Search

Purpose: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). Patients and Methods: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable. Conclusion: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Significance: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression.

Background Carbapenemase producing gram-negative bacteria (GNB) has become a huge problem in majority of tertiary care centers worldwide. They are associated with very high morbidity and mortality rates, especially when they cause invasive infections. Therefore, rapid detection of these organisms is very important for prompt and adequate antibiotic therapy as well as infection control. The aim of this study was rapid detection of carbapenemase genes and thereby likely carbapenem resistance, 24–48 hours in advance, directly from the positive-flagged blood culture bottles using CHROMagar and Xpert® Carba-R. Methods Aspirate from positively flagged blood culture bottles was subjected to differential centrifuge. All gram-negative bacilli on gram stain from the deposit were processed in Xpert® Carba-R and inoculated on CHROMagar. The presence of genes and growth on CHROMagar was compared with carbapenem resistance on VITEK-2 Compact. Results A total of 119 GNB isolates were processed. One or more of the carbapenemase genes were detected in 80 isolates. On comparison with VITEK-2 result, 92 samples showed concordance for carbapenem resistance 48 hours in advance. There was discordance in 21 isolates with 12 major errors and 09 minor errors. The sensitivity of direct Xpert® Carba-R test for rapid detection of carbapenem resistance, 48 hours in advance, was 81.42%. The sensitivity of direct CHROMagar test for accurate detection of carbapenem resistance, 24 hours in advance, was 92.06%. Conclusion The ability to detect carbapenem resistance with very high accuracy, 48 hours in advance, helps in appropriate antibiotic therapy and implementation of effective infection control practices.

Background: The objective of this study was to evaluate appropriateness of packed red blood cell (PRBC) and fresh frozen plasma transfusion (FFP) in post-surgical adult patients admitted in ICU and its outcome. Methods: A total number of 800 ICU adult patients were enrolled. Out of these 600 patients received PRBC transfusion and 200 received FFP transfusions. Transfusion pattern was analyzed with respect to the number of units transfused, pre and post transfusion hemoglobin levels and coagulation profile. The outcome was measured in terms of mortality, morbidity and length of ICU stay. Transfusions were categorized into appropriate and inappropriate based on transfusion triggers used as per BSH guidelines (British Society for Hematology). The SPSS software was used for analyses. Results: Out of six hundred, 384 were those with appropriate red cell transfusion. In the appropriate transfusion group, majority i.e. 167 (43.49%) underwent more units of PRBC transfusion. The mean duration of mechanical ventilation in appropriate group was 7.43±4.1 days and in inappropriate group was 5.95±3.34 days. (p0.05). Conclusions: Analysis of appropriateness of transfusion according to BSH guidelines shows a high rate of irrational transfusions in Indian subjects. Further studies including large sample size are needed in this context.

BACKGROUND: In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection. METHODS: From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community. RESULTS: A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age. CONCLUSIONS: The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

UDC 512.5 The concept of Lie regular elements and Lie regular units was defined and studied by Kanwar, Sharma and Yadav in Lie regular generators of general linear groups, Comm. Algebra, 40, № 4, 1304–1315 (2012)]. We introduce Jordan regular elements and Jordan regular units. It is proved that the order of the set of Jordan regular units in M ( 2 , Z 2 n ) is equal to a half of the order of U ( M ( 2 , Z 2 n ) ) . Further, we show that the group ring K G of a group G over a field K of characteristic 2 has no Jordan regular units.

Approximated and simplified real-atmospheric process impact in physical parameterization is a primary correspondent of biases in the model, particularly for extreme events. The present study discusses how event genesis in the small and large-scale quintessential environment is incongruously simulated within a set of multiple convection parameterizations. Despite a few inherent errors, most of the selected convective parameterization schemes could indicate 10-15 days in advance the Uttarakhand heavy rains resulted from large-scale background interaction. The runs without any convection scheme, followed by new-Tiedtke and BMJ schemes, outperform in this case. Further, almost all schemes except new-Tiedtke flunked for the case of Mount-Abu flood originated from relatively local-scale interaction even from 5-day advance initialization. Results are further extended for a few other cases using best performers of both extreme events and new-Tiedtke found to be more efficient. The better representation of convection (especially the shallow) and low clouds in this scheme makes it superior to other schemes for simulating extreme precipitation events.

UDC 512.5 Let F be a finite field of characteristic p . The structures of the unit groups of group algebras over F of the three groups D 24 , S 4 and S L ( 2 , ℤ 3 ) of order 24 are completely described in numerous works. We present the unit groups of the group algebras over F for the remaining groups of order 24 , namely, C 24 , C 12 × C 2 , C 2 3 × C 3 , C 3 ⋊ C 8 , C 3 ⋊ Q 8 , D 6 × C 4 , C 6 ⋊ C 4 , C 3 ⋊ D 8 , C 3 × D 8 , C 3 × Q 8 , A 4 × C 2 , and D 12 × C 2 .

Investigating the trends and changes in rainfall over vulnerable regions is of huge importance in this global warming era. The present study intensively investigates the rainfall over the Indian state, Andhra Pradesh (AP), and its 13 districts using a high-resolution (0.25°×0.25°) gridded rainfall analysis dataset from India Meteorological Department (IMD) for the study period of 118 years (1901-2018). For this, normality, homogeneity, persistence, and change-point tests are performed and changes in the district-level rainfall in the present global warming period (1991-2018) as compared to the pre-global warming period (1901-1990) is also analyzed. The results suggest that the long-term average annual rainfall over AP is 882 mm and most of the rainfall is contributed by the monsoon (55.7%) and the post-monsoon rainfall (32.8%). The coefficient of variation is low (high) during monsoon (winter). The coastal region receives more rainfall than the inland districts. The post-monsoon rainfall over AP is more consistent than in other seasons, and the persistence is only during the southwest monsoon season. The southwest monsoon and post-monsoon rainfall have increased (by about 10%) over most of the districts in the recent period. The Nino3.4 region SST (South Oscillation Index; SOI) has a significant negative (positive) relationship with southwest summer monsoon rainfall in most of the districts. The relationship of Nino 3.4 SST and DMI is strikingly similar for post-monsoon and has significantly weakened in recent decades. This study is useful for proper planning and mitigation measures for the agricultural and water resources sector at the district level over AP in this global warming era.

Aims. Through the ATOMIUM project, based on an ALMA large program, we aim to present a consistent view of a sample of 17 nearby cool evolved stars (Aymptotic Giant Branch and red supergiant stars). Methods. Here we present VLT/SPHERE-ZIMPOL polarimetric maps obtained in the visible of 14 out of the 17 ATOMIUM sources. They were obtained contemporaneously with the ALMA high spatial resolution data. To help interpret the polarized signal, we produced synthetic maps of light scattering by dust, through 3D radiative transfer simulations with the RADMC3D code. Results. The degree of linear polarization (DoLP) observed by ZIMPOL spreads across several optical filters. We infer that it primarily probes dust located just outside of the point spread function, and in or near the plane of the sky, with a total optical depth close to unity in the line of sight, representing only a fraction of the total circumstellar dust. The maximum DoLP ranges from 0.03-0.38 depending on the source, fractions that can be reproduced by our 3D pilot models for grains composed of common dust species. The spatial structure of the DoLP shows a diverse set of shapes. Only for three sources do we note a correlation between the ALMA CO and SiO lines, which trace the gas density, and the DoLP, which traces the dust. Conclusion. The clumpiness of the DoLP and the lack of a consistent correlation between the gas and the dust location show that, in the inner circumstellar environment (CSE), dust formation occurs at very specific sites. This has potential consequences for the derived mass-loss rates and dust-to-gas ratio in the inner region of the CSE. Except for $\pi^1$~Gru and perhaps GY Aql, we do not detect interactions between the circumstellar wind and the hypothesized companions that shape the wind at larger scales. This suggests that the orbits of any other companions are tilted out of the plane of the sky., Comment: Accepted for publication in Astronomy & Astrophysics. 22 pages, 15 figures, 5 tables

The present work deals with the effect of water absorption on the mechanical properties of untreated, 10% alkali-treated, and 10% alkali plus 1% silane treated sisal fibers (5%, 10%, and 15%) reinforced polyester composites. Hand lay-up was used to create the composite. The samples were prepared in accordance with ASTM standards, and tests for tensile strength, flexural strength, impact strength, and water absorption were performed. An increase in the tensile, flexural and impact strength was observed with an increase in fibre loading for untreated, alkali-treated and alkali plus silane treated sisal fibre reinforced polyester composites without water absorption, the increase being maximum for 10% alkali plus 1% silane treated fibre composite. Water absorption reduces tensile strength while increasing flexural and impact strength in untreated sisal fiber reinforced composites. There is an increase in tensile, flexural, and impact strength with higher fiber loading for 10% alkali-treated and 10% alkali-treated plus 1% silane treated sisal fiber reinforced polyester composites with and without water absorption. The tensile, flexural, and impact strength of alkali plus silane treated fiber is maximum at any given fiber loading, indicating that the alkali plus silane treatment is effective in improving the fiber matrix interface. Water absorption increases with fiber loading in untreated, 10% alkali-treated, and 10% alkali plus 1% silane treated sisal fiber reinforced polyester composites, with the rate being lowest in alkali plus silane treated fiber reinforced composites.

In the article we analyzed the possibilities of the Classtime platform for all participants in the educational process. We considered the expediency of using this platform in the organization of independent work of students in mathematics lessons. Described the importance of introducing information and communication technologies in the educational process. Developed a fragment of a geometry lesson in the 7th grade using the Classtime platform.

The response to treatment of widely disseminated disease can vary depending on the site of metastasis. In some cases, lesions at one site respond to treatment, while disease at other sites continues to grow. This is seen in the context of melanoma treatment with targeted therapy, with some patients having good responses in the liver, while disease in the brain and bone continues apace. This can be attributed to differences in the microenvironment of lesions in different organs, although other factors undoubtedly contribute. It is also increasingly clear that there is an interplay between the site of metastasis and responses to immunotherapy. Liver metastases are particularly difficult to treat compared to other metastatic locations. Moreover, the presence of liver metastases reduces the efficacy of immunotherapy to control disease at other sites in the same patient. Thus, liver metastases confer systemic tolerance. This is likely linked to the liver being a ‘tolerogenic’ organ with a role in modulating the body’s response to commensal bacteria in the gut. To investigate this, we have established an experimental melanoma model of systemic immune tolerance being conferred by liver metastases. We will present results on the mechanism by which liver metastases hinder not only their response to immunotherapy, but also the response of other distant lesions. Citation Format: Erik Sahai. Organ-specific responses to targeted and immunotherapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY21-03.

COVID-19 has had an impact on all aspects of life. Especially when it comes to Education, which has been the most severely impacted by the Pandemic, it compelled many great nations to impose lockdown, effectively bringing everything to a halt for a while. All educational activities were stopped in India as around 32 crore students left their current schools or universities. The COVID-19 epidemic has shown us that change is inevitable. It has been a catalyst for educational institutions to develop and choose platforms with hitherto unexplored technology. This Pandemic has radically changed the learning, teaching, and evaluating approaches. This paper will go over the difficulties faced by Indian students pursuing Education during the Pandemic. It also seeks to determine its effect on teaching, learning, and evaluation approaches, both positively and negatively. This study explores the opinions and worries of college and university teachers and students about taking required online courses in the wake of COVID-19. KEYWORDS: Covid-19 , Education , lockdown , Services

Cardiovascular conditions such as hypertension, arrhythmias, and heart failure are common in patients undergoing anesthesia for surgical or other procedures. Numerous guidelines from various specialty societies offer variable recommendations for the perioperative management of these medications. The Society for Perioperative Assessment and Quality Improvement identified a need to provide multidisciplinary evidence-based recommendations for preoperative medication management. The society convened a group of 13 members with expertise in perioperative medicine and training in anesthesiology or internal medicine. The aim of this consensus effort is to provide perioperative clinicians with guidance on the management of cardiovascular medications commonly encountered during the preoperative evaluation. We used a modified Delphi process to establish consensus. Twenty-one classes of medications were identified: α-adrenergic receptor antagonists, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor-neprilysin inhibitors, β-adrenoceptor blockers, calcium-channel blockers, centrally acting sympatholytic medications, direct-acting vasodilators, loop diuretics, thiazide diuretics, potassium-sparing diuretics, endothelin receptor antagonists, cardiac glycosides, nitrodilators, phosphodiesterase-5 inhibitors, class III antiarrhythmic agents, potassium-channel openers, renin inhibitors, class I antiarrhythmic agents, sodium-channel blockers, and sodium glucose cotransportor-2 inhibitors. We provide recommendations for the management of these medications preoperatively.

We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65–74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele (P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (ΔV(50)) = ∼−15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV(50) = ∼−30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy. NEW & NOTEWORTHY Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V(50) of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.

PURPOSE: Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing. METHODS: Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses. RESULTS: Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%). CONCLUSION: Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines.

16 pags., 8 figs., 5 tabs.-- Unified Astronomy Thesaurus concepts: Circumstellar matter (241); Planetary nebulae nuclei (1250); Stellar mass loss (1613); White dwarf stars (1799); Circumstellar dust (236); Planetary nebulae (1249); James Webb Space Telescope (2291); Hubble Space Telescope (761); Gaia (2360); Ultraviolet spectroscopy (2284); Close binary stars (254); Orbit determination (1175), The planetary nebula (PN) NGC 3132 is a striking example of the dramatic but poorly understood mass-loss phenomena that (1-8) M ⊙ stars undergo during their death throes as they evolve into white dwarfs (WDs). From an analysis of JWST multiwavelength (0.9-18 μm) imaging of NGC 3132, we report the discovery of an extended dust cloud around the WD central star (CS) of NGC 3132, seen most prominently in the 18 μm image, with a surface-brightness-limited radial extent of ≳2″. We show that the A2V star located 1.″7 to CS’s northeast (and 0.75 kpc from Earth) is gravitationally bound to the latter, as evidenced by the detection of relative orbital angular motion of 0.°24 ± 0.°045 between these stars over ∼20 yr. Using aperture photometry of the CS extracted from the JWST images, together with published optical photometry and an archival UV spectrum, we have constructed the spectral energy distribution (SED) of the CS and its extended emission over the UV to mid-IR (0.091-18 μm) range. We find that fitting the SED of the CS and the radial intensity distributions at 7.7, 12.8, and 18 μm with thermal emission from dust requires a cloud that extends to a radius of ≳1785 au, with a dust mass of ∼1.3 × 10−2 M ⊕ and grains that are 70% silicate and 30% amorphous carbon. We propose plausible origins of the dust cloud and an evolutionary scenario in which a system of three stars—the CS, a close low-mass companion, and a more distant A2V star—forms a stable hierarchical triple system on the main sequence but becomes dynamically unstable later, resulting in the spectacular mass ejections that form the current, multipolar PN., V.B. acknowledges support from the EVENTs/NEBULAE WEB research program, Spanish AEI grant PID2019-105203GB-C21. C.S.C.’s work is part of the I+D+i project PID2019-105203GB-C22 funded by the Spanish MCIN/AEI/10.13039/501100011033. G.Q.-L. thanks Ministerio de Ciencia e Innovación of Spain (MICIU) for funding support through projectsPID2019-107115GB-C21/AEI/10.13039/501100011033. The TMAW tool (http://astro.uni-tuebingen.de/TMAW) used for this paper was constructed as part of the activities of the German Astrophysical Virtual Observatory

This document outlines the important aspects of caring for patients who have been diagnosed with advanced pelvic cancer. It is primarily aimed at those who are establishing a service that adequately caters to this patient group. The relevant literature has been summarized and an attempt made to simplify the approach to management of these complex cases.

Background: Since covid has emerged as the most dreadful global health crisis and data on diagnostic profile and morbidity mortality indicators in it is still limited, we propose to study the correlation of morbidity and mortality with values of Inflammatory markers in these patients. To STUDY variations in INFLAMMATORY MARKERS IN Aim: COVID19 PATIENTS and correlating it with severity of disease. using CLIA technique, four Materials and Methods: inflammatory markers ( TROPONIN -I , ferritin, procalcitonin, IL -6) were studied among 400 patients. This was correlated with severity of the disease outcome among the patients. Among the inflammatory markers we studied Results: IL-6 ,Ferritin,Troponin -I ,Procalcitonin. Raised values of IL-6 and raised ferritin levels were associated with severity. Troponin I (91%) ,Ferritin( 70.8%) ,Calcitonin ( 78.5%) were increased but showed no association with mortality. However only IL-6 seems to be associated with increased mortality among Covid patients. On the basi Conclusion: s of findings in this study Inflammatory markers particularly IL -6 and ferritin can be concluded as important predictors of disease severity and outcome.These parameters can be used to identify high-risk patients at resource-limited settings

The present work deals with the effect of water absorption on the mechanical properties of alkali plus silane treated wheat straw reinforced polystyrene composites. Wheat straw polystyrene composite was prepared with different fibre loading (5%, 10%, 15%, 20%, 25%) by compounding process using twin screw extruder. Samples were prepared by the compression moulding process. There was a decrease in the tensile strength initially at 5% fibre loading followed by an increase in it with higher fibre loading. There is an increase in flexural strength up to 15% fibre loading followed by decrease in it with higher fibre loading. There is an increase in the hardness initially at 5% fibre loading followed by decrease in it with higher fibre loading. There is an increase in water absorption with percentage increase in fibre loading. Tensile strength, flexural strength, and hardness of alkali plus silane treated wheat straw reinforced polystyrene composites with water absorption is always less than alkali plus silane treated wheat straw reinforced polystyrene composites without water absorption.

OBJECTIVE Long posterior cervical decompression and fusion (PCF) is commonly performed to surgically treat patients with multilevel cervical pathology. In cases in which constructs may necessitate crossing the cervicothoracic junction (CTJ), recommendations for appropriate caudal fusion level vary in the literature. The aim of this study was to report the clinical and radiological outcomes of multilevel PCFs ending at C7 versus those crossing the CTJ. METHODS A systematic search of PubMed, CINAHL Plus, and Scopus was conducted to identify articles that evaluated clinical and radiological outcomes of long PCFs that ended at C7 (cervical group) or crossed the CTJ (thoracic group). Based on heterogeneity, random-effects models of a meta-analysis were used to estimate the pooled estimates and the 95% confidence intervals. RESULTS PCF outcome data of 1120 patients from 10 published studies were included. Compared with the cervical group, the thoracic group experienced greater mean blood loss (453.0 ml [95% CI 333.6–572.5 ml] vs 303.5 ml [95% CI 203.4–403.6 ml]), longer operative times (235.5 minutes [95% CI 187.7–283.3 minutes] vs 198.5 minutes [95% CI 157.9–239.0 minutes]), and a longer length of stay (6.7 days [95% CI 3.3–10.2 days] vs 6.2 days [95% CI 3.8–8.7 days]); however, these differences were not statistically significant. None of the included studies specifically investigated factors that led to the decision of whether to cross the CTJ. The cervical group had a mean fusion rate of 86% (95% CI 71%–94%) compared with the thoracic group with a rate of 90% (95% CI 81%–95%). Of patients in the cervical group, 17% (95% CI 10%–28%) required revision surgery compared with 7% (95% CI 4%–13%) of those in the thoracic group, but this difference was not statistically significant. The proportion of patients who experienced complications in the cervical group was found to be 28% (95% CI 12%–52%) versus 14% (95% CI 7%–26%) in the thoracic group; however, this difference was not statistically significant. There was no significant difference (no overlap of 95% CIs) in the incidence of adjacent-segment disease, pseudarthrosis, or wound-related complications between groups. CONCLUSIONS This meta-analysis suggests similar clinical and radiographic outcomes in multilevel PCF, regardless of inclusion of the CTJ. The lowest instrumented level did not significantly affect revision rates or complications. The ideal stopping point must be tailored to each patient on an individualized basis.

In this experiment, we analyzed drivers’ visual attention during their first experiences with automated driving (AD). At the beginning of the study, participants ( n = 45) received one of three AD training modules: paper, video, or practice. They then drove two sessions on a public road with a Wizard-Of-Oz vehicle, each ending with a request to intervene (RTI). The first session (forward path) included 10 min of AD with a mandatory non-driving-related task (NDRT). The second session (return path) included 10 min of AD with a nonmandatory NDRT. Control checks (number and duration of gazes) toward the road and rear-view mirrors and three self-assessment questionnaires (trust, acceptability, and technophilia) were measured during both sessions. The results indicated a decrease in road and rear-view mirror gazes over time, mainly for the practice group. Drivers with a low level of trust glanced at the road and mirrors more often than participants with a high level of trust. In addition, participants with a high level of technophilia spent less time controlling the road traffic but only during the forward path. Visual attention on the road decreased rapidly during the first minutes of AD, mainly among drivers who followed the practice training and those who had a high level of trust and were tech-savvy. We observed that participants looked at the rear-view mirrors after 10 and 14 s on average after the RTI. These results raise questions about driver situation awareness in critical situations, including the capacity to intervene in an efficient and safe way during takeover requests.

We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65-74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele (P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (ΔV50) = ~-15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV50 = ~30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy.

Background Patients with pancreatic cancer are at high risk of developing venous thromboembolism (VTE). It is unknown if aspirin reduces the risk of VTE in this setting. Objectives We sought to determine whether there is an association between aspirin use and VTE risk in patients with pancreatic cancer receiving chemotherapy with a central venous catheter (CVC). Patients/Methods We conducted a single-center, retrospective cohort study of adult patients diagnosed with pancreatic cancer and treated with chemotherapy using a CVC. Subjects were excluded if they were on anticoagulation at the time of CVC placement. The probability of VTE was analyzed using a time-to-event analysis framework for the development of VTE using the product-limit method of Kaplan and Meier (univariate) and adjusting for important confounding covariates using Cox proportional hazards regression (cause-specific hazard) and again using Fine and Gray regression (subdistributional hazard) with death prior to VTE considered a competing event. Results The final analysis included 314 cases (125 with any aspirin use and 189 without). Patients with any aspirin use had fewer VTE events (34.4%) compared with those without aspirin use (42.3%; p = 0.021) by log-rank test and after adjustment for multiple covariates using a Cox proportional hazards model (hazard ratio [HR] = 0.60; 95% confidence interval [CI]: 0.40–0.92; p = 0.019). Using Fine and Gray regression to account for death as a competing event, the effect of aspirin remained in the direction of benefit, but was not statistically significant (HR = 0.70; 95% CI: 0.47–1.05, p = 0.083). Higher body mass index, active smoking, and metastatic stage of cancer were associated with VTE events in the Cox proportional hazards model. Rates of major bleeding or clinically relevant minor bleeding were similar between treatment groups. Conclusions Aspirin may reduce the risk of VTE in patients with pancreatic cancer with a CVC. We did not observe a significant increase in the rates of major bleeding or clinically relevant nonmajor bleeding.

Coronavirus disease 2019 (COVID-19), during the second wave in early 2021, has created disastrous chaos. Adding more burdens to such a challenging situation, mucormycosis is an angioinvasive, fulminant fungal infection has seen a sudden raise in patients with COVID-19. Mucormycosis commonly affects the patients with compromised immunity. Early diagnosis, elimination of the predisposing factor, and antifungal therapy along with surgical debridement are the key factors responsible for successful treatment and patient survival. Mucormycosis is presented by various clinical forms. This paper reviews about the clinical presentation, diagnosis, and various treatment modalities for managing mucormycosis patients.

PURPOSE: Patients who carry reduced-activity DPYD polymorphisms have increased fluoropyrimidine (FP) toxicity risk. Although pretreatment DPYD testing is recommended throughout most of Europe, it is not recommended in the United States, and adoption has been limited. The objective of this survey was to describe the current practice in the United States regarding pretreatment DPYD testing and understand the factors deterring oncologists from ordering testing. METHODS: Survey invitations were e-mailed to 325 medical oncologists practicing in the United States who are members of the SWOG Cancer Research Network Gastrointestinal Cancer, Breast Cancer, or Early Therapeutics Committees. Descriptive statistics were used to evaluate survey responses. RESULTS: Responses were collected from 59 (18.2%) US medical oncologists, of whom 98% strongly or somewhat agree that patients with dihydropyrimidine dehydrogenase (DPD) deficiency have increased toxicity risk and 96% would modify FP dosing for a patient with known DPD deficiency. However, only 32% strongly or somewhat agree that pretreatment DPYD testing is useful to inform FP treatment, 20% have ever ordered pretreatment testing, and 3% order testing for at least 10% of their FP-treated patients. The most important factors that deter oncologists from ordering testing were low prevalence of DPD deficiency (54%) and lack of clinical practice guideline recommendations (48%). CONCLUSION: Clinical adoption of pretreatment DPYD testing is extremely limited in the United States. Utilization may be substantially increased by inclusion in the oncology clinical practice guideline recommendations, coverage through health insurance, and potentially education of medical oncologists regarding available treatment modification guidelines.

Sulfur is important to planetary habitability, but the early sulfur cycle is poorly understood. In particular, S[IV] species (HSO, SO), derived from volcanogenic SO, are critically invoked in recent proposals for origins-of-life chemistry and also influence atmospheric sulfur haze formation, but their abundance in early natural waters is unclear. Here, we combine new laboratory constraints on the kinetics of S[IV] disproportionation with a novel aqueous photochemistry model to estimate the concentrations of S[IV] in natural waters on prebiotic Earth. We show that S[IV] disproportionation is slow in pH≥7 waters, with timescale T≥1 year at room temperature, meaning that S[IV] was present in prebiotic natural waters. However, we also show that photolysis of S[IV] limits [S[IV]]< 100 μM in global-mean steady state. Marine S[IV] was sub-saturation with respect to atmospheric SO, meaning that climate-altering, UV-attenuating sulfur hazes did not persist on prebiotic Earth. [S[IV]] was much lower in natural waters compared to the concentrations generally invoked in laboratory simulations of origins-of-life chemistry (≥10 mM), meaning further work is needed to confirm whether S[IV]-dependent prebiotic chemistries discovered in the lab could have realistically functioned in nature. [S[IV]]≥1 μM in terrestrial waters for: (1) SO outgassing ≥20× modern, (2) pond depths

Context Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. Objective To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. Design We conducted a retrospective medical chart review of pediatric patients with ALD. Setting All patients were seen in a leukodystrophy clinic in an academic medical center. Patients We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). Main Outcome Measures We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Results Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p Conclusions Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Supplementary Figures 11-14 and associated legends.

Study Schema