Imprinted SARS-CoV-2-specific memory lymphocytes define hybrid immunity.

Immune memory is tailored by cues that lymphocytes perceive during priming. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic created a situation in which nascent memory could be tracked through additional antigen exposures. Both SARS-CoV-2 infection and vaccination induce multifaceted, functional immune memory, but together, they engender improved protection from disease, termed hybrid immunity. We therefore investigated how vaccine-induced memory is shaped by previous infection. We found that following vaccination, previously infected individuals generated more SARS-CoV-2 RBD-specific memory B cells and variant-neutralizing antibodies and a distinct population of IFN-γ and IL-10-expressing memory SARS-CoV-2 spike-specific CD4+ T cells than previously naive individuals. Although additional vaccination could increase humoral memory in previously naive individuals, it did not recapitulate the distinct CD4+ T cell cytokine profile observed in previously infected subjects. Thus, imprinted features of SARS-CoV-2-specific memory lymphocytes define hybrid immunity.

Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is causing a global pandemic, and cases continue to rise. Most infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that could contribute to immunity. We performed a longitudinal assessment of individuals recovered from mild COVID-19 to determine whether they develop and sustain multifaceted SARS-CoV-2-specific immunological memory. Recovered individuals developed SARS-CoV-2-specific immunoglobulin (IgG) antibodies, neutralizing plasma, and memory B and memory T cells that persisted for at least 3 months. Our data further reveal that SARS-CoV-2-specific IgG memory B cells increased over time. Additionally, SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral function: memory T cells secreted cytokines and expanded upon antigen re-encounter, whereas memory B cells expressed receptors capable of neutralizing virus when expressed as monoclonal antibodies. Therefore, mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity.

Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis.

BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).

Microbially catalyzed conjugation of GABA and tyramine to bile acids.

Bile acids (BAs) are cholesterol-derived molecules that aid in digestion and nutrient absorption, regulate host metabolic processes, and influence physiology of the gut microbiota. Both the host and its microbiome contribute to enzymatic modifications that shape the chemical diversity of BAs in the gut. Several bacterial species have been reported to conjugate standard amino acids to BAs, but it was not known if bacteria conjugate BAs to other amine classes. Here, we show that Bacteroides fragilis strain P207, isolated from a bacterial bloom in the J-pouch of a patient with ulcerative colitis pouchitis, conjugates standard amino acids and the neuroactive amines γ-aminobutyric acid (GABA) and tyramine to deoxycholic acid. We extended this analysis to other human gut isolates and identified species that are competent to conjugate GABA and tyramine to primary and secondary BAs, and further identified diverse BA-GABA and BA-tyramine amides in human stool. A longitudinal metabolomic analysis of J-pouch contents of the patient from whom B. fragilis P207 was isolated revealed highly reduced levels of secondary bile acids and a shifting BA amide profile before, during, and after onset of pouchitis, including temporal changes in several BA-GABA amides. Treatment of pouchitis with ciprofloxacin was associated with a marked reduction of nearly all BA amides in the J-pouch. Our study expands the known repertoire of conjugated bile acids produced by bacteria to include BA conjugates to GABA and tyramine and demonstrates that these molecules are present in the human gut. IMPORTANCE BAs are modified in multiple ways by host enzymes and the microbiota to produce a chemically diverse set of molecules that assist in the digestive process and impact many physiological functions. This study reports the discovery of bacterial species that conjugate the neuroactive amines, GABA and tyramine, to primary and secondary BAs. We further present evidence that BA-GABA and BA-tyramine conjugates are present in the human gut, and document a shifting BA-GABA profile in a human pouchitis patient before, during, and after inflammation and antibiotic treatment. GABA and tyramine are common metabolic products of the gut microbiota and potent neuroactive molecules. GABA- and tyramine-conjugated BAs may influence receptor-mediated regulatory mechanisms of humans and their gut microbes, and absorption of these molecules and their entry into enterohepatic circulation may impact host physiology at distal tissue sites. This study defines new conjugated bile acids in the human gut.

Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study.

BACKGROUND AND AIMS: ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA). APPROACH AND RESULTS: Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events. CONCLUSIONS: Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

PET imaging of Aspergillus infection using Zirconium-89 labeled anti-ß-glucan antibody fragments.

PURPOSE: Invasive fungal diseases, such as pulmonary aspergillosis, are common life-threatening infections in immunocompromised patients and effective treatment is often hampered by delays in timely and specific diagnosis. Fungal-specific molecular imaging ligands can provide non-invasive readouts of deep-seated fungal pathologies. In this study, the utility of antibodies and antibody fragments (Fab) targeting ß-glucans in the fungal cell wall to detect Aspergillus infections was evaluated both in vitro and in preclinical mouse models. METHODS: The binding characteristics of two commercially available ß-glucan antibody clones and their respective antigen-binding Fabs were tested using biolayer interferometry (BLI) assays and immunofluorescence staining. In vivo binding of the Zirconium-89 labeled antibodies/Fabs to fungal pathogens was then evaluated using PET/CT imaging in mouse models of fungal infection, bacterial infection and sterile inflammation. RESULTS: One of the evaluated antibodies (HA-ßG-Ab) and its Fab (HA-ßG-Fab) bound to ß-glucans with high affinity (KD = 0.056 & 21.5 nM respectively). Binding to the fungal cell wall was validated by immunofluorescence staining and in vitro binding assays. ImmunoPET imaging with intact antibodies however showed slow clearance and high background signal as well as nonspecific accumulation in sites of infection/inflammation. Conversely, specific binding of [89Zr]Zr-DFO-HA-ßG-Fab to sites of fungal infection was observed when compared to the isotype control Fab and was significantly higher in fungal infection than in bacterial infection or sterile inflammation. CONCLUSIONS: [89Zr]Zr-DFO-HA-ßG-Fab can be used to detect fungal infections in vivo. Targeting distinct components of the fungal cell wall is a viable approach to developing fungal-specific PET tracers.

Alterations in exocrine pancreatic function after acute pancreatitis.

Exocrine pancreatic dysfunction (EPD) is a malabsorptive complication of pancreatic disorders that can lead to a host of symptoms ranging from flatulence to diarrhea and contribute to weight loss and metabolic bone disease. It is increasingly recognized to occur after acute pancreatitis (AP), including episodes with mild severity. The risk of developing EPD after AP is influenced by a range of factors, including the degree of acinar cell destruction and inflammation during AP, and persistent structural derangements following AP. In this article, we discuss the epidemiology, pathophysiology, and clinical management of EPD after AP while highlighting key knowledge gaps.

Evaluating models of expert judgment to inform assessment of ecosystem viability and collapse.

Expert judgment underpins assessment of threatened ecosystems. However, experts are often narrowly defined, and variability in their judgments may be substantial. Models built from structured elicitation with large diverse expert panels can contribute to more consistent and transparent decision-making. We conducted a structured elicitation under a broad definition of expertise to examine variation in judgments of ecosystem viability and collapse in a critically endangered ecosystem. We explored whether variation in judgments among 83 experts was related to affiliation and management expertise and assessed performance of an average model based on common ecosystem indicators. There were systematic differences among individuals, much of which were not explained by affiliation or expertise. However, of the individuals affiliated with government, those in conservation and environmental departments were more likely to determine a patch was viable than those in agriculture and rural land management. Classification errors from an average model, in which all individuals were weighted equally, were highest among government agriculture experts (27%) and lowest among government conservation experts (12%). Differences were mostly cases in which the average model predicted a patch was viable but the individual thought it was not. These differences arose primarily for areas that were grazed or cleared of mature trees. These areas are often the target of restoration, but they are also valuable for agriculture. These results highlight the potential for conflicting advice and disagreement about policies and actions for conserving and restoring threatened ecosystems. Although adoption of an average model can improve consistency of ecosystem assessment, it can fail to capture and convey diverse opinions held by experts. Structured elicitation and models of ecosystem viability play an important role in providing data-driven evidence of where differences arise among experts to support engagement and discussion among stakeholders and decision makers and to improve the management of threatened ecosystems.

Análisis de los modelos de opiniones de expertos para informar la evaluación de la viabilidad y el colapso ambiental Resumen La evaluación de los ecosistemas amenazados se basa en la opinión de los expertos. Sin embargo, la definición de experto suele ser limitada y la variabilidad de sus juicios puede ser considerable. Los modelos elaborados a partir de consultas estructuradas con grupos de expertos amplios y diversos pueden contribuir a una toma de decisiones más coherente y transparente. Realizamos una consulta estructurada con una definición amplia de experto para analizar la variación en los juicios sobre la viabilidad y el colapso de un ecosistema en peligro crítico. Exploramos si la variación en los juicios entre 83 expertos estaba relacionada con la afiliación y la experiencia en gestión y evaluamos el rendimiento de un modelo medio basado en indicadores comunes del ecosistema. Observamos diferencias sistemáticas entre los expertos, gran parte de las cuales no se explicaban por la afiliación o la experiencia. Sin embargo, entre los expertos vinculados a la administración pública, los de los departamentos de conservación y medio ambiente tenían más probabilidades de determinar que una parcela era viable que los de agricultura y gestión de tierras rurales. Los errores de clasificación de un modelo medio con todos los individuos ponderados por igual, fueron mayores entre los expertos gubernamentales en agricultura (27%) y menores entre los expertos gubernamentales en conservación (12%). En la mayoría de los casos, las diferencias se debían a que el modelo medio predecía que una parcela era viable, pero el individuo pensaba que no lo era. Estas diferencias surgieron sobre todo en zonas que habían sido pastoreadas o con una tala total de árboles maduros. Estas zonas suelen ser objeto de restauración, pero también son valiosas para la agricultura. Estos resultados ponen de manifiesto la posibilidad de que se produzcan consejos contradictorios y desacuerdos sobre las políticas y acciones de conservación y restauración de los ecosistemas pastoreados y forestales. Si bien la adopción de un modelo medio puede mejorar la coherencia de la evaluación de los ecosistemas, también puede fallar a la hora de captar y transmitir las diversas opiniones de los expertos. Las consultas estructuradas y los modelos de viabilidad de los ecosistemas desempeñan un papel importante a la hora de aportar pruebas basadas en datos de dónde surgen las diferencias entre los expertos para apoyar el compromiso y el debate entre las partes interesadas y los responsables de la toma de decisiones, así como para mejorar la gestión de los ecosistemas amenazados.

Are periprosthetic hip fractures more severe than native hip fractures? A systematic review of outcomes and resource utilization.

BACKGROUND: There is a paucity of data comparing periprosthetic hip fracture (PPHFx) outcomes and resource utilization to native fractures. Many surgeons consider periprosthetic hip fractures to be more severe injuries than native fractures. The aim of this systematic review is to characterize the outcomes of PPHFx and assess their severity relative to native hip fractures (NHFx). METHODS: A Preferred Reporting Items for Systematic Reviews and Meta-Analysis systematic review was conducted using Medline, Biosis, and Cinahl. Primary outcomes were time to surgery, length of stay (LOS), cost of management, disposition, complication rates, readmission rates, and mortality. RESULTS: 14 articles (13,489 patients) from 2010 to 2018 were included in the study. Study quality was generally low. Patient follow-up ranged from 1 month to 3.2 years. LOS ranged from 5.2 to 38 days. US cost of management was best estimated at $53,669 ± 19,817. Discharge to skilled nursing facilities ranged from 64.5 to 74.5%. Time to surgery ranged from 1.9 to 5.7 days. Readmission rates ranged from 12 to 32%. Per Clavien-Dindo classification, 33.9% suffered minor complications; 14.3% suffered major complications. 1 month and 1 year mortality ranged from 2.9% to 10% and 9.7% to 45%, respectively. CONCLUSION: Time to surgery and LOS were longer for PPHFx relative to NHFx. Complications' rates were higher for PPHFx compared to NHFx. There is no evidence for differences in LOS, cost, discharge, readmission rates, or mortality between PPHFx and NHFx. These results may serve as a baseline in future evaluation of PPHFx management.

The Promise of Molecular Imaging: Focus on Central Nervous System Infections.

Central nervous system (CNS) infections can lead to high mortality and severe morbidity. Diagnosis, monitoring, and assessing response to therapy of CNS infections is particularly challenging with traditional tools, such as microbiology, due to the dangers associated with invasive CNS procedures (ie, biopsy or surgical resection) to obtain tissues. Molecular imaging techniques like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging have long been used to complement anatomic imaging such as computed tomography (CT) and magnetic resonance imaging (MRI), for in vivo evaluation of disease pathophysiology, progression, and treatment response. In this review, we detail the use of molecular imaging to delineate host-pathogen interactions, elucidate antimicrobial pharmacokinetics, and monitor treatment response. We also discuss the utility of pathogen-specific radiotracers to accurately diagnose CNS infections and strategies to develop radiotracers that would cross the blood-brain barrier.

Imaging Tumor-Targeting Bacteria Using 18F-Fluorodeoxysorbitol Positron Emission Tomography.

BACKGROUND: Microbial-based cancer treatments are an emerging field, with multiple bacterial species evaluated in animal models and some advancing to clinical trials. Noninvasive bacteria-specific imaging approaches can potentially support the development and clinical translation of bacteria-based cancer treatments by assessing the tumor and off-target bacterial colonization. METHODS: 18F-Fluorodeoxysorbitol (18F-FDS) positron emission tomography (PET), a bacteria-specific imaging approach, was used to visualize an attenuated strain of Yersinia enterocolitica, currently in clinical trials as a microbial-based cancer treatment, in murine models of breast cancer. RESULTS: Y. enterocolitica demonstrated excellent 18F-FDS uptake in in vitro assays. Whole-body 18F-FDS PET demonstrated a significantly higher PET signal in tumors with Y. enterocolitica colonization compared to those not colonized, in murine models utilizing direct intratumor or intravenous administration of bacteria, which were confirmed using ex vivo gamma counting. Conversely, 18F-fluorodeoxyglucose (18F-FDG) PET signal was not different in Y. enterocolitica colonized versus uncolonized tumors. CONCLUSIONS: Given that PET is widely used for the management of cancer patients, 18F-FDS PET could be utilized as a complementary approach supporting the development and clinical translation of Y. enterocolitica-based tumor-targeting bacterial therapeutics.

Are the non-weight bearing guidelines for the after treatment of calcaneal fractures still decisive? A Dutch survey among orthopaedic and trauma surgeons.

PURPOSE: The current rehabilitation for patients with surgically treated displaced intra-articular calcaneal fractures (DIACFs) consists of non-weightbearing for 8-12 weeks. The purpose of the present survey was to investigate the current pre-, peri- and post-operative practices among Dutch foot and ankle surgeons. Moreover, it aims to analyze whether surgeons comply to the Arbeitsgemeinschaft für Osteosynthesefragen (AO) guidelines and which decision criteria were used in the determination of the start of weightbearing. METHODS: A survey was distributed among Dutch trauma and orthopaedic surgeons to determine the most common practices in postoperative weightbearing in patients with DIACFs. RESULTS: 75 surgeons responded to the survey. 33% of the respondents adhered to the AO guidelines. 4% of the respondents strictly followed non-weightbearing guidelines, while 96% interpret the AO guidelines or their local protocol freely, in any frequency. When respondents tended to deviate from the AO guidelines or local protocol, a good patients' compliance to therapy was expected. 83% of the respondents started weightbearing on the fracture, based on reported patient complaints. 87% of the respondents did not see any relation between early weightbearing and the occurrence of complications, including loosening of osteosynthesis materials. CONCLUSION: This study demonstrates that there is limited consensus on the rehabilitation for DIACFs. Moreover, it shows that most surgeons are inclined to interpret the current (AO) guideline or their own local protocol freely. New guidelines, supported with well-founded literature, could help surgeons in a more appropriate daily practice in weightbearing for the rehabilitation of calcaneal fractures.

Impact of Changes to Concealed-Carry Weapons Laws on Fatal and Nonfatal Violent Crime, 1980-2019.

The United States faces rapidly rising rates of violent crime committed with firearms. In this study, we sought to estimate the impact of changes to laws that regulate the concealed carrying of weapons (concealed-carry weapons (CCW) laws) on violent crimes committed with a firearm. We used augmented synthetic control models and random-effects meta-analyses to estimate state-specific effects and the average effect of adopting shall-issue CCW permitting laws on rates of 6 violent crimes: homicide with a gun, homicide by other means, aggravated assault with a gun, aggravated assault with a knife, robbery with a gun, and robbery with a knife. The average effects were stratified according to the presence or absence of several shall-issue permit provisions. Adoption of a shall-issue CCW law was associated with a 9.5% increase in rates of assault with a firearm during the first 10 years after law adoption and was associated with an 8.8% increase in rates of homicide by other means. When shall-issue laws allowed violent misdemeanants to acquire CCW permits, the laws were associated with higher rates of gun assaults. It is likely that adoption of shall-issue CCW laws has increased rates of nonfatal violent crime committed with firearms. Harmful effects of shall-issue laws are most clear when provisions intended to reduce risks associated with civilian gun-carrying are absent.

Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC.

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. METHODS: Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. RESULTS: Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277-468 U/L) and 417 U/L (IQR, 196-801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, -8.3% [IQR, -25.9% to 11.0%]; P = .066), GGT (-29.8% [IQR, -42.3% to -13.9%]; P < .001), alanine aminotransaminase (ALT) (-29.8% [IQR, -43.7% to -6.6%]; P = .002), and aspartate aminotransaminase (AST) (-16.7% [IQR, -35.3% to 1.0%]; P = .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P = .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (-29.8% [IQR, -64.3% to -8.5%]; P = .001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased -23.9% (IQR, -44.4% to -0.6%; P = .006) at week 48 (n = 28) and -25.7% (IQR, -35.9% to 53.7%; P = .91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, -17.3% [IQR, -39.3% to 8.8%]; P = .018; CK18 M65, -43.5% [IQR, -54.9% to 15.3%]; P = .096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P = .028). CONCLUSIONS: In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. CLINICALTRIALS: gov identifier: NCT02943460.

Chromothripsis: A New Mechanism for Rapid Karyotype Evolution.

Chromosomal rearrangements are generally thought to accumulate gradually over many generations. However, DNA sequencing of cancer and congenital disorders uncovered a new pattern in which multiple rearrangements arise all at once. The most striking example, chromothripsis, is characterized by tens or hundreds of rearrangements confined to a single chromosome or to local regions over a few chromosomes. Genomic analysis of chromothripsis and the search for its biological mechanism have led to new insights on how chromosome segregation errors can generate mutagenesis and changes to the karyotype. Here, we review the genomic features of chromothripsis and summarize recent progress on understanding its mechanism. This includes reviewing new work indicating that one mechanism to generate chromothripsis is through the physical isolation of chromosomes in abnormal nuclear structures (micronuclei). We also discuss connections revealed by recent genomic analysis of cancers between chromothripsis, chromosome bridges, and ring chromosomes.

Evaluation and management of exocrine pancreatic insufficiency: pearls and pitfalls.

PURPOSE OF REVIEW: The diagnosis and management of exocrine pancreatic dysfunction (EPD) can be challenging. EPD classically results from conditions that cause loss of pancreatic acinar cell function and decreased digestive enzyme production. However, several conditions may contribute to signs or symptoms of EPD with otherwise normal pancreatic exocrine function. A thoughtful approach to considering these conditions, along with their specific therapies, can guide a tailored management approach. RECENT FINDINGS: An EPD severity classification schema has been proposed, which emphasizes a shift towards a more restrictive prescription of pancreas enzyme replacement therapy (PERT) for patients with milder EPD. In contrast, PERT use has been associated with a measurable survival benefit among individuals with EPD and pancreatic cancer, so the prescription of PERT may be more liberal in this population. Recent publications in the cystic fibrosis population offer pearls guiding the titration and optimization of PERT. SUMMARY: Among individuals with severe EPD, PERT is an effective therapy. Among individuals with milder EPD, although PERT is effective, there may be opportunities to provide additional and potentially more effective therapies.

The importance of expert selection when identifying threatened ecosystems.

Identifying threatened ecosystem types is fundamental to conservation and management decision-making. When identification relies on expert judgment, decisions are vulnerable to inconsistent outcomes and can lack transparency. We elicited judgements of the occurrence of a widespread, critically endangered Australian ecosystem from a diverse pool of 83 experts. We asked 4 questions. First, how many experts are required to reliably conclude that the ecosystem is present? Second, how many experts are required to build a reliable model for predicting ecosystem presence? Third, given expert selection can narrow the range opinions, if enough experts are selected, do selection strategies affect model predictions? Finally, does a diverse selection of experts provide better model predictions? We used power and sample size calculations with a finite population of 200 experts to calculate the number of experts required to reliably assess ecosystem presence in a theoretical scenario. We then used boosted regression trees to model expert elicitation of 122 plots based on real-world data. For a reliable consensus (90% probability of correctly identifying presence and absence) in a relatively certain scenario (85% probability of occurrence), at least 17 experts were required. More experts were required when occurrence was less certain, and fewer were needed if permissible error rates were relaxed. In comparison, only ∼20 experts were required for a reliable model that could predict for a range of scenarios. Expert selection strategies changed modeled outcomes, often overpredicting presence and underestimating uncertainty. However, smaller but diverse pools of experts produced outcomes similar to a model built from all contributing experts. Combining elicited judgements from a diverse pool of experts in a model-based decision support tool provided an efficient aggregation of a broad range of expertise. Such models can improve the transparency and consistency of conservation and management decision-making, especially when ecosystems are defined based on complex criteria.

La importancia de seleccionar expertos para identificar ecosistemas amenazados Resumen La identificación de los tipos de ecosistemas amenazados es fundamental para decidir sobre su conservación y gestión. Cuando la identificación se basa en la opinión de expertos, las decisiones son vulnerables a resultados incoherentes y pueden carecer de transparencia. Recabamos la opinión de 83 expertos sobre la presencia de un ecosistema australiano extendido y en peligro crítico. Se plantearon cuatro preguntas: ¿Cuántos expertos son necesarios para concluir con fiabilidad que el ecosistema está presente?; ¿Cuántos expertos son necesarios para construir un modelo fiable de predicción de la presencia del ecosistema?; ya que la selección de expertos puede reducir el rango de opiniones, si se seleccionan suficientes expertos, ¿afectan las estrategias de selección a las predicciones del modelo; y ¿Una selección diversa de expertos proporciona mejores predicciones del modelo? Utilizamos cálculos de potencia y tamaño de muestra con una población finita de 200 expertos para obtener el número de expertos necesarios para evaluar de forma fiable la presencia de ecosistemas en un escenario teórico. Después usamos árboles de regresión reforzada para modelar la consulta de expertos de 122 parcelas basadas en datos del mundo real. Para obtener un consenso fiable (90% de probabilidad de identificar correctamente la presencia y la ausencia) en un escenario relativamente seguro (85% de probabilidad de ocurrencia), se necesitaban al menos 17 expertos. Se necesitaban más expertos cuando la ocurrencia era menos segura, y menos si se relajaban los porcentajes de error permitidos. En comparación, sólo se necesitaron unos 20 expertos para obtener un modelo fiable que pudiera predecir una serie de escenarios. Las estrategias de selección de expertos modificaron los resultados modelados, a menudo con sobre predicción de la presencia y subestimación de la incertidumbre. Sin embargo, los grupos de expertos más pequeños pero diversos produjeron resultados similares a los de un modelo construido a partir de todos los expertos participantes. La combinación de las opiniones obtenidas de un grupo diverso de expertos en una herramienta de apoyo a la toma de decisiones basada en un modelo proporcionó una agregación eficiente de una amplia gama de conocimientos. Estos modelos pueden mejorar la transparencia y coherencia de la toma de decisiones en materia de conservación y gestión, especialmente cuando los ecosistemas se definen en función de criterios complejos.

Paleolimnological evaluation of metal(loid) enrichment from oil sands and gold mining operations in northwestern Canada.

Abundant reserves of metals and oil have spurred large-scale mining developments across northwestern Canada during the past 80 years. Historically, the associated emissions footprint of hazardous metal(loid)s has been difficult to identify, in part, because monitoring records are too short and sparse to have characterized their natural concentrations before mining began. Stratigraphic analysis of lake sediment cores has been employed where concerns of pollution exist to determine pre-disturbance metal(loid) concentrations and quantify the degree of enrichment since mining began. Here, we synthesize the current state of knowledge via systematic re-analysis of temporal variation in sediment metal(loid) concentrations from 51 lakes across four key regions spanning 670 km from bitumen mining in the Alberta Oil Sands Region (AOSR) to gold mining (Giant and Con mines) at Yellowknife in central Northwest Territories. Our compilation includes upland and floodplain lakes at varying distances from the mines to evaluate dispersal of pollution-indicator metal(loid)s from bitumen (vanadium and nickel) and gold mining (arsenic and antimony) via atmospheric and fluvial pathways. Results demonstrate 'severe' enrichment of vanadium and nickel at near-field sites (≤20 km) within the AOSR and 'severe' (near-field; ≤ 40 km) to 'considerable' (far-field; 40-80 km) enrichment of arsenic and antimony due to gold mining at Yellowknife via atmospheric pathways, but no evidence of enrichment of vanadium or nickel via atmospheric or fluvial pathways at the Peace-Athabasca Delta and Slave River Delta. Findings can be used by decision makers to evaluate risks associated with contaminant dispersal by the large-scale mining activities. In addition, we reflect upon methodological approaches to be considered when evaluating paleolimnological data for evidence of anthropogenic contributions to metal(loid) deposition and advocate for proactive inclusion of paleolimnology in the early design stage of environmental contaminant monitoring programs.

Examination of bidirectional relationships between fear of negative evaluation and weight/shape concerns over 3 years: A longitudinal cohort study of Australian adolescents.

OBJECTIVE: Adolescents commonly experience both fear of negative evaluation and weight/shape concerns. However, evidence concerning the prospective associations between these constructs during adolescence is limited. The current study examined the bidirectional relationships between fear of negative evaluation and weight/shape concerns over a 3-year period in adolescents. METHOD: Australian high school students (n = 2073; 55% girls) completed self-report measures at three timepoints, each 1 year apart. RESULTS: Findings showed a bidirectional relationship, whereby increases in fear of negative evaluation predicted exacerbated weight/shape concerns, and vice versa. Results point towards a vicious maintenance cycle between fear of negative evaluation and weight/shape concerns. DISCUSSION: Findings from the current study highlight the importance of considering both fear of negative evaluation and weight/shape concerns in the development of health promotion and prevention programs designed to reduce the occurrence and adverse effects of body dissatisfaction or improve general mental health. PUBLIC SIGNIFICANCE: Many adolescents experience some level of fear of negative evaluation (i.e., worry about being judged by others) and worry about their weight and/or shape. This study examined the prospective relationship between both constructs. Findings showed a bidirectional relationship, whereby higher fear of negative evaluation predicted increased weight/shape concerns, and vice versa. Programs designed to reduce body dissatisfaction might be improved by targeting both fear of negative evaluation and weight/shape concerns.

Patients with alcohol-related liver disease hospitalized during the COVID-19 pandemic experienced worse outcomes.

INTRODUCTION AND OBJECTIVES: Psychosocial stressors related to the coronavirus-19 (COVID-19) pandemic increased alcohol consumption. The effect on patients with alcohol-related liver diseases remains unclear. MATERIALS AND METHODS: Hospitalizations at a tertiary care center due to alcohol-related liver disease from March 1 through August 31 in 2019 (pre-pandemic cohort) and 2020 (pandemic cohort) were reviewed retrospectively. Differences in patient demographics, disease features, and outcomes were estimated in patients with alcoholic hepatitis utilizing T-tests, Mann-Whitney tests, Chi-square and Fisher Exact Tests and Anova models and logistic regression models in patients with alcoholic cirrhosis. RESULTS: 146 patients with alcoholic hepatitis and 305 patients with alcoholic cirrhosis were admitted during the pandemic compared to 75 and 396 in the pre-pandemic cohort. Despite similar median Maddrey Scores (41.20 vs. 37.45, p=0.57), patients were 25% less likely to receive steroids during the pandemic. Patients with alcoholic hepatitis admitted during the pandemic were more likely to have hepatic encephalopathy (0.13; 95% CI:0.01, 0.25), variceal hemorrhage (0.14; 95% CI:0.04, 0.25), require oxygen (0.11; 95% CI:0.01, 0.21), vasopressors (OR:3.49; 95% CI:1.27, 12.01) and hemodialysis (OR:3.70; 95% CI:1.22, 15.13). On average, patients with alcoholic cirrhosis had MELD-Na scores 3.77 points higher (95% CI:1.05, 13.46) as compared to the pre-pandemic and had higher odds of experiencing hepatic encephalopathy (OR:1.34; 95% CI:1.04, 1.73), spontaneous bacterial peritonitis (OR:1.88; 95% CI:1.03, 3.43), ascites (OR:1.40, 95% CI:1.10, 1.79), vasopressors (OR:1.68, 95% CI:1.14, 2.46) or inpatient mortality (OR:2.00, 95% CI:1.33, 2.99) than the pre-pandemic. CONCLUSIONS: Patients with alcohol-related liver disease experienced worse outcomes during the pandemic.