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Journal of Clinical and Experimental... 2024Limited data exist on the safety of early nasogastric (NG) feeding in patients with cirrhosis after endotherapy for variceal bleeding (VB). We studied the impact of...
BACKGROUND AND AIMS
Limited data exist on the safety of early nasogastric (NG) feeding in patients with cirrhosis after endotherapy for variceal bleeding (VB). We studied the impact of early NG tube feeding in these patients in this proof-of-concept open-label randomized controlled trial.
METHODS
Eligible patients with cirrhosis undergoing endotherapy for VB were randomized to receive either a liquid diet through a 14 Fr NG tube (commencing 1 h after endotherapy) (early feeding [EF] group) or sips of water and lemon water orally (standard-of-care [SOC] group) for total duration of 48 h. The primary outcome was 5-day rebleeding in both arms. Other outcomes included 5-day infection rate, hepatic encephalopathy during hospitalization, and 6-week mortality.
RESULTS
Eighty patients (Mean age: 41 ± 11.5 years; males [82.5%]; alcohol etiology [55%]) were included. Baseline median Child-Pugh and MELD scores were similar (CTP: 8 [IQR: 8-9] vs 9 [8-9.25]; = 0.47 and MELDNa: 13 [10.75-16.25] vs 15 [12-18.25]; = 0.16). The 5-day rebleeding rates in EF and SOC groups were 2.5% and 5%, respectively ( = 0.55), and non-inferiority or superiority of either could not be demonstrated. The incidence of infection (2.5% [EF] vs 2.5% [SOC]; = 1.00) and development of HE (5% [EF] vs 2.5% [SOC]; = 0.36) during hospitalization were comparable. The average daily calorie and protein intake in the EF group during the 48 h was 1318 ± 240 Kcals and 43.4 ± 9.2 g of proteins. No patient in the EF group had feed intolerance.
CONCLUSION
Early initiation of NG tube-based feeding after endotherapy in VB appears safe and well tolerated without the additional risk of rebleeding or encephalopathy.
PubMed: 38076376
DOI: 10.1016/j.jceh.2023.07.413 -
Journal of Clinical and Experimental... 2024Diabetes mellitus (DM) increases morbidity and mortality in advanced cirrhosis. Information on the prognostic impact of DM in compensated cirrhosis is scarce. We aimed...
BACKGROUND AND OBJECTIVES
Diabetes mellitus (DM) increases morbidity and mortality in advanced cirrhosis. Information on the prognostic impact of DM in compensated cirrhosis is scarce. We aimed to explore the effect of DM and glycemic control on the natural history of compensated cirrhotic patients.
METHODS
This retrospective longitudinal cohort study included Child A/B cirrhosis without or free from decompensation or hospitalization > 1 year. Data on survival, unplanned hospitalization, hepatic decompensation (ascites, portal hypertension-related bleeding, hepatic encephalopathy, acute kidney injury), new infection, and hepatocellular carcinoma (HCC) were collected.
RESULTS
457 patients were included (71.3% Child A, model for end-stage liver disease [MELD] 9.9 ± 3.1, alcohol/hepatitis B virus/hepatitis C virus 39.2%/21.7%/15.1%, 34.4% had DM). The cumulative overall survival was lower in DM group (75.7% vs. 86.5% at 10 yrs, = 0.01). By multivariable Cox regression models adjusted with Child-Pugh and MELD score, DM was associated with higher mortality (hazards ratio [HR] 2.4, = 0.014, and HR 2.03, = 0.04, respectively). The cumulative incidences of unplanned hospitalizations (46.3% vs. 24.8% at 5 yrs, < 0.001), hepatic decompensation (45% vs. 20.8% at 5 yrs, < 0.001), new infection (47.2% vs. 20.2% at 5 yrs, < 0.001), and HCC (29.3% vs. 16.8% at 10 yrs, = 0.03) were higher in DM group. In patients with DM, 27.4% patients had poor glycemic control (HbA1c ≥7.0% for ≥80% of the study period). The cumulative overall survival was lower in poor glycemic control group (52.3% vs. 85.2% at 10 yrs, = 0.02). By univariable Cox regression model, poor glycemic control was associated with higher mortality (HR 2.67, = 0.025).
CONCLUSIONS
In compensated cirrhosis, when coexisting with DM, the complications and mortality rates magnify. Poor glycemic control reduces survival in cirrhotic patients with DM. Proper diabetic screening and management should be emphasized in the care of these patients.
PubMed: 38076358
DOI: 10.1016/j.jceh.2023.07.410 -
ESC Heart Failure Feb 2024Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ivabradine, a medical treatment for heart failure (HF), reduces heart rate (HR) and prolongs diastolic perfusion time. It is frequently prescribed to patients with HF who have a suboptimal response or intolerance to beta-blockers. Degenerative mitral regurgitation (MR) is a valvular heart disease often associated with the development of HF and atrial fibrillation (AF). However, studies comparing the effects of ivabradine and beta-blockers on MR are lacking. Therefore, this study aimed to explore the potential therapeutic effects of ivabradine and carvedilol on MR using a rat model.
METHODS AND RESULTS
Using a novel echo-guided mini-invasive surgery, MR was created in 12-weeks-old Sprague-Dawley rats. After 2 weeks, the rats were randomized to receive either ivabradine or carvedilol for 4 weeks. Echocardiography was performed at baseline and at two-week intervals. Following haemodynamic studies, postmortem tissues were analysed. Notably, the MR-induced myocardial dysfunction did not improve considerably after treatment with ivabradine or carvedilol. However, in haemodynamic studies, pharmacological therapies, particularly carvedilol, mitigated MR-induced chamber dilatation (end-systolic volume and end-diastolic volume; MR vs. MR + Carvedilol; P < 0.05) and decreased compliance (end-systolic pressure-volume relationship; MR vs. MR + Carvedilol; P < 0.05). Compared with ivabradine, a shorter duration (MR vs. MR + Carvedilol; P < 0.05) and reduced inducibility (MR vs. MR + Carvedilol and MR vs. MR + Ivabradine; P < 0.05) of AF were observed in MR rats treated with carvedilol. Similarly, reduced cardiac fibrosis and apoptosis were observed in the MR rat model in the treatment groups, especially in those treated with carvedilol (MR vs. MR + Carvedilol; P < 0.01).
CONCLUSIONS
Although both ivabradine and carvedilol, at least in part, mitigated MR-induced chamber dilatation and decreased compliance, carvedilol had a better effect on reversing MR-induced cardiac fibrosis, apoptosis, and arrhythmogenesis than ivabradine. When compared with Ivabradine, MR rats treated with carvedilol exhibited a shorter duration and reduced inducibility of AF, thus providing more effective suppression of HCN4. Further investigations are required to validate our findings.
Topics: Humans; Rats; Animals; Carvedilol; Ivabradine; Mitral Valve Insufficiency; Rats, Sprague-Dawley; Adrenergic beta-Antagonists; Heart Failure; Atrial Fibrillation; Fibrosis
PubMed: 37963437
DOI: 10.1002/ehf2.14577 -
MBio Nov 2023is an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels due to its efficient ethanol fermentation and low biomass...
is an alpha-proteobacterium that is a promising platform for industrial scale production of biofuels due to its efficient ethanol fermentation and low biomass generation. is aerotolerant and encodes a complete respiratory electron transport chain, but the benefit of respiration for growth in oxic conditions has never been confirmed, despite decades of research. Growth and ethanol production of wild-type is poor in oxic conditions indicating that it does not benefit from oxidative phosphorylation. Additionally, in previous studies, aerobic growth improved significantly when respiratory genes were disrupted () or acquired point mutations ( and ), even if respiration was significantly reduced by these changes. Here, we obtained clean deletions of respiratory genes and , individually and in combination, and showed, for the first time, that deletion of completely inhibited O respiration and dramatically reduced growth in oxic conditions. Both respiration and aerobic growth were restored by expressing a heterologous, water-forming NADH oxidase, . Oxygen can have many negative effects, including formation of reactive oxygen species (ROS) or directly inactivating oxygen sensitive enzymes. Our results suggest that the effect of molecular oxygen on enzymes had a greater negative impact on than formation of ROS. This result shows that the main role of the electron transport chain in is reducing the intracellular concentration of molecular oxygen, helping to explain why it is beneficial for to use electron transport chain complexes that have little capacity to contribute to oxidative phosphorylation. IMPORTANCE A key to producing next-generation biofuels is to engineer microbes that efficiently convert non-food materials into drop-in fuels, and to engineer microbes effectively, we must understand their metabolism thoroughly. is a bacterium that is a promising candidate biofuel producer, but its metabolism remains poorly understood, especially its metabolism when exposed to oxygen. Although respires with oxygen, its aerobic growth is poor, and disruption of genes related to respiration counterintuitively improves aerobic growth. This unusual result has sparked decades of research and debate regarding the function of respiration in . Here, we used a new set of mutants to determine that respiration is essential for aerobic growth and likely protects the cells from damage caused by oxygen. We conclude that the respiratory pathway of should not be deleted from chassis strains for industrial production because this would yield a strain that is intolerant of oxygen, which is more difficult to manage in industrial settings.
PubMed: 37909744
DOI: 10.1128/mbio.02043-23 -
Nutrients Oct 2023Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models....
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
Topics: Humans; Animals; Mice; Fructose Intolerance; Fructose; Fructose-Bisphosphate Aldolase; Liver Diseases; Digestive System Diseases; Glucose; Mice, Knockout
PubMed: 37892451
DOI: 10.3390/nu15204376 -
The Journal of Clinical Investigation Jan 2024In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically,...
BACKGROUND
In Lewy body diseases (LBDs) Parkinson disease (PD), and dementia with Lewy bodies (DLB), by the time parkinsonism or cognitive dysfunction manifests clinically, substantial neurodegeneration has already occurred. Biomarkers are needed to identify central LBDs in a preclinical phase, when neurorescue strategies might forestall symptomatic disease. This phase may involve catecholamine deficiency in the autonomic nervous system. We analyzed data from the prospective, observational, long-term PDRisk study to assess the predictive value of low versus normal cardiac 18F-dopamine positron emission tomography (PET), an index of myocardial content of the sympathetic neurotransmitter norepinephrine, in at-risk individuals.
METHODS
Participants self-reported risk factor information (genetics, olfactory dysfunction, dream enactment behavior, and orthostatic intolerance or hypotension) at a protocol-specific website. Thirty-four with 3 or more confirmed risk factors underwent serial cardiac 18F-dopamine PET at 1.5-year intervals for up to 7.5 years or until PD was diagnosed.
RESULTS
Nine participants had low initial myocardial 18F-dopamine-derived radioactivity (<6,000 nCi-kg/cc-mCi) and 25 had normal radioactivity. At 7 years of follow-up, 8 of 9 with low initial radioactivity and 1 of 11 with normal radioactivity were diagnosed with a central LBD (LBD+) (P = 0.0009 by Fisher's exact test). Conversely, all 9 LBD+ participants had low 18F-dopamine-derived radioactivity before or at the time of diagnosis of a central LBD, whereas among 25 participants without a central LBD only 1 (4%) had persistently low radioactivity (P < 0.0001 by Fisher's exact test).
CONCLUSION
Cardiac 18F-dopamine PET highly efficiently distinguishes at-risk individuals who are diagnosed subsequently with a central LBD from those who are not.
CLINICALTRIALS
gov NCT00775853.
FUNDING
Division of Intramural Research, NIH, NINDS.
Topics: Humans; Dopamine; Prospective Studies; Lewy Bodies; Positron-Emission Tomography; Parkinson Disease; Norepinephrine
PubMed: 37883190
DOI: 10.1172/JCI172460 -
JAMA Neurology Dec 2023Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Cryptogenic sensory peripheral neuropathy (CSPN) is highly prevalent and often disabling due to neuropathic pain. Metabolic syndrome and its components increase neuropathy risk. Diet and exercise have shown promise but are limited by poor adherence.
OBJECTIVE
To determine whether topiramate can slow decline in intraepidermal nerve fiber density (IENFD) and/or neuropathy-specific quality of life measured using the Norfolk Quality of Life-Diabetic Neuropathy (NQOL-DN) scale.
DESIGN, SETTING, AND PARTICIPANTS
Topiramate as a Disease-Modifying Therapy for CSPN (TopCSPN) was a double-blind, placebo-controlled, randomized clinical trial conducted between February 2018 and October 2021. TopCSPN was performed at 20 sites in the National Institutes of Health-funded Network for Excellence in Neurosciences Clinical Trials (NeuroNEXT). Individuals with CSPN and metabolic syndrome aged 18 to 80 years were screened and randomly assigned by body mass index (<30 vs ≥30), which is calculated as weight in kilograms divided by height in meters squared. Patients were excluded if they had poorly controlled diabetes, prior topiramate treatment, recurrent nephrolithiasis, type 1 diabetes, use of insulin within 3 months before screening, history of foot ulceration, planned bariatric surgery, history of alcohol or drug overuse in the 2 years before screening, family history of a hereditary neuropathy, or an alternative neuropathy cause.
INTERVENTIONS
Participants received topiramate or matched placebo titrated to a maximum-tolerated dose of 100 mg per day.
MAIN OUTCOMES AND MEASURES
IENFD and NQOL-DN score were co-primary outcome measures. A positive study was defined as efficacy in both or efficacy in one and noninferiority in the other.
RESULTS
A total of 211 individuals were screened, and 132 were randomly assigned to treatment groups: 66 in the topiramate group and 66 in the placebo group. Age and sex were similar between groups (topiramate: mean [SD] age, 61 (10) years; 38 male [58%]; placebo: mean [SD] age, 62 (11) years; 44 male [67%]). The difference in change in IENFD and NQOL-DN score was noninferior but not superior in the intention-to-treat (ITT) analysis (IENFD, 0.21 fibers/mm per year; 95% CI, -0.43 to ∞ fibers/mm per year and NQOL-DN score, -1.52 points per year; 95% CI, -∞ to 1.19 points per year). A per-protocol analysis excluding noncompliant participants based on serum topiramate levels and those with major protocol deviations demonstrated superiority in NQOL-DN score (-3.69 points per year; 95% CI, -∞ to -0.73 points per year). Patients treated with topiramate had a mean (SD) annual change in IENFD of 0.56 fibers/mm per year relative to placebo (95% CI, -0.21 to ∞ fibers/mm per year). Although IENFD was stable in the topiramate group compared with a decline consistent with expected natural history, this difference did not demonstrate superiority.
CONCLUSION AND RELEVANCE
Topiramate did not slow IENFD decline or affect NQOL-DN score in the primary ITT analysis. Some participants were intolerant of topiramate. NQOL-DN score was superior among those compliant based on serum levels and without major protocol deviations.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02878798.
Topics: Aged; Female; Humans; Male; Middle Aged; Diabetic Neuropathies; Double-Blind Method; Metabolic Syndrome; Neuralgia; Quality of Life; Topiramate; Adolescent; Young Adult; Adult; Aged, 80 and over
PubMed: 37870862
DOI: 10.1001/jamaneurol.2023.3711 -
Cureus Sep 2023Introduction Skin hydration is important for maintaining adequate skin barrier function. After delivery, the baby's skin faces the most difficult challenge as they are...
Introduction Skin hydration is important for maintaining adequate skin barrier function. After delivery, the baby's skin faces the most difficult challenge as they are exposed to the exterior world's environmental changes, friction, and microorganisms. The management is further complicated by the availability of a large range of infant skin-care products with varying claims. The first-ever Indian study on babies was done to analyze the test product (Venusia baby moisturizer; Dr. Reddy's Laboratories Ltd., Hyderabad, India) in order to bring scientific clarity to consumers. This product is devoid of parabens, alcohol, and animal origin (Dr. Reddy's Laboratories Ltd., Hyderabad, India) and is designed for skin hydration and in-use tolerance in babies with dry and/or normal skin. The endpoints were hydration and clinical evaluation of the skin, evaluated using a moisture meter scale (MMSC; Delfin Technologies Ltd., Kuopio, Finland) and parent self-assessment questionnaire, respectively. Material and methods A total of 136 healthy babies aged between six months to two years were enrolled in a four-group, monocentric, non-randomized, evaluator-blinded study: Group 1 (Venusia baby cream for dry skin), Group 2 (Venusia baby lotion for Dry Skin), Group 3 (Venusia baby cream for normal skin), and Group 4 (Venusia baby lotion for normal skin). The endpoints were hydration and clinical evaluation of the skin, evaluated using an MMSC and parent self-assessment questionnaire, respectively. Results In babies with dry skin, skin hydration was improved with Venusia baby cream (37.50%) and Venusia baby lotion (66.40%). Additionally, 66.66% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; 76.47% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. In babies with normal skin, skin hydration was improved with Venusia baby cream (12.20%) and Venusia baby lotion (7.20%); 59.37% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; and 84.84% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. Conclusion Significant improvement was seen in skin hydration using Venusia baby cream and Venusia baby lotion in babies with dry skin and normal skin. No skin intolerances and product-related adverse or serious adverse events were clinically observed or reported during the study duration. Venusia baby lotion had the highest effect (66.4%) on skin hydration in babies with dry skin, where there was a significant shift from dry skin to normal skin range.
PubMed: 37842370
DOI: 10.7759/cureus.45032 -
ANZ Journal of Surgery Nov 2023The frequency of oxycodone adverse reactions, subsequent opioid prescription, effect on pain and patient care in general surgery patients are not well known. This study...
BACKGROUND
The frequency of oxycodone adverse reactions, subsequent opioid prescription, effect on pain and patient care in general surgery patients are not well known. This study aimed to determine prevalence of documented oxycodone allergy and intolerances (independent variables) in a general surgical cohort, and association with prescribing other analgesics (particularly opioids), subjective pain scores, and length of hospital stay (dependent variables).
METHODS
This retrospective cohort study included general surgery patients from two South Australian hospitals between April 2020 and March 2022. Multivariable logistic regression evaluated associations between previous oxycodone allergies and intolerances, prescription records, subjective pain scores, and length of hospital stay.
RESULTS
Of 12 846 patients, 216 (1.7%) had oxycodone allergies, and 84 (0.7%) oxycodone intolerances. The 216 oxycodone allergy patients had lower odds of receiving oxycodone (OR 0.17, P < 0.001), higher odds of tramadol (OR 3.01, P < 0.001) and tapentadol (OR 2.87, P = 0.001), but 91 (42.3%) still received oxycodone and 19 (8.8%) morphine. The 84 with oxycodone intolerance patients had lower odds of receiving oxycodone (OR 0.23, P < 0.001), higher odds of fentanyl (OR 3.6, P < 0.001) and tramadol (OR 3.35, P < 0.001), but 42 (50%) still received oxycodone. Patients with oxycodone allergies and intolerances had higher odds of elevated subjective pain (OR 1.60, P = 0.013; OR 2.36, P = 0.002, respectively) and longer length of stay (OR 1.36, P = 0.038; OR 2.24, P = 0.002, respectively) than patients without these.
CONCLUSIONS
General surgery patients with oxycodone allergies and intolerances are at greater risk of worse postoperative pain and longer length of stay, compared to patients without. Many still receive oxycodone, and other opioids that could cause cross-reactivity.
Topics: Humans; Analgesics, Opioid; Oxycodone; South Australia; Length of Stay; Tramadol; Retrospective Studies; Practice Patterns, Physicians'; Australia; Pain, Postoperative; Hypersensitivity
PubMed: 37837230
DOI: 10.1111/ans.18722 -
Microbial Cell Factories Sep 2023Methanol, synthesized from CO, is a potentially sustainable one-carbon (C1) resource for biomanufacturing. The use of methanol as a feedstock to produce single cell...
BACKGROUND
Methanol, synthesized from CO, is a potentially sustainable one-carbon (C1) resource for biomanufacturing. The use of methanol as a feedstock to produce single cell protein (SCP) has been investigated for decades as an alternative to alleviate the high global demand for animal-derived proteins. The methylotrophic yeast Pichia pastoris is an ideal host for methanol-based SCP synthesis due to its natural methanol assimilation ability. However, improving methanol utilization, tolerance to higher temperature, and the protein content of P. pastoris are also current challenges, which are of great significance to the economical industrial application using methanol as a feedstock for SCP production.
RESULTS
In the present work, adaptive laboratory evolution (ALE) has been employed to overcome the low methanol utilization efficiency and intolerance to a higher temperature of 33 °C in P. pastoris, associated with reduced carbon loss due to the lessened detoxification of intracellular formaldehyde through the dissimilation pathway and cell wall rearrangement to temperature stress resistance following long-term evolution as revealed by transcriptomic and phenotypic analysis. By strengthening nitrogen metabolism and impairing cell wall synthesis, metabolic engineering further increased protein content. Finally, the engineered strain via multi-strategy produced high levels of SCP from methanol in a pilot-scale fed-batch culture at 33 °C with a biomass of 63.37 g DCW/L, methanol conversion rate of 0.43 g DCW/g, and protein content of 0.506 g/g DCW. SCP obtained from P. pastoris contains a higher percentage of protein compared to conventional foods like soy, fish, meat, whole milk, and is a source of essential amino acids, including methionine, lysine, and branched-chain amino acids (BCAAs: valine, isoleucine, leucine).
CONCLUSIONS
This study clarified the unique mechanism of P. pastoris for efficient methanol utilization, higher temperature resistance, and high protein synthesis, providing a P. pastoris cell factory for SCP production with environmental, economic, and nutritional benefits.
Topics: Animals; Methanol; Pichia; Carbon; Recombinant Proteins
PubMed: 37770920
DOI: 10.1186/s12934-023-02198-9