Advances in acute and chronic pancreatitis.

Acute pancreatitis (AP) and chronic pancreatitis are the third leading gastrointestinal causes for admissions and readmissions to hospitals in the United States. This review of articles published between 2019-2022 (December) from international sources identified four categories of crucial new findings: The report includes (1) New genetic pathogenic mutations (TRPV6); expected genetic outcomes in a Northern European population; (2) a new serum diagnostic marker for AP-fatty acid ethyl esters-distinguishing acute pancreatitis associated with alcohol; explanations of the impact of monocytes/macrophages on the inflammatory process that defines their future in diagnosis, staging, and treatment; (3) innovations in timing of per os low-fat, solid food intake immediately on admission; resolution of concepts of aggressive parenteral fluid intake; dramatic shifts to non-operative from operative treatment of infected pancreatic necrosis. Each modification reduced interventions, complications, and lengths-of-stay; and (4) authoritarian recommendations for medical treatment of chronic pain. These advances offer opportunities to initiate newly proven treatments to enhance outcomes, alter the natural history, and envision the future of two diseases that have no known cure.

Small Vessel Disease, a Marker of Brain Health: What the Radiologist Needs to Know.

Small vessel disease, a disorder of cerebral microvessels, is an expanding epidemic and a common cause of stroke and dementia. Despite being almost ubiquitous in brain imaging, the clinicoradiologic association of small vessel disease is weak, and the underlying pathogenesis is poorly understood. The STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria have standardized the nomenclature. These include white matter hyperintensities of presumed vascular origin, recent small subcortical infarcts, lacunes of presumed vascular origin, prominent perivascular spaces, cerebral microbleeds, superficial siderosis, cortical microinfarcts, and brain atrophy. Recently, the rigid categories among cognitive impairment, vascular dementia, stroke, and small vessel disease have become outdated, with a greater emphasis on brain health. Conventional and advanced small vessel disease imaging markers allow a comprehensive assessment of global brain heath. In this review, we discuss the pathophysiology of small vessel disease neuroimaging nomenclature by means of the STRIVE criteria, clinical implications, the role of advanced imaging, and future directions.

Experimental and Theoretical Study of the Electronic Structures of Lanthanide Indium Perovskites LnInO3.

Ternary lanthanide indium oxides LnInO3 (Ln = La, Pr, Nd, Sm) were synthesized by high-temperature solid-state reaction and characterized by X-ray powder diffraction. Rietveld refinement of the powder patterns showed the LnInO3 materials to be orthorhombic perovskites belonging to the space group Pnma, based on almost-regular InO6 octahedra and highly distorted LnO12 polyhedra. Experimental structural data were compared with results from density functional theory (DFT) calculations employing a hybrid Hamiltonian. Valence region X-ray photoelectron and K-shell X-ray emission and absorption spectra of the LnInO3 compounds were simulated with the aid of the DFT calculations. Photoionization of lanthanide 4f orbitals gives rise to a complex final-state multiplet structure in the valence region for the 4f n compounds PrInO3, NdInO3, and SmInO3, and the overall photoemission spectral profiles were shown to be a superposition of final-state 4f n-1 terms onto the cross-section weighted partial densities of states from the other orbitals. The occupied 4f states are stabilized in moving across the series Pr-Nd-Sm. Band gaps were measured using diffuse reflectance spectroscopy. These results demonstrated that the band gap of LaInO3 is 4.32 eV, in agreement with DFT calculations. This is significantly larger than a band gap of 2.2 eV first proposed in 1967 and based on the idea that In 4d states lie above the top of the O 2p valence band. However, both DFT and X-ray spectroscopy show that In 4d is a shallow core level located well below the bottom of the valence band. Band gaps greater than 4 eV were observed for NdInO3 and SmInO3, but a lower gap of 3.6 eV for PrInO3 was shown to arise from the occupied Pr 4f states lying above the main O 2p valence band.

Brain and Lung Imaging Correlation in Patients with COVID-19: Could the Severity of Lung Disease Reflect the Prevalence of Acute Abnormalities on Neuroimaging? A Global Multicenter Observational Study.

PURPOSE: Our aim was to study the association between abnormal findings on chest and brain imaging in patients with coronavirus disease 2019 (COVID-19) and neurologic symptoms. MATERIALS AND METHODS: In this retrospective, international multicenter study, we reviewed the electronic medical records and imaging of hospitalized patients with COVID-19 from March 3, 2020, to June 25, 2020. Our inclusion criteria were patients diagnosed with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infection with acute neurologic manifestations and available chest CT and brain imaging. The 5 lobes of the lungs were individually scored on a scale of 0-5 (0 corresponded to no involvement and 5 corresponded to >75% involvement). A CT lung severity score was determined as the sum of lung involvement, ranging from 0 (no involvement) to 25 (maximum involvement). RESULTS: A total of 135 patients met the inclusion criteria with 132 brain CT, 36 brain MR imaging, 7 MRA of the head and neck, and 135 chest CT studies. Compared with 86 (64%) patients without acute abnormal findings on neuroimaging, 49 (36%) patients with these findings had a significantly higher mean CT lung severity score (9.9 versus 5.8, P < .001). These patients were more likely to present with ischemic stroke (40 [82%] versus 11 [13%], P < .0001) and were more likely to have either ground-glass opacities or consolidation (46 [94%] versus 73 [84%], P = .01) in the lungs. A threshold of the CT lung severity score of >8 was found to be 74% sensitive and 65% specific for acute abnormal findings on neuroimaging. The neuroimaging hallmarks of these patients were acute ischemic infarct (28%), intracranial hemorrhage (10%) including microhemorrhages (19%), and leukoencephalopathy with and/or without restricted diffusion (11%). The predominant CT chest findings were peripheral ground-glass opacities with or without consolidation. CONCLUSIONS: The CT lung disease severity score may be predictive of acute abnormalities on neuroimaging in patients with COVID-19 with neurologic manifestations. This can be used as a predictive tool in patient management to improve clinical outcome.

Clinical and Genetic Characteristics of Colorectal Cancer in Persons under 50 Years of Age: A Review.

BACKGROUND: The incidence of colorectal cancer (CRC) in persons under the age of 50 years (EOCRC) is increasing even as the incidence of CRC in persons over age 50 is decreasing. This has led to recommendations to lower the age of CRC screening to age 45. It is not clear whether EOCRC is identical to CRCs in older patients or whether there are distinctive features between the two groups. AIMS AND METHODS: We reviewed the literature on the clinical and genetic aspects of EOCRC. RESULTS: We found that there is an increased likelihood of a strong genetic basis for EOCRC, but that at least 80% of cases do not come from the known high-penetrance cancer syndromes. Early-onset CRCs tend to occur in the distal colon or rectum, are more likely to be detected due to cancer-related symptoms, appear to be increasing in whites more than non-whites on a population-wide analysis, and are more likely to present in an advanced stage of disease. There are some unique genetic features of EOCRC, including an increased proportion of tumors with LINE-1 hypomethylation, and combined chromosomal and microsatellite stability. CONCLUSIONS: EOCRC deserves additional attention because of the high number of life years at risk with EOCRC, and the implications for earlier CRC screening. Additional focus is needed on determining whether some cases of EOCRC have a unique mechanistic basis.

Characterization and Identification of Colorectal Cancer in Persons Younger Than 50 Years.

The proportion of colorectal cancer (CRC) cases in persons younger than age 50, referred to as early onset CRC (EOCRC), has increased from 6% to 11% over the past 25 years, whereas the incidence of CRC has decreased in persons age 50 and older, referred to as late-onset CRC (LOCRC) in the United States.1 It is not known if EOCRC is caused by the same factors that cause LOCRC, or whether there are unique causes that alter the clinical features.2 This study was designed to analyze the clinical and genetic characteristics of EOCRC as presented at a community hospital.

Solution-Processed BiI3 Films with 1.1 eV Quasi-Fermi Level Splitting: The Role of Water, Temperature, and Solvent during Processing.

We present a mechanistic explanation of the BiI3 film formation process and an analysis of the critical factors in preparing high-quality solution-processed BiI3 films. We find that complexation with Lewis bases, relative humidity, and temperature are important factors during solvent vapor annealing (SVA) of films. During SVA, water vapor and higher temperatures limit the formation of the BiI3-dimethylformamide coordination complex. SVA with an optimized water content and temperature produces films with 300-500 nm grains. Films that formed solvent coordination compounds at lower temperatures showed preferential crystal orientation after solvent removal, and we elucidate its implications for carrier transport. Addition of dimethyl sulfoxide to highly concentrated tetrahydrofuran-BiI3 inks prevents film cracking after spin-coating. We have measured a quasi-Fermi level splitting of 1.1 eV and a diffusion length of 70 nm from films processed with optimal temperature and humidity. The best device produced by optimized SVA has a power conversion efficiency of 0.5%, I sc of ∼4 mA/cm2, and V OC of ∼400 mV. The low photocurrent and voltage we attribute to the low diffusion length and the unfavorable band alignment between the absorber and the adjacent transport layers. The deep understanding of the relationship between morphology/crystal structure and optoelectronic properties gained from this work paves the way for future optimization of BiI3-based solar cells.

Pharmacokinetics and dynamics of mycophenolate mofetil after single-dose oral administration in juvenile dachshunds.

Mycophenolate mofetil (MMF) is recommended as an alternative/complementary immunosuppressant. Pharmacokinetic and dynamic effects of MMF are unknown in young-aged dogs. We investigated the pharmacokinetics and pharmacodynamics of single oral dose MMF metabolite, mycophenolic acid (MPA), in healthy juvenile dogs purpose-bred for the tripeptidyl peptidase 1 gene (TPP1) mutation. The dogs were heterozygous for the mutation (nonaffected carriers). Six dogs received 13 mg/kg oral MMF and two placebo. Pharmacokinetic parameters derived from plasma MPA were evaluated. Whole-blood mitogen-stimulated T-cell proliferation was determined using a flow cytometric assay. Plasma MPA Cmax (mean ± SD, 9.33 ± 7.04 µg/ml) occurred at <1 hr. The AUC0-∞ (mean ± SD, 12.84±6.62 hr*µg/ml), MRTinf (mean ± SD, 11.09 ± 9.63 min), T1/2 (harmonic mean ± PseudoSD 5.50 ± 3.80 min), and k/d (mean ± SD, 0.002 ± 0.001 1/min). Significant differences could not be detected between % inhibition of proliferating CD5+ T lymphocytes at any time point (p = .380). No relationship was observed between MPA concentration and % inhibition of proliferating CD5+ T lymphocytes (R = .148, p = .324). Pharmacodynamics do not support the use of MMF in juvenile dogs at the administered dose based on existing therapeutic targets.

Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression.

CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of life span. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for the development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function and development of histopathological myocardial lesions. Progressive increases in the plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in the heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

Sudden cardiac arrest due to a single sodium channel mutation producing a mixed phenotype of Brugada and Long QT3 syndromes.

Inherited arrhythmia syndromes are a known, albeit rare, cause of sudden cardiac arrest which may present with characteristic electrocardiogram changes in patients with structurally normal heart. There are a variety of distinct arrhythmogenic syndromes that arise from mutations in voltage gated sodium channels, resulting in either gain or loss of function. We describe a patient with a primary inherited arrhythmia syndrome which presented as sudden cardiac arrest. Further workup revealed that her arrest was due to a combination of Brugada syndrome and Long QT3 syndrome secondary to a deleterious mutation of voltage-gated, sodium channel, type V alpha subunit (SCN5A Thr1709Met).

Hepatic drug transporters: the journey so far.

INTRODUCTION: The key role of transporter biology in both the manifestation and treatment of disease is now firmly established. Experiences of sub-optimal drug exposure due to drug-transporter interplay have supported incorporation of studies aimed at understanding the interactions between compounds and drug transporters much earlier in drug discovery. While drug transporters can impact the most pivotal pharmacokinetic parameter with respect to human dose and exposure projections, clearance, at a renal or hepatobiliary level, the latter will form the focus of this perspective. AREAS COVERED: A synopsis of guidelines on which transporters to study together with an overview of the currently available toolkit is presented. A perspective on when to conduct studies with various hepatic transporters is also provided together with structural "alerts" which should prompt early investigation. EXPERT OPINION: Great progress has been made in individual laboratories and via consortia to understand the role of drug transporters in disease, drug disposition, drug-drug interactions and toxicity. A systematic analysis of the value posed by the available approaches and an inter-lab comparison now seems warranted. The emerging ability to use physico-chemical properties to guide future screening cascades promises to revolutionise the efficiency of early drug discovery.

Shin-splints: common exercise-related syndromes affecting the lower leg.

Lower leg pain is a common complaint of athletically active individuals, often limiting physical activities. As such, the group of lower leg conditions related to athletic pursuits and physical exercise confer considerable operational implications for the military. Whilst acute injuries to the lower limb are commonly encountered and are clearly of significance, this article focuses instead on chronic conditions related to physical activity. These include insults to bone such as stress fractures and medial tibial stress syndrome, and those related to the soft tissues such as chronic exertional compartment syndrome. In this article we will examine the presentation and management of these conditions.

Dissecting the relative contribution of OATP1B1-mediated uptake of xenobiotics into human hepatocytes using siRNA.

1. Organic anion transporting polypeptide 1B1 plays a pivotal role in the disposition of many anionic drugs. Significant overlap in substrate specificity between individual OATP isoforms has hampered the identification of the relative importance of individual isoforms for hepatic uptake of xenobiotics. 2. The present study focused on the use of siRNA technology to decrease OATP1B1 selectively in human hepatocytes. Following delivery of siRNA by the novel lipid, AtuFECT01, mRNA expression of OATP1B1 was reduced by 94%-98% with no significant toxicity. Off-target effects were also shown to be minimal as evidenced by the expression of common drug metabolizing enzymes, transporters, nuclear receptors and associated co-regulators. Uptake of estrone-3-sulfate (5 nM) by OATP1B1 was reduced by 82%-95%. This methodology was subsequently used to assess the relative contribution of OATP1B1 uptake in human hepatocytes for olmesartan (42%-62%), valsartan (28%-81%), rosuvastatin (64%-72%), pitavastatin (84%-98%) and lopinavir (64%-89%). These data are consistent with previous values obtained using a relative activity factor approach. 3. The siRNA approach provides a robust and reproducible method for assessing the relative contribution of OATP1B1 to hepatic uptake of new chemical entities. The technique also has potential utility in facilitating detailed characterization of drug-drug interactions involving hepatic drug transporters.

Colorectal cancer screening in women with endometrial cancer: are we following the guidelines?

INTRODUCTION: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. There is an association between CRC and endometrial cancer (EC). Up to 10% of this linkage may be due to hereditary non-polyposis colorectal cancer but in the majority of patients a genetic disorder is not found. The National Comprehensive Cancer Network (NCCN) guidelines on CRC since 2005 have suggested that women with endometrial or ovarian cancer diagnosed at less than 60 years of age have CRC screening with colonoscopy beginning at age 40 or at time of diagnosis of the gynecologic tumor. We assessed our population of women with EC to determine if women were receiving CRC screening after a diagnosis of EC. METHODS: Electronic medical records of all women diagnosed at our institution with EC predominantly between 1997 and 2007 were reviewed. We assessed age at diagnosis, tumor type, family history of malignancy, CRC screening, and findings at CRC screening and recorded the information in a database. Patients were evaluated for the Amsterdam and Bethesda criteria. This study was approved by the Institutional Review Board. RESULTS: Two hundred sixty-seven women with EC were evaluated. The median age was 66; 39% were less than age 60 at diagnosis. Family history of CRC was present in 25 (9.4%) of EC patients. Of these women, 125 (46.8%) had CRC screening, with 12 (9.6%) being screened for CRC within 1 year of diagnosis and 33 (26.4%) screened for CRC before diagnosis of endometrial cancer. Of the women, 142 (53.2%) did not have CRC screening reported. Of the women screened, ten had adenomatous polyps with one of those polyps being greater than 1 cm, four had tubulovillous histology, and three had CRC. Colonoscopy was performed in 59.2% of women who underwent CRC screening. One woman met criteria for Amsterdam and Bethesda criteria. CONCLUSIONS: Less than half of women with EC received screening for CRC. Women who were screened had significant pathology in 13.6% of cases and 2.4% had colon cancer. The NCCN guidelines should be more aggressively followed by physicians who care for women. A prospective colonoscopy screening study on these women with EC to assess the yield and utility in screening in this population is needed.

Impact of a family history of colorectal cancer on the prevalence of advanced neoplasia at colonoscopy in 4,967 asymptomatic patients.

BACKGROUND AND AIMS: A family history of colorectal cancer is considered an independent risk factor for advanced neoplasia at colonoscopy. The expected outcome for screening colonoscopy in patients with a family history is not well established in all populations. METHODS: We designed a large, prospective study of an unselected population in San Diego, California to assess the impact of a family history of colorectal cancer on the prevalence of advanced neoplasia on screening colonoscopy. RESULTS: We evaluated 6,905 consecutive patients referred for colonoscopy between January 2005 and December 2006. Of the 4,967 who met the inclusion criteria, the mean age was 58.8 and consisted of 58.6% women. Overall 930 (18.7%) had neoplasia and 249 (5%) had advanced neoplasia, eight (0.16%) of which were cancer. The 4,967 patients were divided into 643 with and 4,324 without a family history of colorectal cancer. Of the 643 patients with a family history, 38 (5.9%) had advanced neoplasia, one of which was cancer. Of the 4,324 patients without a family history, 211 (4.9%) had advanced neoplasia including seven cancers. The relative risk for finding advanced neoplasia in patients with a single affected first degree relative was 1.21 (95% CI, 0.87-1.69; P = 0.31). CONCLUSIONS: A family history of one first-degree relative with colorectal cancer did not predict a significantly higher prevalence of advanced neoplasia at screening colonoscopy in this Southwestern cohort.

Prevalence of advanced adenomas in small and diminutive colon polyps using direct measurement of size.

BACKGROUND AND AIMS: Most studies reporting polyp size use visual estimates. Determining the prevalence of advanced histology based on direct measurement of polyp size may help guide the management of polyps found at optical colonoscopy (OC) and CT colonography (CTC). METHODS: We designed a large, prospective study to assess the prevalence of advanced adenomas based on direct measurement of polyp size by a certified pathologists' assistant as reported in the pathology report. Patients between 40 and 89 years of age who presented for screening colonoscopy were included in our study. Advanced adenomas were defined as ≥10 mm or ≥25% villous features, high grade dysplasia or cancer. Polyps were divided by size into three groups: diminutive (≤5 mm), small (6-9 mm) and large (≥10 mm). If more than one adenoma was present, the most advanced was used for analysis. RESULTS: We evaluated 6,905 consecutive patients referred for colonoscopy between January 2005 and December 2006. Of the 4,967 who met the inclusion criteria, the mean age was 58.8 and consisted of 59% women. Overall, 930 (18.7%) had an adenoma; 248 (5%) were advanced adenomas including 8 (0.16%) cancers. Of 89 polyps≥10 mm, 76 (85%) had advanced histology; of 247 polyps 6-9 mm, 67 (27%) were advanced; of 1,025 polyps ≤5 mm, 105 (10%) were advanced. Thus, 172 of 248 (69%) patients with advanced adenomas had small or diminutive adenomas. CONCLUSIONS: Our data indicate the majority (69%) of advanced adenomas are <10 mm. Even among polyps≤5 mm, there was an appreciable prevalence of advanced adenomas (10%). These findings may help guide the management of sub-centimeter colon polyps found by OC or CTC.

Effects of body condition on measures of intramuscular and rump fat, endocrine factors, and calving rate of beef cows grazing common bermudagrass or endophyte-infected tall fescue.

Multiparous beef cows were managed to achieve marginal (BCS = 4.7 ± 0.07; n = 106) or good (BCS = 6.6 ± 0.06; n = 121) body condition (BC) to determine the influence of forage environment on BW and BC changes, intramuscular fat percentage (IMF), rump fat (RF), and serum hormones during 2 yr. Cows within each BC were randomly assigned to graze either common bermudagrass (CB; n = 3 pastures/yr) or toxic endophyte-infected tall fescue (EI; n = 3 pastures/yr) during a 60-d breeding season. Blood samples were collected at d 0, 30, and 60 of the breeding season, and serum concentrations of prolactin (PRL), IGF-I, and cortisol (CORT) were quantified; PRL and progesterone (P(4)) also were quantified 10 d before the breeding season (d -10). Body weight and BCS were recorded during the breeding season (d 0, 30, and 60). Cow IMF and RF were measured via ultrasonography at the start and end of the breeding season. Cows with increased (>1 ng/mL) P(4) at the beginning of the breeding season (cyclic) had greater (P < 0.02) concentrations of PRL on d 30 and 60 compared with anestrous cows. A forage environment × BC interaction tended (P = 0.07) to influence PRL. Cows grazing CB independent of BC had increased PRL compared with cows grazing EI. Prolactin was decreased in good-BC cows grazing EI compared with cows grazing CB, and cows in marginal BC grazing EI had the least concentrations of PRL. Concentrations of IGF-I were similar (P > 0.10) among good- and marginal-BC cows grazing CB, as well as good-BC cows grazing EI; however, marginal-BC cows grazing EI had reduced (P < 0.04) concentrations of IGF-I compared with all other groups. Cows in marginal BC grazing CB gained (P = 0.02) the most BW during the breeding season, whereas good-BC cows grazing EI gained the least amount of BW. Marginal-BC cows grazing CB tended (P = 0.06) to increase BC during the breeding season, whereas good-BC cows grazing either CB or EI lost BC. Rump fat tended (P = 0.07) to increase during the breeding season in marginal-BC cows compared with cows in good BC. Calving rates were similar (P > 0.10) among good- (82%) and marginal- (84%) BC cows grazing CB, and good-BC cows grazing EI (79%); however, marginal-BC cows grazing EI had a reduced (P = 0.04) calving rate (61%). Cattle grazing EI during the breeding season lost BC. That reduction in BC may be communicated to the pituitary via hormones that include IGF-I or PRL or both, resulting in decreased calving rates.