 years). METHODS: Building on a previous meta-analysis of exposure-based therapy for PTSD, we searched PsycINFO and Medline in December 2021, July 2022, and March 2023 to include randomized controlled trials of exposure-based treatments for adult PTSD assessing QOL. We screened 295 abstracts for initial eligibility; 20 articles met inclusion criteria and were included (N = 2729 participants). Risk of bias was evaluated using the Cochrane Risk of Bias tool 2.0. RESULTS: At posttreatment, exposure-based therapies showed a medium effect on QOL relative to control conditions (k = 25, g = 0.67). This effect was not observed at follow-up for the small subset of studies with follow-up data (k = 8, g = 0.16). At posttreatment, effect size varied significantly as a function of the control condition (p < .0001). There were no differences in QOL effects across exposure therapies at posttreatment or follow-up (p = .09). CONCLUSION: Exposure therapy was associated with greater improvement in QOL compared to control conditions at posttreatment. Exposure was not superior to control conditions at follow-up, and the longer-term impact of exposure on QOL is unclear. The implications of these findings are discussed, along with the need for more PTSD treatment studies to examine QOL outcomes at posttreatment and follow-up.

Screening for late-onset gestational diabetes: Are there any clinical benefits?

OBJECTIVE: To determine whether screening for gestational diabetes mellitus (GDM) in the third trimester and managing those who are screen positive on a diabetes pathway affects obstetric and neonatal outcomes. DESIGN: Retrospective study of prospectively collected data. SETTING: London Teaching Hospital. POPULATION OR SAMPLE: A total of 14 366 women delivering between 1 January 2018 and 31 December 2020. METHODS: Retrospective chart analysis. MAIN OUTCOME MEASURES: Diagnosis of late-onset GDM, obstetric and neonatal outcomes. RESULTS: Five hundred and thirty-one women were tested by home glucose monitoring for late-onset GDM from 33 weeks of gestation. In all, 244 were diagnosed as having GDM (group 1) and managed accordingly, and 287 (group 2) were returned to normal care. A total of 1415 women had GDM diagnosed by oral glucose tolerance test before 33 weeks of gestation (group 3). Of the women in group 2, 49.5% had a spontaneous onset of labour compared with only 25.8% and 27% in groups 1 and 3. However, women in group 2 were significantly more likely to have a macrosomic baby (≥4000 g, 25.4%) than groups 1 (16.0%) or 3 (7.2%), and their babies were more likely to be admitted to special care (5.2% versus 2% in group 1). Macrosomic babies were associated with significantly higher rates of shoulder dystocia, third- and fourth-degree tears and postpartum haemorrhage. CONCLUSIONS: Apparent late-onset GDM affects a significant proportion of women, and targeted intervention was associated with better obstetric and neonatal outcomes. These results suggest that all pregnancies with risk factors for late-onset GDM might benefit from active GDM management irrespective of specific glucose thresholds. TWEETABLE ABSTRACT: Women with risk factors for GDM in the third trimester, and their babies, would probably benefit from active management of their blood sugars irrespective of threshold values.

The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK.

Kaufman oculocerebrofacial syndrome (KOS) is a recessive neurodevelopmental disorder characterized by intellectual disability and lack of speech. KOS is caused by inactivating mutations in UBE3B, but the underlying biological mechanisms are completely unknown. We found that loss of Ube3b in mice resulted in growth retardation, decreased grip strength, and loss of vocalization. The brains of Ube3b-/- mice had hypoplasia of the corpus callosum, enlarged ventricles, and decreased thickness of the somatosensory cortex. Ube3b-/- cortical neurons had abnormal dendritic morphology and synapses. We identified 22 UBE3B interactors and found that branched-chain α-ketoacid dehydrogenase kinase (BCKDK) is an in vivo UBE3B substrate. Since BCKDK targets several metabolic pathways, we profiled plasma and cortical metabolomes from Ube3b-/- mice. Nucleotide metabolism and the tricarboxylic acid cycle were among the pathways perturbed. Substrate-induced mitochondrial respiration was reduced in skeletal muscle but not in liver of Ube3b-/- mice. To assess the relevance of these findings to humans, we identified three KOS patients who had compound heterozygous UBE3B mutations. We discovered changes in metabolites from similar pathways in plasma from these patients. Collectively, our results implicate a disease mechanism in KOS, suggest that it is a metabolic encephalomyopathy, and provide an entry to targeted therapies.

Negative mood regulation expectancies moderate the effect of childhood maltreatment on compulsive buying.

OBJECTIVE: Two studies investigated childhood maltreatment, alexithymia-the inability to identify one's mood-and negative mood regulation expectancies (NMRE)-confidence that one can alleviate one's negative moods-as predictors of compulsive buying (CB). METHOD: Participants were recruited from internet CB forums and undergraduate psychology classes. Online, they completed questionnaires and a behavioral task that assessed impulsive spending. RESULTS: In Study 1 (N = 646), analyses indicated that NMRE, alexithymia, and childhood maltreatment were significant independent predictors of CB. For Study 2, a subset of participants from the Study 1 pool (N = 295) who met the criterion for clinical levels of CB were selected, based on their self-report. Analyses revealed that NMRE buffered the effect of maltreatment: among participants with high NMRE-higher levels of maltreatment were associated with minimal increases in CB and impulsive spending behavior. CONCLUSION: Being confident that one can control one's unpleasant moods was a protective factor from the maladaptive consequences of childhood maltreatment. Increasing NMRE early in psychotherapy for CB may result in clients' using more adaptive coping strategies.

Understanding the role of Facebook to support women with endometriosis: A Malaysian perspective.

AIMS: To examine the pertinent issues discussed by endometriosis patients in Malaysia on MyEndosis Facebook group as an alternative platform for online support. METHODS: Using thematic analysis based on three frameworks, 120 posted messages and comments were examined from MyEndosis Facebook group-a support group for women with endometriosis from January to July 2014. RESULTS: Results showed the issues discussed were (a) personal struggles, (b) medication and treatment, (c) alternative medication, (d) side effects, and (e) medication recommended by doctors. While using this social medium, users found (a) emotional support, (b) esteem support, (c) information support, (d) network support, and (e) tangible assistance in their engagement with others. CONCLUSION: The analysis suggested that users' interactions were structured around information, emotion, and community building, which many doctors and nurses were not aware of. The group was shaped as a social network where peer users share social support, cultivate companionship, and exert social influence.

The impact of socioeconomic status on the link between osteoarthritis and the onset of common comorbidities.

OBJECTIVES: The temporal relationship between osteoarthritis and comorbidity is unclear and may vary with socioeconomic status. The aims of this study were to identify if osteoarthritis was associated with onset of common comorbidities, and if the association was moderated by deprivation. METHODS: Prospective cohort study combining questionnaire and medical record data (n=3910). Associations between osteoarthritis and onset of comorbidity at the three-year follow-up were examined using regression models. Interaction terms and stratified analysis were used to examine moderation. RESULTS: Osteoarthritis was associated with onset of all comorbidities (p<0.05). After adjusting for confounders, osteoarthritis was associated with onset of widespread pain (adjusted odds ratio 2.49; 95% confidence interval 1.96-3.17) and insomnia (1.58;1.14-1.19). Interactions between osteoarthritis and change in income and onset cognitive impairment (p=0.047; onset was higher when income became inadequate), and between osteoarthritis and education and onset widespread pain (p=0.012; onset was higher in those with high levels of education) were significant. CONCLUSIONS: Consulters for osteoarthritis were more likely to develop physical and psychological comorbidities than those without osteoarthritis. The moderation analyses indicated that mechanisms to comorbidity differ by socio-economic strata and a need for different approaches to prevent comorbidity for consulters with OA from different levels of deprivation.

Palliative care for patients with motor neurone disease and their bereaved carers: a qualitative study.

BACKGROUND: Internationally, it is widely accepted that holistic care is as an integral part of the care for people with motor neurone disease (MND), and their informal carers. However the optimal role of generalist and specialist palliative care, and how it integrates with specialist neurology services, is not fully established. Using a qualitative approach we sought to examine end of life care for people with MND in Northern Ireland, and the role of specialist and generalist palliative care. METHODS: Qualitative study involving a convenience sample of 13 bereaved carers recruited using the Northern Ireland MND Register. Data collection consisted of semi-structured interviews with the bereaved carers of patients who had died 3-24 months previously with a diagnosis of MND. Data were analysed using thematic analysis. RESULTS: Findings illuminated variations in relation to the levels of holistic care provided to this cohort of patients. Unmanaged respiratory and psychological symptoms caused perceived distress amongst patients. Participants' experiences additionally highlighted reluctance amongst patients with MND to engage with services such as specialist palliative care. Conversely, for those who received input from specialist palliative care services carers portrayed these services to be of great benefit to the patient. CONCLUSIONS: Patients with MND in Northern Ireland may have many unmet holistic care needs. Key areas that require particular focus in terms of service development include neuromuscular respiratory physiotherapy and psychological services for patients. Future research must explore an optimal model of holistic care delivery for patients with MND and how this can be effectively integrated to best meet this patient cohorts palliative care needs.

Significance of coarse cereals in health and nutrition: a review.

This review assesses the nutritional attributes of coarse cereals and also their utilization as food and as formulated foods. These cereals are laden with phytochemicals including phenolic acids, tannins, anthocyanins, phytosterols, avenenathramides and policosanols. They possess high antioxidant properties in vitro than staple cereals and fruits by different purported pathways. There are also some anti-nutritional factors that may be reduced by certain processing treatments. Several epidemiological studies show that these cereals are helpful in reducing several kinds of chronic diseases like cancers, cardiovascular diseases, type II diabetes and various gastrointestinal disorders. Being coarse in nature, they cannot replace our staple cereals, but can be used in different proportions with rice and wheat to formulate various nutritional products. They can be used to make porridges, biscuits, cakes, cookies, tortillas, bread, probiotic drinks, ladoo, ghatta, flakes and several fermented foods. The coarse cereals also have good potential in manufacturing bioethanol, paper, oil and biofilms.

Chronic pramlintide decreases feeding via a reduction in meal size in male rats.

Amylin, a pancreatic hormone, is well-established to suppress feeding by enhancing satiation. Pramlintide, an amylin analog that is FDA-approved for the treatment of diabetes, has also been shown to produce hypophagia. However, the behavioral mechanisms underlying the ability of pramlintide to suppress feeding are unresolved. We hypothesized that systemic pramlintide administration in rats would reduce energy intake, specifically by reducing meal size. Male rats were given b.i.d. administration of intraperitoneal pramlintide or vehicle for 1 week, and chow intake, meal patterns, and body weight were monitored throughout the test period. Consistent with our hypothesis, pramlintide decreased chow intake mainly via suppression of meal size, with corresponding reductions in meal duration on several days. Fewer effects on meal number or feeding rate were detected. Pramlintide also reduced weight gain over the 1-week study. These results highlight that the behavioral mechanisms by which pramlintide produces hypophagia are similar to those driven by amylin itself, and provide important insight into the ability of this pharmacotherapy to promote negative energy balance over a period of chronic administration.

Asian Indians in the United States and Posttraumatic Stress Disorder Interventions: A Narrative Literature Review.

Topic. Limited research has examined trauma and posttraumatic stress disorder (PTSD) among Asian Indians in the U.S. Thus, we (1) synthesize literature on trauma, PTSD, disparities in treatment for PTSD, the burden of untreated PTSD, and culturally-adapted (CA) PTSD interventions; and (2) discuss recommendations for clinicians/researchers working with this population.Method. We searched two databases using keywords related to Asian Indians, PTSD, and interventions. Of 238 identified articles, we used content from 26 articles to inform our review.Findings. Asian Indians report traumatic experiences before, during, or after immigration to the U.S. and consequential PTSD symptoms. Further, Asian Indians in the U.S. are disproportionately impacted by socio-cultural and economic determinants of poor mental health (e.g., shame/stigma associated with seeking mental health services, few culturally-responsive services), which may contribute to the under-reporting of PTSD and (interpersonal) traumas and less willingness to seek treatment. Additionally, CA PTSD interventions tailored to Asian Indians in the U.S. have not been developed. Socio-cultural considerations that can inform CA PTSD interventions for Asian Indians include: causal conditions (e.g., culturally-rooted beliefs about trauma/PTSD), intervening conditions/barriers (e.g., emotional inhibition), and mitigating/coping strategies (e.g., religious/spiritual practices, cultural idioms of distress). These considerations influence clinician/treatment preferences (e.g., solution-oriented and structured therapy, less emotional exposure). Lastly, we outline recommendations for clinicians/researchers: (1) need for national studies on trauma, PTSD, treatment utilization, and the burden of untreated PTSD; (2) consideration of immigration-related experiences influencing PTSD; (3) consideration of socio-cultural elements for CA PTSD interventions; and (4) need for culturally-valid PTSD assessments.

Impact of Structured Training Program about Cadaver Organ Donation and Transplantation on Knowledge and Perception of Nursing Students at Public and Private Nursing Teaching Institute of Northern India - An Interventional Study.

Background: "Donation gap" refers to the shortage of organ donors worldwide. The medical/nursing students and various healthcare workers have poor awareness and attitude toward organ donation. Objective: We conducted this study to assess the current level of knowledge and perception regarding cadaver organ donation and transplantation among nursing students and to evaluate the impact of structured training interventions on their baseline knowledge and perception level. Methods: It was a single-group pre-post interventional study done by nursing students of one government and one private nursing college.A pre-tested questionnaire was used as a study tool. Statistical Analysis: Various statistical tests like one-way repeated measure ANOVA, Mauchly's test of sphericity, and Greenhouse-Geisser correction were used. Pairwise comparisons used Bonferroni corrections. Results: The pre-test group had the lowest mean knowledge (50.2346, SD = 15.35188), and immediately after training group had the highest (57.3900, SD = 14.34626). After one month, knowledge decreased but was still higher than pretraining (mean = 52.3607, SD = 13.28141). Conclusions: The positive attitude of nursing students may augment cadaver organ donation and transplantation in the future. The study has also highlighted the further training needs of the participants.

Impact of structured training program about Hospital Infection Control practices on Knowledge and Perception of nursing students at public and private nursing teaching institute of Northern India- An interventional study.

BACKGROUND: Hospital-acquired infections (HAIs) are a primary cause of illness and death and increased expenditure due to prolonged hospitalization and poor prognosis. HAI is a global safety concern, according to World Health Organization (WHO). This study assesses the current level of knowledge and perception regarding hospital infection control practices among nursing students and evaluates the impact of structured training interventions on their baseline knowledge and perception level. METHODS AND MATERIALS: It was a single group, a pre-post interventional study done on nursing students of one government and one private nursing college in the year 2021. A pretested questionnaire consisting of was used as a study tool. Various statistical tests like one repeated-measure ANOVA, Mauchly's Test of Sphericity, and Greenhouse-Geisser correction were used. RESULTS: The mean knowledge was minimum in the pretest group (Mean = 79.4430, SD = 17.49746) and maximum immediately after the training group (Mean = 96.5443, SD = 25.42322). But after one month, knowledge decreased; however, it was more than pre-training Knowledge (Mean = 84.4937, SD = 22.40313). CONCLUSIONS: Annual educational/training modules help retain knowledge in hospital infection control practices and HAI prevention. All healthcare workers need regular training.

Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity.

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (KDM5A), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.

The genetics of autism spectrum disorder in an East African familial cohort.

Autism spectrum disorder (ASD) is a group of complex neurodevelopmental conditions affecting communication and social interaction in 2.3% of children. Studies that demonstrated its complex genetic architecture have been mainly performed in populations of European ancestry. We investigate the genetics of ASD in an East African cohort (129 individuals) from a population with higher prevalence (5%). Whole-genome sequencing identified 2.13 million private variants in the cohort and potentially pathogenic variants in known ASD genes (including CACNA1C, CHD7, FMR1, and TCF7L2). Admixture analysis demonstrated that the cohort comprises two ancestral populations, African and Eurasian. Admixture mapping discovered 10 regions that confer ASD risk on the African haplotypes, containing several known ASD genes. The increased ASD prevalence in this population suggests decreased heterogeneity in the underlying genetic etiology, enabling risk allele identification. Our approach emphasizes the power of African genetic variation and admixture analysis to inform the architecture of complex disorders.

Death at the interface: Nanotechnology's challenging frontier against microbial surface colonization.

The emergence of antimicrobial-resistant bacterial strains has led to novel approaches for combating bacterial infections and surface contamination. More specifically, efforts in combining nanotechnology and biomimetics have led to the development of next-generation antimicrobial/antifouling nanomaterials. While nature-inspired nanoscale topographies are known for minimizing bacterial attachment through surface energy and physicochemical features, few studies have investigated the combined inhibitory effects of such features in combination with chemical alterations of these surfaces. Studies describing surface alterations, such as quaternary ammonium compounds (QACs), have also gained attention due to their broad spectrum of inhibitory activity against bacterial cells. Similarly, antimicrobial peptides (AMPs) have exhibited their capacity to reduce bacterial viability. To maximize the functionality of modified surfaces, the integration of patterned surfaces and functionalized exteriors, achieved through physical and chemical surface alterations, have recently been explored as viable alternatives. Nonetheless, these modifications are prone to challenges that can reduce their efficacy considerably in the long term. Their effectiveness against a wider array of microbial cells is still a subject of investigation. This review article will explore and discuss the emerging trends in biomimetics and other antimicrobials while raising possible concerns about their limitations and discussing future implications regarding their potential combined applications.

Do you know your ceramics? Part 5: zirconia.

Zirconia has increasingly become the ceramic material of choice, satisfying the desired criteria of both optical and physical properties. Zirconia, the ceramic steel, has immense strength and toughness, which is ideal for restorations in posterior regions. Development of the material has improved the optical properties, enabling it to be a potential option for anterior indirect restorations. By exploring the microstructure that influences the material properties, clinicians can confidently select the material most suitable.

Do you know your ceramics? Part 4: alumina.

Alumina is a well-known dental ceramic material that has made waves within the dental industry for its good aesthetics and strength when compared to older materials for fixed prostheses, such as crown and bridgework. To be able to confidently use this material, a clinician should understand the physical and optical properties so as to know why and how this material might work in various clinical settings. This part of the ceramic series aims to explore the various alumina-based ceramic systems available on the market and discuss their properties, applications and indications. We also intend to briefly describe the preparation design requirements and cementation protocol for this type of ceramic.

Do you know your ceramics? Part 1: classification.

This is the first part of a six-part series exploring the main ceramic materials used for the fabrication of all-ceramic, indirect restorations to aid clinicians in their selection. We have detailed the history of how dental ceramics were introduced and how they have been revolutionised with the help of improvements within technology and understanding of the material. Dental ceramics can be classified in a few ways. One way is according to their ratio of glass to crystalline content and the other is how it is processed. Having a good in-depth understanding of this will allow clinicians to make the best decision for their patients who require ceramic restorations. This article aims to explore all the above to aid clinicians in making that decision.

Do you know your ceramics? Part 3: lithium disilicate.

Lithium disilicate has become very popular and is very commonly used, especially for highly aesthetic cases. It has also proven to be a very durable material and can be used in a variety of clinical situations. It is important as a clinician, technician or ceramist to be able to confidently use this material by appreciating the detail in its construction. The microstructure has a significant impact on the optical and physical properties of this material. Hence, before the prescription of this type of restoration, it is imperative to be knowledgeable in this aspect. This article explores lithium disilicate as a dental ceramic material in detail.