Early Hypophosphatemia as a Prognostic Marker in Acute Pancreatitis.

OBJECTIVES: Acute pancreatitis (AP) is a complex disease representing a significant portion of gastrointestinal-related hospitalizations in the U.S. Understanding risk factors of AP might provide attractive therapeutic targets. We evaluated hypophosphatemia a prognostic marker in AP. METHODS: We performed a retrospective review of electronic health records of patients with AP from 01/ 01/2012-12/31/2021 at Cedars-Sinai Medical Center with serum phosphate measured within 48 hours of admission. Multivariable logistic regression modeling was used to evaluate associations with ICU admission and AP severity. Multivariable log-linear modeling was employed to examine associations with length of stay (LOS). RESULTS: Of 1526 patients admitted for AP, 33% (499) had a serum phosphate level measured within 48 hours. Patients with hypophosphatemia were more likely to have ICU admission (adjusted odds ratio (AOR) = 4.57; 95% confidence interval (CI): 2.75-7.62; P < 0.001), have a longer hospital stay (log-LOS = 0.34; SE; 0.09; 95% CI: 0.17-0.52; P < 0.001), and have moderate or severe AP (AOR = 1.80; 95% CI: 1.16-2.80; P < 0.001) compared with those without hypophosphatemia. CONCLUSION: Serum phosphate is infrequently measured in patients with AP and shows promise as an early prognostic marker for outcomes of AP.

Correction to: Amanita Mushroom Toxin Poisoning in Los Angeles County.

[This corrects the article DOI: 10.14309/crj.0000000000001246.].

Amanita Mushroom Toxin Poisoning in Los Angeles County.

Mushroom (amatoxin) poisoning from ingestion is a rare but life-threatening medical emergency characterized by gastrointestinal symptoms before progression to multisystem organ failure in severe cases. Many therapies of amatoxin intoxication have been described, including supportive care, medical therapies, detoxification strategies, and liver transplant. The evidence supporting these therapies remains limited due to the rarity of amatoxin poisoning and challenge of a timely diagnosis. We report a case of amatoxin poisoning in Los Angeles causing severe liver injury without acute liver failure treated successfully using medical therapies, gallbladder drainage, and plasma exchange.

Single-fraction Radiation Treatment Dose Response in a Genetically Engineered Mouse Model of Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of children. Although standard of care radiotherapy for pediatric medulloblastoma (PM) can lead to long-term remission or cure in many patients, it can also cause life-long cognitive impairment and other adverse effects. The pathophysiological mechanisms involved in radiation-induced cerebral damage are incompletely understood, and their elucidation may lead to interventions that mitigate radiation toxicity. To explore the mechanisms of radiation-induced cerebral damage, transgenic mouse models of PM and non-tumor-bearing controls were exposed to radiation doses that ranged from 0 to 30 Gy. Between 0-20 Gy, a significant dose-dependent reduction in tumor-associated hydrocephalus and increase in overall survival were observed. However, at 30 Gy, hydrocephalus incidence increased and median overall survival fell to near-untreated levels. Immunohistochemistry revealed that both tumor-bearing and non-tumor-bearing mice treated with 30 Gy of radiation had significantly more reactive astrocytes and microvascular damage compared to untreated controls. This effect was persistent across mice that were given 1 and 2 weeks of recovery time after irradiation. Our data suggest that radiation therapy promotes neural death by inducing long-term neuroinflammation in PM, suggesting radiation delivery methods that limit inflammation may be effective at widening the therapeutic window of radiation therapy in PM patients.

Ataxia-telangiectasia mutated ( Atm ) disruption sensitizes spatially-directed H3.3K27M/TP53 diffuse midline gliomas to radiation therapy.

Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, which presents therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Genetic or pharmacologic disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (ATM) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models with different p53 mutations to identify transactivation-independent p53 activity as a key mediator of such radiosensitivity. These studies deeply profile a genetically faithful and versatile model of a lethal brain tumor to identify resistance mechanisms for a therapeutic strategy currently in clinical trials.

Pooled genetic screens to identify vulnerabilities in TERT-promoter-mutant glioblastoma.

Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found in >80% of glioblastomas. We first developed a platform to detect perturbations that cause long-term growth defects in a TPM-mutated glioblastoma cell line. However, we could not detect dependencies on either TERT itself or on an E-twenty six transcription (ETS) factor known to activate TPMs. To explore this finding, we cataloged TPM status for 441 cell lines and correlated this with genome-wide screening data. We found that TPM status was not associated with differential dependency on TERT, but that E-twenty six (ETS) transcription factors represent key dependencies in both TPM+ and TPM- lines. Further, we found that TPMs are associated with expression of gene programs regulated by a wide array of ETS-factors in both cell lines and primary glioblastoma tissues. This work contributes a unique TPM cell line reagent, establishes TPM status for many deeply-profiled cell lines, and catalogs TPM-associated vulnerabilities. The results highlight challenges in executing genetic screens to detect TPM-specific vulnerabilities, and suggest redundancy in the genetic network that regulates TPM function with therapeutic implications.

Spatial and temporal variation in toxicity and inorganic composition of hydraulic fracturing flowback and produced water.

Hydraulic fracturing for oil and gas extraction produces large volumes of wastewater, termed flowback and produced water (FPW), that are highly saline and contain a variety of organic and inorganic contaminants. In the present study, FPW samples from ten hydraulically fractured wells, across two geologic formations were collected at various timepoints. Samples were analyzed to determine spatial and temporal variation in their inorganic composition. Results indicate that FPW composition varied both between formations and within a single formation, with large compositional changes occurring over short distances. Temporally, all wells showed a time-dependent increase in inorganic elements, with total dissolved solids increasing by up to 200,000 mg/L over time, primarily due to elements associated with salinity (Cl, Na, Ca, Mg, K). Toxicological analysis of a subset of the FPW samples showed median lethal concentrations (LC50) of FPW to the aquatic invertebrate Daphnia magna were highly variable, with the LC50 values ranging from 1.16% to 13.7% FPW. Acute toxicity of FPW significantly correlated with salinity, indicating salinity is a primary driver of FPW toxicity, however organic components also contributed to toxicity. This study provides insight into spatiotemporal variability of FPW composition and illustrates the difficulty in predicting aquatic risk associated with FPW.

Female patients delay seeking medical care with alcohol-associated acute pancreatitis.

BACKGROUND/OBJECTIVE: Alcohol consumption is increasing in women, who more frequently report abdominal symptoms compared to men. We aimed to examine differences in presentation of acute pancreatitis [AP] in male and female patients hospitalized with alcohol-associated AP. METHODS: We analyzed 138 patients enrolled in an ongoing case-crossover study of alcohol-associated AP conducted across 5 medical centers in the U.S. Patients meeting the Revised Atlanta Classification of AP and who scored 3 or higher on the AUDIT-C instrument were invited to participate in the study and were interviewed while hospitalized with AP. Sex differences in the timing and type of pancreas-associated pain, alcohol consumption, clinical presentation, and quality of life were examined by Chi-squared tests, Wilcoxon rank sum tests and t-tests. RESULTS: Female patients reported significantly longer interval from onset of pain to deciding to seek medical attention (median 40 h, interquartile range [IQR] 14, 74) as compared to males (14 h, IQR 4, 50; p = 0.005). While male patients were more likely to have been admitted to the intensive care unit [ICU] (21%) as compared to female patients (7%; p = 0.04), the incidence of SIRS or severe AP did not differ by sex. Quality of life measures as reported through the PROMIS-29 instrument were equally suboptimal in both sexes. Anxiety disorders were diagnosed more frequently among females (61%) than in males (41%, p = 0.009). CONCLUSION: In a large case series of alcohol-associated AP, we found that female patients delayed seeking medical care compared to males. However, there were no differences in the type, location and intensity of abdominal pain.

Persisting Effects in Daphnia magna Following an Acute Exposure to Flowback and Produced Waters from the Montney Formation.

Hydraulic fracturing extracts oil and gas through the injection of water and proppants into subterranean formations. These injected fluids mix with the host rock formation and return to the surface as a complex wastewater containing salts, metals, and organic compounds, termed flowback and produced water (FPW). Previous research indicates that FPW is toxic to Daphnia magna (D. magna), impairing reproduction, molting, and maturation time; however, recovery from FPW has not been extensively studied. Species unable to recover have drastic impacts on populations on the ecological scale; thus, this study sought to understand if recovery from an acute 48 h FPW exposure was possible in the freshwater invertebrate, D. magna by using a combination of physiological and molecular analyses. FPW (0.75%) reduced reproduction by 30% and survivorship to 32% compared to controls. System-level quantitative proteomic analyses demonstrate extensive perturbation of metabolism and protein transport in both 0.25 and 0.75% FPW treatments after a 48 h FPW exposure. Collectively, our data indicate that D. magna are unable to recover from acute 48 h exposures to ≥0.25% FPW, as evidence of toxicity persists for at least 19 days post-exposure. This study highlights the importance of considering persisting effects following FPW remediation when modeling potential spill scenarios.

Coupling spin defects in hexagonal boron nitride to titanium dioxide ring resonators.

Spin-dependent optical transitions are attractive for a plethora of applications in quantum technologies. Here we report on utilization of high quality ring resonators fabricated from TiO2 to enhance the emission from negatively charged boron vacancies (VB-) in hexagonal Boron Nitride. We show that the emission from these defects can efficiently couple into the whispering gallery modes of the ring resonators. Optically coupled VB- showed photoluminescence contrast in optically detected magnetic resonance signals from the hybrid coupled devices. Our results demonstrate a practical method for integration of spin defects in 2D materials with dielectric resonators which is a promising platform for quantum technologies.

The Effect of Atm Loss on Radiosensitivity of a Primary Mouse Model of Pten-Deleted Brainstem Glioma.

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase, ataxia-telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if ATM inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by ATM deletion, which may guide the design of future clinical trials.

Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions.

Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.

Antibiotics to modify sickle cell disease vaso-occlusive crisis?

Despite the availability of hydroxyurea, the clinical use of the medication among patients with sickle cell disease (SCD) remains low in the United States. Given the high healthcare utilization cost, SCD requires new therapeutic approaches. Recent studies demonstrated bacterial overgrowth and dysbiosis-related intestinal pathophysiological changes in SCD. Intestinal microbes regulate neutrophil ageing. Aged and activated neutrophils contribute to the pathogenesis of vaso-occlusive crisis (VOC) in SCD. In this paper, we will review the pre-clinical and clinical data on how antibiotics might reduce the intestinal microbial density and influence the course of VOC. Based on these observations, we will discuss rationales for and potential challenges to antibiotic-based therapeutic approaches that may modify the clinical course of VOC in SCD.

Obesity and diabetes mellitus in patients with sickle cell disease.

Obesity and diabetes mellitus are prevalent among the African-American/Black population. They result in multiple chronic conditions that impact the quality and lifespan of the patients. Their occurrence in patients with sickle cell disease (SCD) will increase the risks for multimorbidity in these patients. We have carried out a chart survey of a cohort of 449 patients with SCD to determine the prevalence rates of obesity and diabetes mellitus in these patients. SCD patients were less likely to develop obesity and diabetes mellitus, compared to their peers of the same race/ethnicity. The lower prevalence rates were observed in those over the age of 6 years, irrespective of the gender of the patients. Their life-time probabilities for obesity and diabetes mellitus were also low. Within this group of SCD patients, obesity was associated with significantly higher prevalence of diabetes mellitus. The underlying reasons for our observed results of low prevalence rate of obesity in SCD remain speculative but may be related to reduced calorie intake, increased calorie use due to hypermetabolism, reduced intestinal absorption, or intestinal dysbiosis.

A burning issue: The effect of organic ultraviolet filter exposure on the behaviour and physiology of Daphnia magna.

Ultraviolet (UV) filters are compounds utilized in many manufacturing processes and personal care products such as sunscreen to protect against UV-radiation. These highly lipophilic compounds are emerging contaminants of concern in aquatic environments due to their previously observed potential to bioaccumulate and exert toxic effects in marine ecosystems. Currently, research into the toxic effects of UV filter contamination of freshwater ecosystems is lacking, thus the present study sought to model the effects of acute and chronic developmental exposures to UV filters avobenzone, oxybenzone and octocrylene as well as a mixture of these substances in the freshwater invertebrate, Daphnia magna, at environmentally realistic concentrations. Median 48-hour effect and lethal concentrations were determined to be in the low mg/L range, with the exception of octocrylene causing 50% immobilization near environmental concentrations. 48-hour acute developmental exposures proved to behaviourally impair daphnid phototactic response; however, recovery was observed following a 19-day post-exposure period. Although no physiological disruptions were detected in acutely exposed daphnids, delayed mortality was observed up to seven days post-exposure at 200 µg/L of avobenzone and octocrylene. 21-day chronic exposure to 7.5 µg/L octocrylene yielded complete mortality within 7 days, while sublethal chronic exposure to avobenzone increased Daphnia reproductive output and decreased metabolic rate. 2 µg/L oxybenzone induced a 25% increase in metabolic rate of adult daphnids, and otherwise caused no toxic effects at this dose. These data indicate that UV filters can exert toxic effects in freshwater invertebrates, therefore further study is required. It is clear that the most well-studied UV filter, oxybenzone, may not be the most toxic to Daphnia, as both avobenzone and octocrylene induced behavioural and physiological disruption at environmentally realistic concentrations.

Evaluation of bioabsorbable calcium sulfate hemihydrate beads for local delivery of carboplatin.

The objectives of this study were to evaluate a novel kit of resorbable calcium sulfate beads marketed specifically for use in veterinary medicine and generally used for local delivery of antimicrobials as carboplatin-delivery system. The study characterized the elution of carboplatin in vitro, and investigated whether the initial dose and formulation of carboplatin, or the bead size significantly influences carboplatin elution in vitro. Calcium sulfate hemihydrate beads of 3- and 5-mm diameter were prepared. Five doses and two formulations of carboplatin (20, 50, 100, and 500 mg carboplatin per kit in powder formulation; 20 mg in liquid formulation) were tested in triplicates for each diameter beads. Beads were placed in 37°C phosphate buffered saline for 72 hours. Carboplatin concentrations in the eluent were measured by high-performance liquid chromatography at 11 time points with a modified United States Pharmacopeia assay. Concentrations of carboplatin in the eluent proportionally increased with the initial dose and peaked between 13 and 52 hours, ranging from 42.1% to 79.3% of the incorporated load. Higher peak concentrations, percentages released, and elution rates were observed with the liquid formulation and with higher carboplatin doses. There was no significant difference in maximum carboplatin concentrations between 3- and 5-mm diameter beads, but 5-mm diameter beads had slower elution rates. The novel kit can be used for preparation of carboplatin-impregnated resorbable calcium sulfate beads at variable doses, sizes and formulations. Further study is warranted to define the in vivo requirements and effective carboplatin dose, spatial diffusion and desired duration of elution.

Controlled Doping of GeV and SnV Color Centers in Diamond Using Chemical Vapor Deposition.

Group IV color centers in diamond (Si, Ge, Sn, and Pb) have recently emerged as promising candidates for realization of scalable quantum photonics. However, their synthesis in nanoscale diamond is still in its infancy. In this work we demonstrate controlled synthesis of selected group IV defects (Ge and Sn) into nanodiamonds and nanoscale single crystal diamond membranes by microwave plasma chemical vapor deposition. We take advantage of inorganic salts to prepare the chemical precursors that contain the required ions that are then incorporated into the growing diamond. Photoluminescence measurements confirm that the selected group IV emitters are present in the diamond without degrading its structural quality. Our results are important to expand the versatile synthesis of color centers in diamond.

Photonic Nanobeam Cavities with Nanopockets for Efficient Integration of Fluorescent Nanoparticles.

Integrating fluorescent nanoparticles with high-Q, small mode volume cavities is indispensable for nanophotonics and quantum technologies. To date, nanoparticles have largely been coupled to evanescent fields of cavity modes, which limits the strength of the interaction. Here, we developed both a cavity design and a fabrication method that enable efficient coupling between a fluorescent nanoparticle and a cavity optical mode. The design consists of a fishbone-shaped, one-dimensional photonic crystal cavity with a nanopocket located at the electric field maximum of the fundamental optical mode. Furthermore, the presence of a nanoparticle inside the pocket reduces the mode volume substantially and induces subwavelength light confinement. Our approach opens exciting pathways to achieve tight light confinement around fluorescent nanoparticles for applications in energy, sensing, lasing, and quantum technologies.