Bayesian networks and imaging-derived phenotypes highlight the role of fat deposition in COVID-19 hospitalisation risk.

Objective: Obesity is a significant risk factor for adverse outcomes following coronavirus infection (COVID-19). However, BMI fails to capture differences in the body fat distribution, the critical driver of metabolic health. Conventional statistical methodologies lack functionality to investigate the causality between fat distribution and disease outcomes. Methods: We applied Bayesian network (BN) modelling to explore the mechanistic link between body fat deposition and hospitalisation risk in 459 participants with COVID-19 (395 non-hospitalised and 64 hospitalised). MRI-derived measures of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and liver fat were included. Conditional probability queries were performed to estimate the probability of hospitalisation after fixing the value of specific network variables. Results: The probability of hospitalisation was 18% higher in people living with obesity than those with normal weight, with elevated VAT being the primary determinant of obesity-related risk. Across all BMI categories, elevated VAT and liver fat (>10%) were associated with a 39% mean increase in the probability of hospitalisation. Among those with normal weight, reducing liver fat content from >10% to <5% reduced hospitalisation risk by 29%. Conclusion: Body fat distribution is a critical determinant of COVID-19 hospitalisation risk. BN modelling and probabilistic inferences assist our understanding of the mechanistic associations between imaging-derived phenotypes and COVID-19 hospitalisation risk.

Poor glycaemic control and ectopic fat deposition mediates the increased risk of non-alcoholic steatohepatitis in high-risk populations with type 2 diabetes: Insights from Bayesian-network modelling.

Background: An estimated 55.5% and 37.3% of people globally with type 2 diabetes (T2D) will have concomitant non-alcoholic fatty liver disease (NAFLD) and the more severe fibroinflammatory stage, non-alcoholic steatohepatitis (NASH). NAFLD and NASH prevalence is projected to increase exponentially over the next 20 years. Bayesian Networks (BNs) offer a powerful tool for modelling uncertainty and visualising complex systems to provide important mechanistic insight. Methods: We applied BN modelling and probabilistic reasoning to explore the probability of NASH in two extensively phenotyped clinical cohorts: 1) 211 participants with T2D pooled from the MODIFY study & UK Biobank (UKBB) online resource; and 2) 135 participants without T2D from the UKBB. MRI-derived measures of visceral (VAT), subcutaneous (SAT), skeletal muscle (SMI), liver fat (MRI-PDFF), liver fibroinflammatory change (liver cT1) and pancreatic fat (MRI-PDFF) were combined with plasma biomarkers for network construction. NASH was defined according to liver PDFF >5.6% and liver cT1 >800ms. Conditional probability queries were performed to estimate the probability of NASH after fixing the value of specific network variables. Results: In the T2D cohort we observed a stepwise increase in the probability of NASH with each obesity classification (normal weight: 13%, overweight: 23%, obese: 36%, severe obesity: 62%). In the T2D and non-T2D cohorts, elevated (vs. normal) VAT conferred a 20% and 1% increase in the probability of NASH, respectively, while elevated SAT caused a 7% increase in NASH risk within the T2D cohort only. In those with T2D, reducing HbA1c from the 'high' to 'low' value reduced the probability of NASH by 22%. Conclusion: Using BNs and probabilistic reasoning to study the probability of NASH, we highlighted the relative contribution of obesity, ectopic fat (VAT and liver) and glycaemic status to increased NASH risk, namely in people with T2D. Such modelling can provide insights into the efficacy and magnitude of public health and pharmacological interventions to reduce the societal burden of NASH.

Volunteers as adjunct researchers in a cancer prevention trial: the American Cancer Society Colon Polyp Prevention Study.

BACKGROUND: In April 1991, the Virginia Division of the American Cancer Society (ACS) initiated the feasibility phase of the Colon Polyp Prevention Study (CPPS) to determine whether a high fiber supplement would decrease new adenomatous colorectal polyp occurrence. The feasibility phase had two specific objectives: 1) to evaluate accrual and compliance to the designed protocol and 2) to evaluate and demonstrate the effectiveness of volunteers as research assistants. The CPPS is an innovative project in which trained volunteers play a significant role in the research process. METHODS: In the CPPS, volunteer adjunct researchers (VARs) were trained to perform individual dietary data collection and intervention and other general study monitoring functions. VARs were trained, certified, and monitored in the performance of their assigned tasks by ACS staff and expert consultants. RESULTS: A total of 119 volunteers were trained as VARs, 74 of whom were certified and matched to a study participant. Between 1991-1995, only six VARs left the study. After active accrual of participants to the study ceased in 1995, 38 VARs (50% of the certified VARs) continued to monitor the active study participants. All VARs were consistently able to conduct the functions for which they were trained. CONCLUSIONS: In spite of expected volunteer attrition rates, a core of 38 dedicated VARs were matched to 72 participants and demonstrated the ability to perform selected data collecting activities on a consistent and efficient basis. The use of trained volunteers has allowed the CPPS to function in its feasibility phase at personnel cost considerably less than that of other similar cancer prevention trials.

Interaction of norfloxacin with divalent and trivalent pharmaceutical cations. In vitro complexation and in vivo pharmacokinetic studies in the dog.

The formation constants of the fluoroquinolones norfloxacin and ciprofloxacin with Mg2+ (log beta 1 = 2.97(4), log beta 2 = 5.6(2)), Zn2+ (log beta 1 = 3.77(2), log beta 2 = 7.59(3)), and Fe2+ (log beta 1 = 3.99(5), log beta 2 = 7.2(5)) were determined by potentiometric titration. The pH at which precipitation occurred in the titration solutions was compared for the metal ions Ca2+, Mg2+, Zn2+, Fe2+, Cu2+, and Al3+. The formation constants were used to predict a rank order of metals that may be expected to hinder the gastrointestinal absorption of the fluoroquinolones, in vivo. The effects of metal ions on the pharmacokinetics of orally-administered norfloxacin in the dog were investigated. Norfloxacin (12 mg/kg) was administered alone or with equimolar doses of each of the chloride salts of Ca2+, Mg2+, Zn2+, Fe2+, and Al3+. Statistically significant reductions in serum norfloxacin concentrations were observed after analysis by HPLC. The Cmax was reduced 29-85%, while the area under the norfloxacin serum concentration-time curve (AUC0-infinity) was reduced by 29-79%. The extent of the reduction in AUC0-infinity was correlated with the magnitude of the formation constant of the 1:1 norfloxacin:metal chelate complex for the divalent metal ions. On coadministration of 12 mg/kg norfloxacin with various doses of Mg2+ (chloride) the AUC0-infinity and Cmax decreased with increasing Mg2+ dose. The interaction peaked at a Mg2+:norfloxacin ratio of 1:2 suggesting the formation of a 1:2 Mg:norfloxacin complex. Formation constant data were used to simulate the percentage of norfloxacin complexed at pH 6.5. Combinations of metal ion and norfloxacin which result in only a small extent (< 20%) of norfloxacin complex formation can result in relatively large decreases in oral bioavailability of this antimicrobial agent.

Copper(II) complexes of the fluoroquinolone antimicrobial ciprofloxacin. Synthesis, X-ray structural characterization, and potentiometric study.

Reaction of the fluoroquinolone antimicrobial ciprofloxacin with copper(II) nitrate in the presence of 2,2'-bipyridine resulted in the isolation of the complex [Cu(cip)(bipy) (Cl)0.7(NO3)0.3] (NO3).2H2O. Reaction of an aqueous solution of ciprofloxacin.HCl and NaCl with CuCl2 at pH 5.0 resulted in the isolation of [Cu(cip)2]Cl2.11H2O. The complex [Cu(cip) (bipy)(Cl)0.7(NO3)0.3] (NO3).2H2O crystallizes in the monoclinic space group P2(1)/n, with a = 13.955(8), b = 14.280(8), c = 14.192(6) A, beta = 93.10(4) degrees, Z = 4 with R = 0.046. The selective broadening of resonances in the 13C NMR spectrum of ciprofloxacin by the addition of Cu2+(aq) was employed to probe metal ion binding sites in the ligand. The protonation constants of norfloxacin and ciprofloxacin, and the formation constants with copper(II), were determined by potentiometric titrations at 25 degrees C. The additions of ciprofloxacin to metal to form ML and ML2 complexes exhibit stepwise formation constants of log K1 6.2(1) and log K2 11.1(3), respectively.

Percutaneous endoscopic gastrojejunostomy: a dual center safety and efficacy trial.

Although jejunal tube placement through a percutaneous endoscopic gastrostomy (PEG) has not been proven to be preferable to PEG feeding, it would be theoretically advantageous for those patients prone to gastrointestinal aspiration. However, reliable placement of a small bowel feeding tube through a PEG has been technically difficult. We have previously reported successful placement of a percutaneous endoscopic gastrojejunostomy (PEG/J) with minimal complications. These results are in contrast to other series that report technical difficulty, frequent tube dysfunction and gastric aspiration. We describe an over-the-wire PEG/J technique performed by multiple operators at two medical centers. Gastrostomy tube placement was successful in 94% of patients. Initial placement of the jejunal tube was successful in 88% of patients. Second attempts were 100% successful. The average procedure time was 36 minutes. The distal duodenal and jejunal placement of the jejunal tube resulted in no episodes of gastroduodenal reflux. Complications included jejunal tube migration (6%), clogging (18%), and unintentional removal (11%). The majority of patients were ultimately converted to either oral or intragastric feedings. We conclude that the PEG/J system is a reliable, reproducible method of small bowel feeding and is associated with no episodes of tube feeding reflux when the jejunal tube is positioned in the distal duodenum or beyond. Furthermore, it provides a temporary nutritional bridge for those patients who are later transitioned to either PEG or oral feeding.

Hepatic lidocaine metabolism and liver histology in patients with chronic hepatitis and cirrhosis.

Recent advances in the medical and surgical treatment of chronic hepatitis and cirrhosis have made it increasingly important to develop noninvasive tests of liver function. Our study has evaluated the hepatic conversion of lidocaine to its primary metabolite monoethylglycinexylodide and compared this with liver histological findings in 225 patients with chronic hepatitis (161 with hepatitis C, 23 with hepatitis B, 21 with autoimmune hepatitis and 20 with cryptogenic hepatitis). One hundred seven (47.7%) patients had cirrhosis at the time of evaluation. A decline in monoethylglycinexylodide production was observed with worsening liver histological conditions from a mean of 81.5 +/- 7.0 ng/ml in patients with chronic persistent hepatitis to 61.2 +/- 5.5 ng/ml for chronic active hepatitis and 20.9 +/- 1.5 ng/ml in patients with cirrhosis (p < 0.05). A further stepwise decline in monoethylglycine xylodide production was observed with worsening Child class: from 25.5 +/- 2.2 ng/ml for class A patients to 8.9 +/- 1.4 ng/ml for patients with Child class C disease (p < 0.05). All patients with monoethylglycinexylodide production less than 20 ng/ml had cirrhosis confirmed on histological examination. In contrast, no relationship was observed between liver histological status and serum transaminases (AST or ALT), bilirubin, albumin and prothrombin time. Thirty-five patients underwent repeat histological evaluation and monoethylglycinexylodide testing after receiving at least 6 mo treatment for chronic hepatitis (interferon for hepatitis B and C and corticosteroids for autoimmune hepatitis). The change in monoethylglycinexylodide production observed in these patients was a linear function of the change in Knodell histological index (r = 0.73, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of hydrophobic bile acids on 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity and mRNA levels in the rat.

We have previously reported that relatively hydrophobic bile acids, decreased hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase (reductase) activity whereas, hydrophilic bile acids had little effect on the enzyme. The purpose of the present study was to determine in more detail the mechanism of down-regulation of hepatic reductase activity by hydrophobic bile salts. Groups of rats were fed bile acids of differing hydrophobicity: ursodeoxycholic, cholic (CA), chenodeoxycholic (CDCA), deoxycholic (DCA), or cholesterol for 14 days. Reductase specific activities and concentrations of reductase protein were determined in hepatic microsomes. Quantitation of "steady state" levels of reductase mRNA was performed using Northern and dot blot hybridization. Reductase gene transcriptional activity (nuclear "run-on") was determined in nuclei isolated from livers of animals fed different bile acids. Hydrophobic bile acids and cholesterol significantly decreased reductase activity: CA (57%), CDCA (77%), DCA (73%), cholesterol (89%), and reductase protein levels as measured by an enzyme-linked immunosorbent assay method were also decreased; CA (27%), CDCA (31%), DCA (42%), and cholesterol (35%). Reductase mRNA levels were also decreased after feeding hydrophobic bile acid: CA (43%), CDCA (47%), DCA (54%), and cholesterol (53%). Ursodeoxycholic, a hydrophilic bile acid, caused a much smaller decrease in reductase activity (18%), protein mass (16%), and mRNA levels (10%). Decreased transcriptional activities were observed in CA- and cholesterol-fed rats. Surprisingly, CDCA- and DCA-fed animals showed transcriptional activities similar to control animals even though steady state mRNA levels were low in CDCA- and DCA-fed animals. We hypothesize a post-transcriptional regulation of reductase mRNA by hydrophobic bile acids.

Experimental unilateral coronal synostosis in rabbits.

Immobilization of the coronal suture was produced unilaterally in 9-day-old rabbits to determine its effect on subsequent craniofacial development. The suture was immobilized unilaterally by the topical application of methylcyanoacrylate adhesive. Subsequent growth effects on the cranial vault, base, and facial skeleton were assessed by serial radiographic cephalometry. Unilateral coronal suture immobilization resulted in significantly decreased bone growth at the coronal suture (mean 0.95 mm +/- 0.35 SE) when compared to sham-treated control animals (mean 5.06 mm +/- 0.20 SE). Frontonasal suture bone growth contralateral to the immobilized half of the coronal suture, however, was significantly increased. The anterior cranial base became significantly shortened, and orbital asymmetry developed. The pattern of induced abnormalities simulates unilateral coronal synostosis in humans.