Neuroinvasive Bacillus cereus Infection in Immunocompromised Hosts: Epidemiologic Investigation of 5 Patients With Acute Myeloid Leukemia.

Background: Bacillus cereus is a ubiquitous gram-positive rod-shaped bacterium that can cause sepsis and neuroinvasive disease in patients with acute leukemia or neutropenia. Methods: A single-center retrospective review was conducted to evaluate patients with acute leukemia, positive blood or cerebrospinal fluid test results for B cereus, and abnormal neuroradiographic findings between January 2018 and October 2022. Infection control practices were observed, environmental samples obtained, a dietary case-control study completed, and whole genome sequencing performed on environmental and clinical Bacillus isolates. Results: Five patients with B cereus neuroinvasive disease were identified. All patients had acute myeloid leukemia (AML), were receiving induction chemotherapy, and were neutropenic. Neurologic involvement included subarachnoid or intraparenchymal hemorrhage or brain abscess. All patients were treated with ciprofloxacin and survived with limited or no neurologic sequelae. B cereus was identified in 7 of 61 environmental samples and 1 of 19 dietary protein samples-these were unrelated to clinical isolates via sequencing. No point source was identified. Ciprofloxacin was added to the empiric antimicrobial regimen for patients with AML and prolonged or recurrent neutropenic fevers; no new cases were identified in the ensuing year. Conclusions: B cereus is ubiquitous in the hospital environment, at times leading to clusters with unrelated isolates. Fastidious infection control practices addressing a range of possible exposures are warranted, but their efficacy is unknown and they may not be sufficient to prevent all infections. Thus, including B cereus coverage in empiric regimens for patients with AML and persistent neutropenic fever may limit the morbidity of this pathogen.

Coherent photo-thermal noise cancellation in a dual-wavelength optical cavity for narrow-linewidth laser frequency stabilisation.

Optical resonators are used for the realisation of ultra-stable frequency lasers. The use of high reflectivity multi-band coatings allows the frequency locking of several lasers of different wavelengths to a single cavity. While the noise processes for single wavelength cavities are well known, the correlation caused by multi-stack coatings has as yet not been analysed experimentally. In our work, we stabilise the frequency of a 729 nm and a 1069 nm laser to one mirror pair and determine the residual-amplitude modulation (RAM) and photo-thermal noise (PTN). We find correlations in PTN between the two lasers and observe coherent cancellation of PTN for the 1069 nm coating. We show that the fractional frequency instability of the 729 nm laser is limited by RAM at 1 × 10-14. The instability of the 1069 nm laser is at 3 × 10-15 close to the thermal noise limit of 1.5 × 10-15.

Harnessing noncanonical crRNAs to improve functionality of Cas12a orthologs.

There is a broad diversity among Cas12a endonucleases that possess nucleic acid detection and gene-editing capabilities, but few are studied extensively. Here, we present an exhaustive investigation of 23 Cas12a orthologs, with a focus on their cis- and trans-cleavage activities in combination with noncanonical crRNAs. Through biochemical assays, we observe that some noncanonical crRNA:Cas12a effector complexes outperform their corresponding wild-type crRNA:Cas12a. Cas12a can recruit crRNA with modifications such as loop extensions and split scaffolds. Moreover, the tolerance of Cas12a to noncanonical crRNA is also observed in mammalian cells through the formation of indels. We apply the adaptability of Cas12a:crRNA complexes to detect SARS-CoV-2 in clinical nasopharyngeal swabs, saliva samples, and tracheal aspirates. Our findings further expand the toolbox for next-generation CRISPR-based diagnostics and gene editing.

Evidence for dopamine production and distribution of dopamine D2 receptors in the equine gastrointestinal mucosa and pancreas.

Insulin dysregulation in horses is characterised by hyperinsulinaemia and/or tissue insulin resistance and is associated with increased risk of laminitis. There is growing evidence in other species that dopamine attenuates insulin release from the pancreas; however, this has yet to be examined in horses. The present study aimed to identify whether there are cells capable of producing or responding to dopamine within the equine gastrointestinal mucosa and pancreas. Tissue samples were collected from the stomach, small and large intestines, and pancreas of six mature horses following euthanasia. Samples of stomach contents and faeces were also collected. Immunohistochemistry was performed to identify tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine production, and dopamine D2 receptors in tissue sections. Additional immunostaining for glucagon, insulin and chromogranin A was performed to identify α cells, ß cells and enteroendocrine cells, respectively. Gastric parietal cells expressed both TH and D2 receptors, indicating that they are capable of both producing and responding to dopamine. Dopamine was quantified in stomach contents and faeces by high-performance liquid chromatography with electrochemical detection, with similar concentrations found at both sites. Dopamine D2 receptors were expressed in duodenal epithelial cells but not more distally. A subset of enteroendocrine cells, located sporadically along the gastrointestinal tract, were found to be immunopositive for the D2 receptor. In pancreatic islets, TH was present in α cells, while D2 receptors were strongly expressed in ß cells and variably expressed in α cells. These findings are consistent with studies of other species; however, dynamic studies are required to further elucidate the role of dopamine in the modulation of insulin and glucagon secretion in horses. This descriptive study provides preliminary evidence for a potential role of dopamine to act as a paracrine messenger in the gastrointestinal mucosa and endocrine pancreas of horses.

When another one bites the dust: Environmental impact of global copper demand on local communities in the Atacama mining hotspot as registered by tree rings.

Assessing the impact of mining activity on the availability of environmental pollutants is crucial for informing health policies in anticipation of future production scenarios of critical minerals essential for the transition to a net-zero carbon society. However, temporal and spatial monitoring is often sparse, and measurements may not extend far enough back in time. In this study, we utilize variations of chemical elements contained in tree-rings collected in local villages from an area heavily affected by copper mining in the Atacama Desert since the early 20th century to evaluate the temporal distribution of pollutants and their relationship with local drivers. By combining time-varying data on local drivers, such as copper production and the dry tailings deposit area, we show how the surge in copper production during the 1990s, fueled by trade liberalization and increased international demand, led to a significant increment in the availability of metal(loid)s related to mining activities on indigenous lands. Our findings suggest that the environmental legislation in Chile may be underestimating the environmental impact of tailing dams in neighboring populations, affecting the well-being of Indigenous Peoples from the Atacama mining hotspot region. We argue that future changes in production rates driven by international demand could have negative repercussions on the environment and local communities. Therefore, mining emissions and the management of tailing dams should be carefully considered to anticipate their potential negative effects on human and ecosystem health.

How much can performance measures explain of the between-cow variation in enteric methane?

Enteric CH4 produced from dairy cows contributes to the greenhouse gas emission from anthropogenic sources. Recent studies have shown that the selection of lower CH4 emitting cows is possible, but this would be simpler if performance measures already recorded on farm could be used, instead of measuring gas emission from individual cows. These performance measures could be used for selection of low emitting cows. The aim of this analysis was to quantify how much of the between-cow variation in CH4 production can be explained by variation in performance measures. A data set with 3 experiments, a total of 149 lactating dairy cows with repeated measures, was used to estimate the between-cow variation (the variation between cow estimates) for performance and gas measures from GreenFeed. The cow estimates were obtained with a linear mixed model with the diet within period effect as a fixed effect and the cow within experiment as a random effect. The cow estimates for CH4 production were first regressed on the performance and gas measures individually, and then performance and CO2 production measures were grouped in 3 subsets for principal component analysis and principal component regression. The variables that explained most of the between-cow variation in CH4 production were DMI (R2 = 0.44), among the performance measures, and CO2 production (R2 = 0.61), among gas measures. Grouping the measures increased the R2 to 0.53, when only performance measures were used, and to 0.66, when CO2 production was added to the significant performance measures. We found the marginal improvement to be insufficient to justify the use of grouped measures rather than an individual measure, since the latter avoid over fitting and simplify the model. Investigation of other measures that can be explored to increase explanatory power of between-cow variation in CH4 production is briefly discussed. Finally, the use of residual CH4 as a measure for CH4 efficiency could be considered by using either DMI or CO2 production as the sole predicting variables.

Clinical Characteristics of Idiopathic Intracranial Hypertension in Older Adults.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition that classically affects obese women of child-bearing age. However, it is sometimes encountered in older patients. The purpose of this study was to help clinicians better understand how this disease can present differently in these age groups. METHODS: This is a retrospective chart review from a single academic center of baseline characteristics of adult patients diagnosed with IIH based on the modified Dandy criteria. The patients were divided into 2 groups: (1) those 18-44 years old and (2) those older than 45 years at diagnosis. RESULTS: One hundred sixty-seven patients were identified; 135 in the younger group and 32 in the older group. The younger group had a higher rate of headaches (90% vs 63%, P = 0.0004), higher body mass index (38.9 vs 36.1, P = 0.046), higher opening pressure (38 vs 31 cm H2O, P = 0.005), and thicker peripapillary retinal nerve fiber layer average thickness (right eye 178 vs 131 µm, P = 0.02; left eye 184 vs 136 µm, P = 0.045). The older group had higher rates of empty sella (90% vs 62%, P = 0.0039). In addition in the younger group, there was a trend toward higher rates of pulsatile tinnitus (63% vs 45%, P = 0.08), transient visual obscurations (50% vs 32%, P = 0.07), and lower rates of spontaneous cerebrospinal fluid leak (4% vs 13%, P = 0.08). Sex, rates of obesity, other MRI findings typical of elevated intracranial pressure, frequency and Frisen grading of papilledema, and visual field loss were not statistically different between the groups. CONCLUSIONS: The older age group had milder signs and symptoms of IIH and a higher prevalence of empty sella than the younger group, but otherwise had typical characteristics. These findings suggest that IIH in the older age group may represent milder chronic disease that was previously undiagnosed.

The influence of risk awareness and government trust on risk perception and preparedness for natural hazards.

Risk perception is considered the primary motivator for taking preparedness actions. But people with prior experience and a high-risk perception are not necessarily more prepared. This relationship is even more complex when assessing preparedness levels for hazards with different characteristics. These inconsistent findings can be explained by how preparedness has been measured and the influence of other factors, such as trust and risk awareness. Thus, the main goal of this study was to analyze the role of risk awareness and trust in authorities on risk perception and intention to prepare for natural hazards in a coastal city in Chile. A representative sample of the city of Concepción, located in the center-south zone of Chile (n = 585), completed a survey. We measured risk awareness, risk perception, trust in authorities, and intention to prepare for two hazards: earthquakes/tsunamis and floods. Through structural equation models, we tested five hypotheses. We found that the perception of risk maintained a direct and positive influence on the intention to prepare for both hazards. The results showed that awareness and risk perception influence the intention to prepare and should be considered different concepts. Finally, trust did not significantly influence risk perception when faced with known hazards for the population. Implications for understanding the relationship between risk perception and direct experience are discussed.

Developmental Neuroendocrinology of Early-Life Stress: Impact on Child Development and Behavior.

Our internal balance, or homeostasis, is threatened or perceived as threatened by stressful stimuli, the stressors. The stress system is a highly conserved system that adjusts homeostasis to the resting state. Through the concurrent activation of the hypothalamic-pituitary-adrenal axis and the locus coeruleus/norepinephrine-autonomic nervous systems, the stress system provides the appropriate physical and behavioral responses, collectively termed as "stress response", to restore homeostasis. If the stress response is prolonged, excessive or even inadequate, several acute or chronic stress-related pathologic conditions may develop in childhood, adolescence and adult life. On the other hand, earlylife exposure to stressors has been recognized as a major contributing factor underlying the pathogenesis of non-communicable disorders, including neurodevelopmental disorders. Accumulating evidence suggests that early-life stress has been associated with an increased risk for attention deficit hyperactivity disorder and autism spectrum disorder in the offspring, although findings are still controversial. Nevertheless, at the molecular level, early-life stressors alter the chemical structure of cytosines located in the regulatory regions of genes, mostly through the addition of methyl groups. These epigenetic modifications result in the suppression of gene expression without changing the DNA sequence. In addition to DNA methylation, several lines of evidence support the role of non-coding RNAs in the evolving field of epigenetics. In this review article, we present the anatomical and functional components of the stress system, discuss the proper, in terms of quality and quantity, stress response, and provide an update on the impact of early-life stress on child development and behavior.

Opportunistic Infections in Patients Receiving Post-Transplantation Cyclophosphamide: Impact of Haploidentical versus Unrelated Donor Allograft.

Post-transplantation cyclophosphamide (PTCy) is an effective strategy for graft-versus-host disease (GVHD) prophylaxis and is the standard of care for haploidentical hematopoietic cell transplantation (HCT). It is increasingly used for matched and mismatched unrelated donor (MUD/MMUD) HCT, but infections remain a concern. The objective of this study was to evaluate the characteristics and risk factors for infections in haploidentical and unrelated donor HCT recipients treated with PTCy-based GVHD prophylaxis. This single-center retrospective study examined 354 consecutive adults undergoing HCT with PTCy-based GVHD prophylaxis (161 MUD/MMUD; 193 haploidentical) between 2015 and 2022. Opportunistic infections (OIs), including cytomegalovirus (CMV), adenovirus (AdV), Epstein-Barr virus (EBV), and invasive fungal disease (IFD), were assessed from day 0 through day +365. The 1-year cumulative incidence functions of OIs and nonrelapse mortality (NRM) were calculated using dates of relapse and repeat HCT as competing risks. Secondary analysis evaluated risk factors for OIs and NRM using univariate and multivariable Cox regression models. Haploidentical HCT recipients had an increased risk of OIs compared to unrelated donor allograft recipients (39% for haploidentical versus 25% for MUD/MMUD; hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.16 to 2.49; P = .006). On multivariable analysis, haploidentical donor (HR, 1.50; 95% CI, 1.01 to 2.23; P = .046), prior HCT (HR, 1.99; 95% CI, 1.29 to 3.09; P = .002), and diagnosis of aGVHD (HR, 1.47; 95% CI, 1.02 to 2.14; P = .041) were associated with increased risk of OIs. NRM within the first year was not significantly different between the 2 cohorts (HR, 1.11; 95% CI, .64 to 1.93; P = .70). Overall, haploidentical donor was a significant risk factor for OIs in patients receiving PTCy, although 1-year NRM was not different between haploidentical HCT and MUD/MMUD HCT recipients. CMV and AdV infections were significantly increased among haploidentical HCT recipients, whereas the incidences of EBV infection and IFD were similar in the 2 cohorts. Our findings may have implications for infection monitoring and prophylaxis in the setting of PTCy, particularly in haploidentical HCT recipients.

Correction: Balaphas et al. Cell Therapy for Anal Sphincter Incontinence: Where Do We Stand? Cells 2021, 10, 2086.

The authors would like to add a new reference to the section "3 [...].

Efficient Concatenated Bosonic Code for Additive Gaussian Noise.

Bosonic codes offer noise resilience for quantum information processing. Good performance often comes at a price of complex decoding schemes, limiting their practicality. Here, we propose using a Gottesman-Kitaev-Preskill code to detect and discard error-prone qubits, concatenated with a quantum parity code to handle the residual errors. Our method employs a simple linear-time decoder that nevertheless offers significant performance improvements over the standard decoder. Our Letter may have applications in a wide range of quantum computation and communication scenarios.

Disentangling the dynamics of energy allocation to develop a proxy for robustness of fattening pigs.

BACKGROUND: There is a growing need to improve robustness of fattening pigs, but this trait is difficult to phenotype. Our first objective was to develop a proxy for robustness of fattening pigs by modelling the longitudinal energy allocation coefficient to growth, with the resulting environmental variance of this allocation coefficient considered as a proxy for robustness. The second objective was to estimate its genetic parameters and correlations with traits under selection and with phenotypes that are routinely collected. In total, 5848 pigs from a Pietrain NN paternal line were tested at the AXIOM boar testing station (Azay-sur-Indre, France) from 2015 to 2022. This farm is equipped with an automatic feeding system that records individual weight and feed intake at each visit. We used a dynamic linear regression model to characterize the evolution of the allocation coefficient between the available cumulative net energy, which was estimated from feed intake, and cumulative weight gain during the fattening period. Longitudinal energy allocation coefficients were analysed using a two-step approach to estimate both the genetic variance of the coefficients and the genetic variance in their residual variance, which will be referred to as the log-transformed squared residual (LSR). RESULTS: The LSR trait, which could be interpreted as an indicator of the response of the animal to perturbations/stress, showed a low heritability (0.05 ± 0.01), a high favourable genetic correlation with average daily growth (- 0.71 ± 0.06), and unfavourable genetic correlations with feed conversion ratio (- 0.76 ± 0.06) and residual feed intake (- 0.83 ± 0.06). Segmentation of the population in four classes using estimated breeding values for LSR showed that animals with the lowest estimated breeding values were those with the worst values for phenotypic proxies of robustness, which were assessed using records routinely collected on farm. CONCLUSIONS: Results of this study show that selection for robustness, based on estimated breeding values for environmental variance of the allocation coefficients to growth, can be considered in breeding programs for fattening pigs.

Long-Term Outcome and Complications of IOL-Exchange.

Purpose: To describe the long-term outcome after intraocular lens (IOL) exchange for IOL-opacification with a focus on any occurring complications. Patients and Methods: Patients with an IOL exchange for opacified IOLs (Lentis LS-502-1) were identified. Medical records and information from the treating ophthalmologists were reviewed. Visual outcomes and any occurring complications after the IOL exchange were analyzed. Results: IOL exchange was performed in 48 eyes of 46 patients and significantly improved best-corrected distance visual acuity from 0.42 ± 0.32 logMar (mean ± SD) in opacified lenses to 0.25 ± 0.28 logMar after IOL exchange. Nine of the 48 eyes (19%) underwent 11 further surgical procedures for complications due to four indications: IOL dislocation (n = 2, 4%), retinal detachment (RD) (n = 6, 12%), epiretinal membrane (n = 2, 4%), and pupillary block (n = 1, 2%). Three eyes (6%) developed a temporarily elevated intraocular pressure. Temporary postoperative cystoid macular edema was found in 2 eyes (4%). Conclusion: IOL exchange can restore vision owing to IOL opacification in most cases. Nonetheless, IOL exchange is not an easy or risk-free procedure. This may lead to sight-threatening complications, even in eyes without predisposing ocular comorbidities.

Olaparib and Ceralasertib (AZD6738) in Patients with Triple-Negative Advanced Breast Cancer: Results from Cohort E of the plasmaMATCH Trial (CRUK/15/010).

PURPOSE: Approximately 10% to 15% of triple-negative breast cancers (TNBC) have deleterious mutations in BRCA1 and BRCA2 and may benefit from PARP inhibitor treatment. PARP inhibitors may also increase exogenous replication stress and thereby increase sensitivity to inhibitors of ataxia telangiectasia and Rad3-related (ATR) protein. This phase II study examined the activity of the combination of PARP inhibitor, olaparib, and ATR inhibitor, ceralasertib (AZD6738), in patients with advanced TNBC. PATIENTS AND METHODS: Patients with TNBC on most recent biopsy who had received 1 or 2 lines of chemotherapy for advanced disease or had relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300 mg twice a day continuously and celarasertib 160 mg on days 1-7 on a 28-day cycle until disease progression. The primary endpoint was confirmed objective response rate (ORR). Tissue and plasma biomarker analyses were preplanned to identify predictors of response. RESULTS: 70 evaluable patients were enrolled. Germline BRCA1/2 mutations were present in 10 (14%) patients and 3 (4%) patients had somatic BRCA mutations. The confirmed ORR was 12/70; 17.1% (95% confidence interval, 10.4-25.5). Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumors with functional homologous recombination deficiency by RAD51 foci. CONCLUSIONS: The response rate to olaparib and ceralasertib did not meet prespecified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to olaparib monotherapy.

The human glucocorticoid receptor.

Glucocorticoids are members of steroid hormones that are biosynthesized in the intermediate cellular zone of the adrenal cortex (zona fasciculata) and released into the peripheral blood as final products of the hypothalamic-pituitary-adrenal (HPA) axis, as well as under the control of the circadian biologic system. These molecules regulate every physiologic function of the organism as they bind to an almost ubiquitous hormone-activated transcription factor, the glucocorticoid receptor (GR), which influences the rate of transcription of a huge number of target genes amounting to up to 20% of the mammalian genome. The evolving progress of cellular, molecular and computational-structural biology and the implication of epigenetics in every-day clinical practice have enabled us a deeper and ever-increasing understanding of how target tissues respond to natural and synthetic glucocorticoids. In this chapter, we summarize the current knowledge on the structure, expression, function and signaling of the human glucocorticoid receptor in normal and pathologic conditions.

Programmable RNA detection with CRISPR-Cas12a.

Cas12a, a CRISPR-associated protein complex, has an inherent ability to cleave DNA substrates and is utilized in diagnostic tools to identify DNA molecules. We demonstrate that multiple orthologs of Cas12a activate trans-cleavage in the presence of split activators. Specifically, the PAM-distal region of the crRNA recognizes RNA targets provided that the PAM-proximal seed region has a DNA target. Our method, Split Activator for Highly Accessible RNA Analysis (SAHARA), detects picomolar concentrations of RNA without sample amplification, reverse-transcription, or strand-displacement by simply supplying a short DNA sequence complementary to the seed region. Beyond RNA detection, SAHARA outperforms wild-type CRISPR-Cas12a in specificity towards point-mutations and can detect multiple RNA and DNA targets in pooled crRNA/Cas12a arrays via distinct PAM-proximal seed DNAs. In conclusion, SAHARA is a simple, yet powerful nucleic acid detection platform based on Cas12a that can be applied in a multiplexed fashion and potentially be expanded to other CRISPR-Cas enzymes.