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Clozapine-induced gastrointestinal hypomotility (CIGH) affects some 75% of patients treated with clozapine. To document the incidence of potentially harmful CIGH in the UK. We studied spontaneous UK pharmacovigilance reports recorded as clozapine-related gastrointestinal adverse drug reactions, 1992-2017. There were 527 patients reported with potentially harmful CIGH; 33% ( = 172) died. Deaths averaged 1 per year 1992-1999, 5 per year 2000-2009 and 15 per year 2010-2017. Those who died were older (median 52 years 49 years) and had been prescribed clozapine for longer than those who recovered (median 11.3 years . 4.8 years), but there was no difference in prescribed dose. Within the first 4 years of clozapine treatment, there were 169 reports of CIGH, of which 3% ( = 5) were fatal. At 10-14 years there were 63 reports of CIGH, of which 25% ( = 16) were fatal. Among the deaths, males were younger (median 51, range 22-89 . median 57, range 24-89 years) with higher clozapine doses (median 450, range 100-900 . median 300, range 12.5-800 mg/d) than females. In non-fatal CIGH, surgery was the most frequent outcome ( = 92). The procedures included appendectomy, ileostomy, total/partial colectomy, colostomy/stoma and proctosigmoidectomy. Clozapine dosage was reduced in 6 patients, stopped and restarted in 23, 'continued' in 6 and discontinued permanently in at least 76 patients. The risk of serious morbidity/mortality from CIGH is substantial. The need to actively monitor bowel function and give laxatives to patients treated with clozapine is clear.

Raman spectroscopy is utilised extensively in pharmaceutical analysis for tasks such as drug discovery, quality control and active pharmaceutical ingredient (API) development. Despite this, access to open-source Raman spectral datasets for modelling and analysis is often a challenge. In laboratory settings, small spectral libraries are typically compiled for one-shot identification of intermediates or unknown chemicals, which restricts availability to comprehensive and high-quality reference data. In this work, we introduce a new open-source Raman dataset consisting of pure chemical compounds commonly employed in the development of APIs. By curating and publishing this dataset, we aim to provide the scientific community with access to high-quality, reusable data. Containing 3,510 samples spanning 32 compounds, this data can be utilised for referencing and can potentially facilitate in the development of more accurate and generalisable calibration models when access to reference data is limited.

Administration of levodopa for Parkinson’s disease (PD) has remained the most effective therapy for symptom management despite being in use for over 50 years. Advancing disease and age, changing tolerability and gastrointestinal (GI) dysfunction may result in change in dietary habits and body weight, as well as unpredictable motor fluctuations and dyskinesias. Dietary proteins which convert into amino acids after digestion are implicated as major factors that inhibit levodopa absorption. For people living with PD (PwP) who experience motor fluctuations, low protein diets (LPD) and protein redistribution diets (PRD) may be effective and are often recommended as a non-pharmacologic approach for improving levodopa bioavailability. However, there is a lack of consensus on a standard definition of these diets and appropriate treatment algorithms for usage. This may be due to the paucity of high-level evidence of LPD and PRD in PwP and whether all or specific subgroups of patients would benefit from these strategies. Managing diet and protein intake with proper education and monitoring may reduce complications associated with these diets such as dyskinesias and unintentional weight loss. Additionally, alterations to medications and GI function may alter levodopa pharmacokinetics. In this narrative review we focus on 1) mechanisms of dietary protein and levodopa absorption in the intestine and blood brain barrier, 2) dietetic approaches to manage protein and levodopa interactions and 3) practical issues for treating PwP as well as future directions to be considered.

Whether to commit limited cellular resources toward growth and proliferation, or toward survival and stress responses, is an essential determination made by Target of Rapamycin Complex 1 (TORC1) for a eukaryotic cell in response to favorable or adverse conditions. Loss of TORC1 function is lethal. The TORC1 inhibitor rapamycin that targets the highly conserved Tor kinase domain kills fungal pathogens like Candida albicans , but is also severely toxic to human cells. The least conserved region of fungal and human Tor kinases are the N-terminal HEAT domains. We examined the role of the 8 most N-terminal HEAT repeats of C . albicans Tor1. We compared nutritional- and stress responses of cells that express a message for N-terminally truncated Tor1 from repressible tetO , with cells expressing wild type TOR1 from tetO or from the native promoter. Some but not all stress responses were significantly impaired by loss of Tor1 N-terminal HEAT repeats, including those to oxidative-, cell wall-, and heat stress; in contrast, plasma membrane stress and antifungal agents that disrupt plasma membrane function were tolerated by cells lacking this Tor1 region. Translation was inappropriately upregulated during oxidative stress in cells lacking N-terminal Tor1 HEAT repeats despite simultaneously elevated Gcn2 activity, while activation of the oxidative stress response MAP kinase Hog1 was weak. Conversely, these cells were unable to take advantage of favorable nutritional conditions by accelerating their growth. Consuming oxygen more slowly than cells containing wild type TOR1 alleles during growth in glucose, cells lacking N-terminal Tor1 HEAT repeats additionally were incapable of utilizing non-fermentable carbon sources. They were also hypersensitive to inhibitors of specific complexes within the respiratory electron transport chain, suggesting that inefficient ATP generation and a resulting dearth of nucleotide sugar building blocks for cell wall polysaccharides causes cell wall integrity defects in these mutants. Genome-wide expression analysis of cells lacking N-terminal HEAT repeats showed dysregulation of carbon metabolism, cell wall biosynthetic enzymes, translational machinery biosynthesis, oxidative stress responses, and hyphal- as well as white-opaque cell type-associated genes. Targeting fungal-specific Tor1 N-terminal HEAT repeats with small molecules might selectively abrogate fungal viability, especially when during infection multiple stresses are imposed by the host immune system.

The UK Government decision to close its Forensic Science Service (FSS) in 2010 left the criminal justice system in England and Wales bereft of impartial, high-level scientific support. The private sector was entrusted to fill the gap and to ensure that all results were accurate, timely, fit for purpose, easy to interpret, and above all gave value for money. In the event, however, a major provider has collapsed necessitating a rescue deal to minimise the impact of the fiasco. Moreover, there have been allegations of data manipulation in another private sector laboratory and possible falsification of evidence in a laboratory set up by a police force in an attempt to fill the gap left by the FSS. As to the future, appropriate laboratory regulation and inspection clearly has a part to play, but ironically ‘quality management’ adds an unnecessary and ever-increasing cost burden that may detract from quality. What is really needed are systems that combine public service and professional integrity with research and development. Involving investigators, coroners/medical examiners/judges, and prosecution and defence lawyers in educational fora would help build cross-professional co-operation and understanding.

BackgroundHomozygous inheritance of a single-nucleotide polymorphism (1245A > C) in HSD3B1 results in an adrenal permissive phenotype of increased adrenal steroid precursor conversion to potent androgens. This is associated with poor outcomes in prostate cancer. We hypothesized that inheritance of the HSD3B1 adrenal permissive genotype would similarly negatively impact breast cancer outcomes.Patients and MethodsGermline HSD3B1 was sequenced in 644 postmenopausal women diagnosed between 2004 and 2015 with stage I–III estrogen receptor-positive (ER+), HER2/neu-negative (HER2−) breast cancer enrolled in a population-based study in western Washington. Primary endpoint was distant metastatic recurrence according to genotype. Secondary endpoint was breast cancer-specific survival. Hazard ratios (HR) were calculated using cause-specific Cox regression accounting for competing risks.ResultsAdrenal restrictive genotype (homozygous wild type) was most prevalent (47%), followed by heterozygous (44%) and adrenal permissive (9%). There were no significant differences comparing demographic, tumor, or treatment characteristics apart from higher frequency of adrenal permissive genotype among non-Hispanic white participants (p = 0.04). After accounting for competing risks, the cumulative incidence of distant metastatic recurrence (15 events) was significantly higher among participants with adrenal permissive compared with the adrenal restrictive genotype (HR 4.9, 95% CI 1.32–18.4, p = 0.02). The adrenal permissive genotype was also predictive of breast cancer-specific mortality (HR 3.5, 95% CI 1.27–9.59, p = 0.02).ConclusionsInheritance of the HSD3B1 adrenal permissive genotype is associated with increased incidence of distant metastasis and higher cause-specific mortality in postmenopausal ER+/HER2− breast cancer. Further research is necessary to understand the effect of excess adrenal androgen metabolism in promoting breast cancer growth and progression.

Radiation detectors installed at major ports of entry are a key component of the overall strategy to protect countries from nuclear terrorism. While the goal of deploying these systems is to intercept special nuclear material as it enters the country, no detector system is foolproof. Mobile, distributed sensors have been proposed to detect nuclear materials in transit should portal monitors fail to prevent their entry in the first place. In large metropolitan areas, a mobile distributed sensor network could be deployed using vehicle platforms such as taxis, Ubers, and Lyfts, which are already connected to communications infrastructure. However, performance and coverage that could be achieved using a network of sensors mounted on commercial passenger vehicles has not been established. Here, we evaluate how a mobile sensor network could perform in New York City using a combination of radiation transport and geographic information systems. The geographic information system is used in conjunction with OpenStreetMap data to isolate roads and construct a grid over the streets. Vehicle paths are built using pickup and drop off data from Uber, and from the New York State Department of Transportation. The results show that the time to first detection increases with source velocity, decreases with the number of mobile detectors, and reaches a plateau that depends on the strength of the source.

The Candida albicans genome contains between ten and fifteen distinct TLO genes that all encode a Med2 subunit of Mediator. In order to investigate the biological role of Med2/Tlo in C . albicans we deleted all fourteen TLO genes using CRISPR-Cas9 mutagenesis. ChIP-seq analysis showed that RNAP II localized to 55% fewer genes in the tlo Δ mutant strain compared to the parent, while RNA-seq analysis showed that the tlo Δ mutant exhibited differential expression of genes required for carbohydrate metabolism, stress responses, white-opaque switching and filamentous growth. Consequently, the tlo Δ mutant grows poorly in glucose- and galactose-containing media, is unable to grow as true hyphae, is more sensitive to oxidative stress and is less virulent in the wax worm infection model. Reintegration of genes representative of the α-, β- and γ- TLO clades resulted in the complementation of the mutant phenotypes, but to different degrees. TLOα1 could restore phenotypes and gene expression patterns similar to wild-type and was the strongest activator of glycolytic and Tye7-regulated gene expression. In contrast, the two γ- TLO genes examined ( i . e ., TLO γ 5 and TLO γ 11 ) had a far lower impact on complementing phenotypic and transcriptomic changes. Uniquely, expression of TLO β 2 in the tloΔ mutant stimulated filamentous growth in YEPD medium and this phenotype was enhanced when Tloβ2 expression was increased to levels far in excess of Med3. In contrast, expression of reintegrated TLO genes in a tlo Δ/ med3Δ double mutant background failed to restore any of the phenotypes tested, suggesting that complementation of these Tlo-regulated processes requires a functional Mediator tail module. Together, these data confirm the importance of Med2/Tlo in a wide range of C . albicans cellular activities and demonstrate functional diversity within the gene family which may contribute to the success of this yeast as a coloniser and pathogen of humans.

Objective: To assess associations between primary cesarean delivery and adverse delivery outcomes with very advanced maternal age. Study Design: We conducted a population-based cohort study including 78 880 births to mothers 25 years and older with singleton births from 2003 to 2012 using Washington State birth certificates and hospital discharge data, excluding births to women with a prior cesarean section. The primary outcome was mode of delivery. Secondary outcomes included maternal transfusion, chorioamnionitis, severe perineal lacerations and prolonged length of stay. Outcomes of births to women of advanced maternal age (35 to 39, 40 to 44) and very advanced maternal age (45 to 49, ⩾50) were compared with referent births among women aged 25 to 34 years. General linear models with a log-link function were used to calculate unadjusted and adjusted relative risks and 95% confidence intervals (CIs). Result: Proportions and risks of primary cesarean section increased with age (25 to 34 years, referent: 20.0%; 35 to 39 years: 25.9%, relative risk (RR)=1.25 (95% CI=1.20 to 1.29); 40 to 44 years: 30.9%, RR=1.45 (95% CI=1.40 to 1.50); 45 to 49 years: 35.7%, RR=1.59 (95% CI=1.45 to 1.75); and ⩾50 years: 60.7%, RR=2.44 (95% CI=1.95 to 3.05); P -trend <0.001). Associations did not differ between primiparous and multiparous women. No differences were noted for measures of maternal morbidity, except there was a trend of increasing risk of prolonged length of stay among births to older women ( P -trend <0.001). Conclusion: Primary cesarean delivery risk continues to increase above age 35 regardless of prior vaginal birth, with the highest risk among women aged 50 years and older.

Concern about the possibility of inadequate resection and recurrent cancer with the use of laparoscopically assisted colectomy prompted this randomized trial comparing laparoscopically assisted with open surgery for colon cancer. The trial involved 863 patients and 66 surgeons at 48 hospitals. Rates of cancer recurrence, operative complications, and survival were similar in the two groups. Laparoscopically assisted surgery is an acceptable alternative to open surgery for colon cancer. Minimally invasive surgery revolutionized the way operations were performed. Gallbladder procedures that previously required long incisions and extended periods of hospitalization were transformed through the use of laparoscopic techniques. 1 , 2 The possibility that this approach could benefit patients undergoing colectomy for colon cancer was first considered in 1990. 3 However, a number of cancer-specific questions arose, including the following: Could minimally invasive surgery achieve a proper oncologic resection, with the same extent of exploration and information about lymph-node staging provided by a standard open resection? Were patterns of tumor-cell dissemination altered or enhanced by the use of laparoscopic techniques? These concerns . . .