Alpha-thalassemia intellectual disability: variable phenotypic expression among males with a recurrent nonsense mutation - c.109C>T (p.R37X).

Alpha-thalassemia intellectual disability, one of the recognizable X-linked disability syndromes, is characterized by short stature, microcephaly, distinctive facies, hypotonic appearance, cardiac and genital anomalies, and marked skewing of X-inactivation in female carriers. With the advent of next generation sequencing, mutations have been identified that result in less severe phenotypes lacking one or more of these phenotypic manifestations. Here we report five unrelated kindreds in which a c.109C>T (p.R37X) mutation segregates with a variable but overall milder phenotype. The distinctive facial appearance of alpha-thalassemia intellectual disability was present in only one of the 18 affected males evaluated beyond the age of puberty, although suggestive facial appearance was present in several during infancy or early childhood. Although the responsible genetic alteration is a nonsense mutation in exon 2 of ATRX, the phenotype appears to be partially rescued by the production of alternative transcripts and/or other molecular mechanisms.

Disruption of gut barrier integrity and host-microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus.

Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Deuterium uptake in magnetic-fusion devices with lithium-conditioned carbon walls.

Lithium wall conditioning has lowered hydrogenic recycling and dramatically improved plasma performance in many magnetic-fusion devices. In this Letter, we report quantum-classical atomistic simulations and laboratory experiments that elucidate the roles of lithium and oxygen in the uptake of hydrogen in amorphous carbon. Surprisingly, we show that lithium creates a high oxygen concentration on a carbon surface when bombarded by deuterium. Furthermore, surface oxygen, rather than lithium, plays the key role in trapping hydrogen.

Trends and causes of severity, size, and number of fires in northwestern California, USA.

Research in the last several years has indicated that fire size and frequency are on the rise in western U.S. forests. Although fire size and frequency are important, they do not necessarily scale with ecosystem effects of fire, as different ecosystems have different ecological and evolutionary relationships with fire. Our study assessed trends and patterns in fire size and frequency from 1910 to 2008 (all fires > 40 ha), and the percentage of high-severity in fires from 1987 to 2008 (all fires > 400 ha) on the four national forests of northwestern California. During 1910-2008, mean and maximum fire size and total annual area burned increased, but we found no temporal trend in the percentage of high-severity fire during 1987-2008. The time series of severity data was strongly influenced by four years with region-wide lightning events that burned huge areas at primarily low-moderate severity. Regional fire rotation reached a high of 974 years in 1984 and fell to 95 years by 2008. The percentage of high-severity fire in conifer-dominated forests was generally higher in areas dominated by smaller-diameter trees than in areas with larger-diameter trees. For Douglas-fir forests, the percentage of high-severity fire did not differ significantly between areas that re-burned and areas that only burned once (10% vs. 9%) when re-burned within 30 years. Percentage of high-severity fire decreased to 5% when intervals between first and second fires were > 30 years. In contrast, in both mixed-conifer and fir/high-elevation conifer forests, the percentage of high-severity fire was less when re-burned within 30 years compared to first-time burned (12% vs. 16% for mixed conifer; 11% vs. 19% for fir/high-elevation conifer). Additionally, the percentage of high-severity fire did not differ whether the re-burn interval was less than or greater than 30 years. Years with larger fires and greatest area burned were produced by region-wide lightning events, and characterized by less winter and spring precipitation than years dominated by smaller human-ignited fires. Overall percentage of high-severity fire was generally less in years characterized by these region-wide lightning events. Our results suggest that, under certain conditions, wildfires could be more extensively used to achieve ecological and management objectives in northwestern California.

A multi-national survey of experience and attitudes towards commencing home parenteral nutrition for patients with advanced cancer.

INTRODUCTION: Advanced cancer (AC) is increasingly an indication for home parenteral nutrition (HPN) but an area with possible variation in practice between geographical locations. The aims of this study are to explore the views and experiences of international multi-disciplinary teams to determine opinions and practices. METHODS: An online questionnaire was developed with members of the Home Artificial Nutrition and Chronic Intestinal Failure interest group of the European Society for Clinical Nutrition and Metabolism (ESPEN) and distributed to colleagues involved in managing patients with AC on HPN. RESULTS: A total of 220 responses were included from 5 continents including 36 countries, with 90% of all responses from Europe. Predicted survival was a key factor influencing the decision to commence HPN for most respondents 152/220 (75%), with the majority of participants reporting that patients should have a predicted survival of ≥3 months if considered for HPN (≥3 months: n = 124, 56% vs. <3 months: n = 47, 21%, p < 0.001). However, most respondents were not confident about predicting overall survival in more than 50% of cases (confident n = 40, 23% vs not confident n = 135, 77%, p < 0.001). Barriers to utilising HPN in AC included colleagues' objections (n = 91, 46%), lack of local expertise (n = 55, 28%) and funding restrictions (n = 34, 17%). CONCLUSIONS: Significant consensus was observed regarding AC as indication for HPN, while areas of variation exist. Survival prognostication is often used as an indication for commencing HPN in people with AC, although the majority of respondents were not confident in prognosticating, suggesting better clinical prognostication tools will be of assistance. Further studies are also required to better understand the obstacles faced by clinical teams to commencing HPN that may explain variations in clinical practice between countries, as well as adressing variation in funding.

Use of local anesthesia for inguinal hernia repair has decreased over time in the VA system.

PURPOSE: In 2003, randomized trials demonstrated potentially improved outcomes when local instead of general anesthesia is used for inguinal hernia repair. Our study aimed to evaluate how the use of local anesthesia for this procedure changed over time following the publication of the trials' level 1 evidence. METHODS: We used the 1998-2018 Veterans Affairs Surgical Quality Improvement Program database to identify adults who underwent open, unilateral inguinal hernia repair under local or general anesthesia. Our primary outcome was the percentage of cases performed under local anesthesia. We used a time-series design to examine the trend and rate of change of the use of local anesthesia. RESULTS: We included 97,437 veterans, of which 22,333 (22.9%) had hernia surgery under local anesthesia. The median age of veterans receiving local anesthesia remained stable at 64-67 years over time. The use of local anesthesia decreased steadily, from 38.2% at the beginning year to 15.1% in the final year (P < 0.0001). The publication of results from randomized trials (in 2003) did not appear to increase the overall use or change the rate of decline in the use of local anesthesia. Overall, we found that the use of local anesthesia decreased by about 1.5% per year. CONCLUSION: The utilization of local anesthesia for inguinal hernia repair in the VA has steadily declined over the last 20 + years, despite data showing equivalence or superiority to general anesthesia. Future studies should explore barriers to the use of local anesthesia for hernia repair.

Continuous improvement of H-mode discharge performance with progressively increasing lithium coatings in the National Spherical Torus Experiment.

Lithium wall coatings have been shown to reduce recycling, improve energy confinement, and suppress edge localized modes in the National Spherical Torus Experiment. Here, we show that these effects depend continuously on the amount of predischarge lithium evaporation. We observed a nearly monotonic reduction in recycling, decrease in electron transport, and modification of the edge profiles and stability with increasing lithium. These correlations challenge basic expectations, given that even the smallest coatings exceeded that needed for a nominal thickness of the order of the implantation range.

Death and illness as depicted in the media.

INTRODUCTION: The media may affect how illness is perceived, in terms of its prevalence, severity and outcomes. The media also influences our perception of death and leads to an overestimation of incidence of some causes of mortality. Articles depicting medical subjects may not be in-depth and are often influenced by non-medical issues. The media has both a positive impact on the population, in providing opportunistic health information, and a negative impact, causing an overestimation of severity and incidence of certain diseases. This article aims to assess if media reporting of illness and death represents national statistics. METHOD: The 10 most common daily read UK newspapers were assessed for articles relating to the most common causes of UK mortality. The searches were performed via each newspaper's online search facility over a 12-month period. Where appropriate, media friendly terms were used as search terms. RESULTS: A total of 18,482 pertinent articles were found relating to the most common causes of death in the UK. When the reportage of illness was compared with the actual incidence cerebrovascular accidents and chronic obstructive pulmonary disease were under-represented in the media, with ratios 0.31 and 0.01 to 1, respectively. Flu/pneumonia, prostate cancer, dementia and breast cancer all have a large media profile, with ratios of 5.52, 3.06, 4.09 and 4.9 to 1, respectively. CONCLUSION: The media has a significant impact on our perceptions of illness and death. This may influence how patients seek medical attention and their concerns at consultation. Strategies to improve the educational content of the media may enhance the dissemination of health information via this resource.

Pharmacy-Led Medication Reconciliation Program Reduces Adverse Drug Events and Improves Satisfaction in a Community Hospital.

Background: Pharmacy-led medication reconciliation identifies and corrects medication errors that can potentially cause moderate to severe harm. This research sought to identify the impact of pharmacy-led medication reconciliation on patient outcomes and describe the changes in healthcare workers' perceptions of the program. Methods: A pharmacy-led admission medication reconciliation program pilot started in July 2019, and a discharge medication reconciliation proof of concept was tested in September 2020 at a 432-bed hospital. The following periods were compared: August 2018 to February 2019 (pre-program implementation) and August 2019 to February 2020 (post-program implementation). Endpoints included patient outcomes, workforce productivity and interdisciplinary healthcare team satisfaction through program surveys. Patient outcomes were assessed with chisquared tests. Survey responses were assessed using the Likert scale. Descriptive statistics were used for productivity outcomes and the number of discharge medication reconciliations completed. Results: Approximately 18,000 admissions were recorded for each period. The adverse drug event (ADE) rate decreased 49% (p < 0.001), and the complication rate decreased 29.7% (p = 0.001). During post-pilot implementation, 6,530 medication histories were completed, and 70,050 medications were reviewed. Of medication histories completed, 22.6% of patient allergies/adverse drug reactions were updated, 52.3% of medications were clarified, and 54.7% of preferred outpatient pharmacies were updated. Pharmacy services completed medication histories in 38.8% of inpatients. In the proof of concept, 168 discharge medication lists were drafted. Survey results showed statistically significant improvement in healthcare team satisfaction. Conclusion: A pharmacy-led medication reconciliation program involving designated pharmacists and pharmacy technicians has shown to decrease ADEs and complications while improving interdisciplinary healthcare team satisfaction.

Offshore pelagic subsidies dominate carbon inputs to coral reef predators.

Coral reefs were traditionally perceived as productive hot spots in oligotrophic waters. While modern evidence indicates that many coral reef food webs are heavily subsidized by planktonic production, the pathways through which this occurs remain unresolved. We used the analytical power of carbon isotope analysis of essential amino acids to distinguish between alternative carbon pathways supporting four key reef predators across an oceanic atoll. This technique separates benthic versus planktonic inputs, further identifying two distinct planktonic pathways (nearshore reef-associated plankton and offshore pelagic plankton), and revealing that these reef predators are overwhelmingly sustained by offshore pelagic sources rather than by reef sources (including reef-associated plankton). Notably, pelagic reliance did not vary between species or reef habitats, emphasizing that allochthonous energetic subsidies may have system-wide importance. These results help explain how coral reefs maintain exceptional productivity in apparently nutrient-poor tropical settings, but also emphasize their susceptibility to future ocean productivity fluctuations.

Microdeletion 15q13.3: a locus with incomplete penetrance for autism, mental retardation, and psychiatric disorders.

BACKGROUND: Microdeletions within chromosome 15q13.3 are associated both with a recently recognised syndrome of mental retardation, seizures, and dysmorphic features, and with schizophrenia. METHODS AND RESULTS: Based on routine diagnostic testing of approximately 8200 samples using array comparative genomic hybridisation, we identified 20 individuals (14 children and six parents in 12 families) with microdeletions of 15q13.3. Phenotypes in the children included developmental delay, mental retardation, or borderline IQ in most and autistic spectrum disorder (6/14), speech delay, aggressiveness, attention deficit hyperactivity disorder, and other behavioural problems. Both parents were available in seven families, and the deletion was de novo in one, inherited from an apparently normal parent in four, and inherited from a parent with learning disability and bipolar disorder in two families. Of the 14 children, six in five families were adopted, and DNA was available for only one of these 10 biological parents; the deletion was very likely inherited for one of these families with two affected children. Among the unavailable parents, two mothers were described as having mental retardation, another mother as having "mental illness", and one father as having schizophrenia. We hypothesise that some of the unavailable parents have the deletion. CONCLUSIONS: The occurrence of increased adoption, frequent autism, bipolar disorder, and lack of penetrance are noteworthy findings in individuals with deletion 15q13.3. A high rate of adoption may be related to the presence of the deletion in biological parents. Unconfirmed histories of antisocial behaviours in unavailable biological parents raise the concern that future research may show that deletion 15q13.3 is associated with such behaviours.

Soft x-ray lasers and their applications.

The emerging technology of soft x-ray lasers has novel applications to microscopy, lithography, and other fields. This article describes the status of soft x-ray laser research with the aim of bringing the rapid developments in this field to the attention of potential users in other disciplines. The different techniques for generating a population inversion and producing a soft x-ray laser are reviewed. The status of current research in the field and the near-term prospects are described. It is expected that the range of potential applications of soft x-ray lasers will increase as their performance improves. Work aimed at increasing the output power and progressing to shorter wavelengths with these devices is also reviewed.

Signal transduction and gene expression in cultured accessory olfactory bulb neurons.

Glutamate and norepinephrine (NE) are believed to mediate the long-lasting synaptic plasticity in the accessory olfactory bulb (AOB) that underlies pheromone recognition memory. The mechanisms by which these neurotransmitters bring about the synaptic changes are not clearly understood. In order to study signals that mediate synaptic plasticity in the AOB, we used AOB neurons in primary culture as a model system. Because induction of pheromone memory requires coincident glutamatergic and noradrenergic input to the AOB, and requires new protein synthesis, we reasoned that glutamate and NE must induce gene expression in the AOB. We used a combination of agonists that stimulate alpha1 and alpha2 adrenergic receptors in combination with N-methyl-d-aspartic acid and tested expression of the immediate-early gene (IEG) c-Fos. We found that the glutamatergic and noradrenergic stimulation caused significant induction of c-Fos mRNA and protein. Induction of c-Fos was significantly reduced in the presence of inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) and phospholipase C. These results suggest that glutamate and NE induce gene expression in the AOB through a signaling pathway mediated by protein kinase C and MAPK.

Factors associated with African Americans' enrollment in a national cancer genetics registry.

This study explored whether reactions to the Cancer Genetics Network (CGN) or CGN enrollment differed by receipt of a standard informational brochure versus a targeted version addressing factors previously associated with African Americans' health behavior decisions and research participation. The 262 participants, identified through tumor registries or clinic contacts, were mailed brochures and completed phone interviews. When asked whether - based on the brochure - they were or were not 'leaning toward' CGN enrollment, about 75% of both standard and targeted groups reported leaning toward. When given the opportunity at the end of the interview, 68% enrolled in the CGN. Trust was strongly related to enrollment. Less education, less satisfaction with cancer care, and individualistic rather than collective orientation were associated with lower trust. Education was also bivariately associated with enrollment, but mediation analysis indicated that the operational mechanism of education's influence on enrollment was through trust.

Unraveling wall conditioning effects on plasma facing components in NSTX-U with the Materials Analysis Particle Probe (MAPP).

A novel Plasma Facing Components (PFCs) diagnostic, the Materials Analysis Particle Probe (MAPP), has been recently commissioned in the National Spherical Torus Experiment Upgrade (NSTX-U). MAPP is currently monitoring the chemical evolution of the PFCs in the NSTX-U lower divertor at 107 cm from the tokamak axis on a day-to-day basis. In this work, we summarize the methodology that was adopted to obtain qualitative and quantitative descriptions of the samples chemistry. Using this methodology, we were able to describe all the features in all our spectra to within a standard deviation of ±0.22 eV in position and ±248 s-1 eV in area. Additionally, we provide an example of this methodology with data of boronized ATJ graphite exposed to NSTX-U plasmas.

Molecular testing (strand displacement assay) for identification of urethral gonorrhoea in men: can it replace culture as the gold standard?

The objective was to evaluate the performance of Becton Dickinson's BD Probe Tec(TM) (BDPT) strand displacement amplification (SDA) test for the detection of Neisseria gonorrhoeae on urethral specimens from men with urethritis compared with conventional culture and to show that SDA improves the diagnostic yield of gonorrhoea infections (GC). Anonymized retrospective testing of stored urethral swab samples from men attending genitourinary services in East London was performed using SDA. The prevalence of GC culture positive infections in this sample was 20/152 (13%). The sensitivity, specificity, positive predictive value and negative predictive value for the BDPT-SDA system compared with culture were 100%, 95%, 77% and 100%, respectively. In this study population, the BDPT-SDA assay was a highly sensitive and specific test for the diagnosis of N. gonorrhoeae from urethral swabs in men. Therefore, SDA can be used to complement culture in the diagnosis of N. gonorrhoeae infection. No ethics committee approval was obtained as all samples were anonymized.

Women's interest in chemoprevention for breast cancer.

BACKGROUND: Chemoprevention is the use of pharmacologic or natural agents to inhibit the development of cancer. Tamoxifen citrate is the only approved chemopreventive agent for breast cancer. We sought to determine whether women are interested in taking a drug to prevent breast cancer and to assess the relationship between objective and subjective breast cancer risk and interest in chemoprevention. METHODS: We conducted telephone interviews (November 3, 1997, to May 6, 1998) among a community sample of women aged 40 to 45 and 50 to 55 years enrolled in a randomized controlled trial to evaluate the efficacy of a tailored mammography decision aid. Objective breast cancer risk was measured using the 5-year Gail score. Subjective breast cancer risk was measured using perceptions of absolute risk, perceptions of comparative risk, and worry about getting breast cancer. At 12-month follow-up (November 2, 1998, to July 20, 1999), we measured interest in taking a drug to prevent breast cancer. RESULTS: Among the 1273 women surveyed, 23% were interested in taking a drug to prevent breast cancer; 8% were potentially eligible for tamoxifen therapy (5-year Gail score > or = 1.66%). Eligibility for chemoprevention, based on the 5-year Gail score, was not associated with interest in taking a drug to prevent breast cancer. Women who were worried about breast cancer were 3 times more likely to be interested in taking a drug to prevent breast cancer than those who were not worried. CONCLUSION: Women's interest in chemoprevention might arise more from worries about getting breast cancer than from their objective risk factors.

Valuing empathy and emotional intelligence in health leadership: a study of empathy, leadership behaviour and outcome effectiveness.

This article examines the relationship between health managers' self-assessed empathy, their leadership behaviours as rated by their staff, and staff's personal ratings on a range of work satisfaction and related outcome measures. Empathy was conceived of as four distinct but related individual dispositions, namely empathic concern (EC), perspective taking (PT), personal distress (PD) and empathic matching (EM). Results showed three empathy scales (EC, PT and EM) were, as postulated, positively related to transformational behaviour (inspiring followers to achieve more than expected). The same three measures, also as expected, showed no relationship to transactional behaviour (motivating followers to achieve expected results) and were negatively associated with laissez-faire leadership (an absence of leadership style). Relationships between empathy scales and outcome measures were selective and moderate in size. Strongest empathy association was evident between the PT scale and most outcome measures. Conversely, the extra effort outcome appeared most sensitive to the range of empathy scales. Where significant relationships did exist between empathy and outcome, leadership behaviour was in all cases a perfect mediator. Whilst not denying the smaller dispositional effects on leadership outcomes, leadership behaviour itself, rather than individual traits such as empathy, appear to be major influencing factors in leadership effectiveness.

Single strand conformation polymorphism (SSCP) analysis for the detection of mutations in the CYP11B1 gene.

The adrenal 11 beta-hydroxylase is a mitochondrial P450 enzyme encoded by the CYP11B1 gene, which is situated on chromosome 8q22 in tandem with the gene for aldosterone synthase (CYP11B2). Deficiency of 11 beta-hydroxylase results in the inability to convert 11-deoxycortisol to cortisol and accounts for 5-8% of cases of congenital adrenal hyperplasia. In the following study the CYP11B1 genes from eight individuals with 11 beta-hydroxylase deficiency were screened for mutations using single strand conformation polymorphism (SSCP) analysis. Sequence analysis of variant exons revealed a 28 bp deletion and a 5 bp duplication exon 2 and five missense mutations, G267R, G267D, Q356X, R427H and C494F, distributed throughout the gene. One of these mutations, G267R, and a G to A transversion at the third nucleotide position of codon 318 occur at the +1 position of the splice donor sites. Mutations were neither the result of gene conversion nor nonhomologous recombination between the two closely related CYP11B genes.

Racemic diastereoisomers of 1-amino-2-hydroxycyclopentanecarboxylic acid.

The synthesis and characterization of the two diastereoisomeric forms of 1-amino-2-hydroxycyclopentanecarboxylic acid have been accomplished. A previously reported synthesis produced a racemic mixture of the threonine analog trans-2-hydroxy-1-aminocyclopentanecarboxylic acid (trans with respect to the hydroxy and carboxyl group). The alternate allothreonine analog was produced by conversion of cyclopentene oxide to trans-2-methoxycyclopentanol, followed by oxidation to 2-methoxycyclopentanone and conversion to a hydantoin. Fractional crystallization of the hydantoin sample, followed by hydrolysis, produced cis-2-hydroxy-1-aminocyclopentanecarboxylic acid (cis with respect to the hydroxy and carboxyl group) in high purity. Neither of the isomeric forms significantly inhibited the growth of the bacterial strains examined nor were they effective in inhibiting Jensen sarcoma cells in tissue culture.