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Aims/BackgroundThe prognostic significance of body composition variables has become a popular area of research over the recent years. This study aimed to determine whether adipose tissue variables and sarcobesity index measured by computed tomography (CT) could predict cardiopulmonary exercise testing (CPET) performance and long-term mortality in patients undergoing major colorectal surgery.MethodsThe Strengthening the Reporting of Cohort Studies in Surgery (STROCSS) statement standards were followed to conduct a retrospective cohort study of consecutive patients who had CPET prior to major colorectal surgery between January 2011 and January 2017. Receiver Operating Characteristic curve analysis was conducted to assess the discriminative performances of adipose tissue variables. The association between CT-derived adipose tissue variables (sarcobesity index, visceral adipose tissue, subcutaneous adipose tissue, and total adipose tissue) and CPET performance and mortality were assessed using regression analyses.Results457 patients were included. Total adipose tissue evaluated via 2-dimensional (2D) and 3-dimensional (3D) approaches predicted oxygen uptake (V̇O2) Rest, V̇O2anaerobic threshold (AT), ventilatory equivalents for carbon dioxide (V̇E/V̇CO2) AT, ventilatory equivalents for oxygen (V̇E/V̇O2) AT, V̇O2peak, exercise time, maximum work, peak metabolic equivalents (METS), peak respiratory rate (RER), and peak oxygen pulse. Sarcobesity index (2D and 3D) predicted V̇O2Rest, V̇O2AT, V̇E/V̇CO2AT, V̇O2peak, maximum work, peak METS, maximum heart rate, and peak RER. Neither total adipose tissue nor sarcobesity index (2D and 3D) predicted 1-year, 3-year, or 5-year mortality. There was no difference in the discriminative performance of adipose tissue variables in predicting mortality.ConclusionThe CPET performance may be predicted by radiologically measured adipose tissue variables and sarcobesity index. However, the prognostic value of the variables may not be significant in this setting.

PHOTOGRAPH JEFF VINNICK GETTY IMAGES PHOTOGRAPH KEVIN C. COX GETTY IMAGES PHOTOGRAPH RICH LAM GETTY IMAGES PHOTOGRAPH CHRISTOPHER MORRIS CORBIS Caption: SAVING THE WORLD CUP: Christine Sinclair looks on as [...]

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Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

The Muddy River provides habitat for several wildlife and endemic aquatic species protected under the Endangered Species Act. Near Moapa, Nevada, in the Bureau of Land Management's Muddy River Floodplain Restoration Project Area, a previously constructed levee on the east side of the river alters the natural hydrology and decreases connectivity between the river and its floodplain. The Bureau of Land Management is interested in restoring the project area to a more natural state and proposed removing the existing levee (at the time of this study in 2019) on the east bank of the river and replacing it with a new levee farther away from the river. The 50-, 20-, 10-, 4-, 2-, and 1-percent annual exceedance probability flood streamflows were estimated based on a flood-frequency analysis of a streamgage in the study area. River cross-sections were surveyed and combined with a digital elevation model of the floodplains to create a coupled one- and two-dimensional hydraulic model of the study area. The estimated flood streamflows were used as inputs in the hydraulic model to simulate how flood-inundation extents would change with the proposed restoration. Simulated inundation extents expand with increasing flood magnitudes, with nearly the entire valley inundated by the 2-percent flood streamflow. Within the project area, inundation extents with restoration increased on the east floodplain and decreased on the west floodplain for the 20-, 10-, 4-, 2-, and 1-percent flood streamflows. Outside the Muddy River Floodplain Restoration Project Area, inundation extents decreased with restoration east of the project area for the 20- and 10-percent flood streamflows, but changes in extent for larger streamflows were minor because most of the streamflow leaves the main river channel upstream of the restoration area. [ABSTRACT FROM AUTHOR]

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To date, two infliximab biosimilar brands have been approved for use in Australia. In 2020, Queensland Health encouraged biosimilar use by removing the infliximab originator from their state formulary and left only one infliximab biosimilar (Renflexis®; Samsung Bioepis, Sydney, NSW, Australia). The aim was to conduct a quality assurance study examining the incidence of infusion reactions after switching all patients to the one approved biosimilar brand of infliximab. This was a retrospective study of medical charts of all patients who received an infliximab dose at a tertiary hospital between 10 June to 30 September 2020. The number of infusion reactions to the first dose of Renflexis® (Samsung Bioepis) was compared to the two doses immediately prior to the switch with an alternative brand. The study received ethics exemption (2020100904CM). A total of 370 doses of infliximab were dispensed to 139 patients, of which 320 doses (86.5%) were Renflexis® (Samsung Bioepis). There were three patients excluded from the study. A total of 119 patients (88%) were switched to the Renflexis® (Samsung Bioepis) brand and two of these patients (1.7%) experienced a true infusion reaction. When compared to doses prior to the switch, three of 116 patients (2.6%) with data available experienced an infusion reaction for the dose immediately prior, and one of 113 patients (0.9%) for two doses prior. No treatment‐naïve patients (n= 17) initiated on Renflexis® (Samsung Bioepis) experienced an infusion reaction. The use of a biosimilar infliximab, in both treatment‐naïve patients and those and switching from alternative brands, does not appear to have an increased incidence of infusion reactions.

Abstract: One of the most complex patient treatment situations encountered by the clinician is the patient who presents with the cluster of signs and symptoms that lead to the diagnosis [...]

The skin is a multifunctional organ, forming a barrier between the external and internal environment, thereby functioning as a safeguard against extrinsic factors. Autophagy has been implicated in epidermal differentiation and in preserving skin homeostasis. LC3-associated phagocytosis (LAP) uses some but not all components of autophagy. The Atg16l1(ΔWD) mouse model lacks the WD40 domain required for LAP and has been widely used to study the effects of LAP deficiency and autophagy on tissue homeostasis and response to infection.

Biocatalytic reductive amination catalyzed by engineered imine reductase (RedAms) is a new and powerful tool for the synthesis of substituted chiral amines. Herein, we describe a streamlined synthesis of compound 3, a key intermediate to a CDK 2/4/6 inhibitor 1, relying on the enzymatic reductive amination of a hydroxyketone to introduce the chiral secondary amine with high diastereoselectivity. The improved synthesis of the hydroxyketone precursor by a titanium-catalyzed reductive cyclization and the process development for two SNAr reactions en route to 3are also presented.

Cosmic-ray muon scattering tomography has gathered attention in the security and nuclear industries in the last 10 years. Muon scattering tomography is capable of identifying atomic numbers of objects, is highly sensitivity to high-atomic-number materials such as uranium, and is very useful for detecting them in a background of low-atomic-number material. The principle, detectors, and applications of muon tomography are presented, as well as its future aspect.

Medication safety is a World Health Organization health priority, with recognition that greater focus is needed to address this long‐standing healthcare challenge. As medication management experts, hospital pharmacists support the safe and quality use of medications and are ideally positioned to optimise medication safety throughout a patient’s hospital journey. However, hospital pharmacist services are commonly limited to business hours. To synthesise evidence for best practice hospital pharmacist services, with a focus on transitions of care, in support of an extended hours seven‐day service model. A literature search was conducted using PubMed, Embase and Google Scholar to identify studies that evaluated the provision of a seven‐day hospital pharmacist service. Primary studies containing keywords ‘7‐day service’ OR ‘after hours service’ OR ’24‐h service’ AND ‘hospital pharmacist’ OR ‘clinical pharmacist’ AND ‘inpatient’ OR ‘hospital’, and related synonyms in the title and/or abstract, published to December 2019, were identified. Additionally, highly cited studies related to hospital pharmacist services were also reviewed to evaluate benefits during hospitalisation. A narrative synthesis was conducted. Only two studies have evaluated the benefits of seven‐day services. A large number of studies, reporting hospital pharmacist services during inpatient admission support the need for pharmacist services beyond the 8–5 model. These studies demonstrate the vital role of pharmacists in medication management across the continuum of care. Hospital pharmacists are essential in ensuring optimal patient outcomes; however, few studies have appraised extended pharmacy services. To deliver equitable patient‐centred care, a robust evaluation of seven‐day services is needed.

The Bcl-2 inhibitor venetoclax has yielded exceptional clinical responses in chronic lymphocytic leukemia (CLL). However, de novo resistance can result in failure to achieve negative minimal residual disease and predicts poor treatment outcomes. Consequently, additional proapoptotic drugs, such as inhibitors of Mcl-1 and Bcl-xL, are in development. By profiling antiapoptotic proteins using flow cytometry, we find that leukemic B cells that recently emigrated from the lymph node (CD69+/CXCR4Low) in vivo are enriched for cell clusters simultaneously overexpressing multiple antiapoptotic proteins (Mcl-1High/Bcl-xLHigh/Bcl-2High) in both treated and treatment-naive CLL patients. These cells exhibited antiapoptotic resistance to multiple BH-domain antagonists, including inhibitors of Bcl-2, Mcl-1, and Bcl-xL, when tested as single agents in a flow cytometry–based functional assay. Antiapoptotic multidrug resistance declines ex vivo, consistent with resistance being generated in vivo by extrinsic microenvironmental interactions. Surviving “persister” cells in patients undergoing venetoclax treatment are enriched for CLL cells displaying the functional and molecular properties of microenvironmentally induced multidrug resistance. Overcoming this resistance required simultaneous inhibition of multiple antiapoptotic proteins, with potential for unwanted toxicities. Using a drug screen performed using patient peripheral blood mononuclear cells cultured in an ex vivo microenvironment model, we identify novel venetoclax drug combinations that induce selective cytotoxicity in multidrug-resistant CLL cells. Thus, we demonstrate that antiapoptotic multidrug-resistant CLL cells exist in patients de novo and show that these cells persist during proapoptotic treatment, such as venetoclax. We validate clinically actionable approaches to selectively deplete this reservoir in patients.

A syndrome similar to rheumatoid arthritis (RA), which is an autoimmune disease, can be induced in rats by sensitizing them to heat shock protein, a type of protein found in the cell walls of certain bacteria. Two different breeds of rats were sensitized by injection with either heat shock protein or purified protein derivative from Mycobacterium tuberculosis. Purified protein derivative was injected into the rats' knee joints seven days later. One breed developed a transient arthritis. The other breed developed a chronic arthritis with intermittent flare-ups, similar to RA. This breed, as do some humans, has a genetic predisposition to develop RA as well as an inborn immune system disorder.

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The enzyme thrombin appears to have a role in both the inflammatory and healing process of rheumatoid arthritis (RA). RA is a systemic disease usually affecting the joints. Thrombin aids in the formation of blood clots. It causes plate aggregation leading to blood coagulation. Thrombin contributes to the inflammatory process by upregulating the synthesis of arachidonic acid. This leads to the proliferation of synovial cells in joints affected by RA. Fibroblasts may inhibit the inflammatory effects by releasing the thrombin inhibitor PN-1 in a dose-dependent relationship. In addition, thrombin and basic fibroblast growth factors can collectively initiate healing through cellular proliferation and angiogenesis, the development of blood vessels.