Mortality risk in patients with obesity and COVID-19 infection: a systematic review and meta-analysis.

Obesity is a risk factor for severe respiratory diseases, including COVID-19 infection. Meta-analyses on mortality risk were inconsistent. We systematically searched 3 databases (Medline, Embase, CINAHL) and assessed the quality of studies using the Newcastle-Ottawa tool (CRD42020220140). We included 199 studies from US and Europe, with a mean age of participants 41.8-78.2 years, and a variable prevalence of metabolic co-morbidities of 20-80 %. Exceptionally, one third of the studies had a low prevalence of obesity of <20 %. Compared to patients with normal weight, those with obesity had a 34 % relative increase in the odds of mortality (p-value 0.002), with a dose-dependent relationship. Subgroup analyses showed an interaction with the country income. There was a high heterogeneity in the results, explained by clinical and methodologic variability across studies. We identified one trial only comparing mortality rate in vaccinated compared to unvaccinated patients with obesity; there was a trend for a lower mortality in the former group. Mortality risk in COVID-19 infection increases in parallel to an increase in BMI. BMI should be included in the predictive models and stratification scores used when considering mortality as an outcome in patients with COVID-19 infections. Furthermore, patients with obesity might need to be prioritized for COVID-19 vaccination.

Defining Misinformation and Related Terms in Health-Related Literature: Scoping Review.

BACKGROUND: Misinformation poses a serious challenge to clinical and policy decision-making in the health field. The COVID-19 pandemic amplified interest in misinformation and related terms and witnessed a proliferation of definitions. OBJECTIVE: We aim to assess the definitions of misinformation and related terms used in health-related literature. METHODS: We conducted a scoping review of systematic reviews by searching Ovid MEDLINE, Embase, Cochrane, and Epistemonikos databases for articles published within the last 5 years up till March 2023. Eligible studies were systematic reviews that stated misinformation or related terms as part of their objectives, conducted a systematic search of at least one database, and reported at least 1 definition for misinformation or related terms. We extracted definitions for the terms misinformation, disinformation, fake news, infodemic, and malinformation. Within each definition, we identified concepts and mapped them across misinformation-related terms. RESULTS: We included 41 eligible systematic reviews, out of which 32 (78%) reviews addressed the topic of public health emergencies (including the COVID-19 pandemic) and contained 75 definitions for misinformation and related terms. The definitions consisted of 20 for misinformation, 19 for disinformation, 10 for fake news, 24 for infodemic, and 2 for malinformation. "False/inaccurate/incorrect" was mentioned in 15 of 20 definitions of misinformation, 13 of 19 definitions of disinformation, 5 of 10 definitions of fake news, 6 of 24 definitions of infodemic, and 0 of 2 definitions of malinformation. Infodemic had 19 of 24 definitions addressing "information overload" and malinformation had 2 of 2 definitions with "accurate" and 1 definition "used in the wrong context." Out of all the definitions, 56 (75%) were referenced from other sources. CONCLUSIONS: While the definitions of misinformation and related terms in the health field had inconstancies and variability, they were largely consistent. Inconstancies related to the intentionality in misinformation definitions (7 definitions mention "unintentional," while 5 definitions have "intentional"). They also related to the content of infodemic (9 definitions mention "valid and invalid info," while 6 definitions have "false/inaccurate/incorrect"). The inclusion of concepts such as "intentional" may be difficult to operationalize as it is difficult to ascertain one's intentions. This scoping review has the strength of using a systematic method for retrieving articles but does not cover all definitions in the extant literature outside the field of health. This scoping review of the health literature identified several definitions for misinformation and related terms, which showed variability and included concepts that are difficult to operationalize. Health practitioners need to exert caution before labeling a piece of information as misinformation or any other related term and only do so after ascertaining accurateness and sometimes intentionality. Additional efforts are needed to allow future consensus around clear and operational definitions.

Classical and Nonclassical Manifestations of Primary Hyperparathyroidism.

This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

A Framework for the Development of Living Practice Guidelines in Health Care.

BACKGROUND: Living practice guidelines are increasingly being used to ensure that recommendations are responsive to rapidly emerging evidence. OBJECTIVE: To develop a framework that characterizes the processes of development of living practice guidelines in health care. DESIGN: First, 3 background reviews were conducted: a scoping review of methods papers, a review of handbooks of guideline-producing organizations, and an analytic review of selected living practice guidelines. Second, the core team drafted the first version of the framework. Finally, the core team refined the framework through an online survey and online discussions with a multidisciplinary international group of stakeholders. SETTING: International. PARTICIPANTS: Multidisciplinary group of 51 persons who have experience with guidelines. MEASUREMENTS: Not applicable. RESULTS: A major principle of the framework is that the unit of update in a living guideline is the individual recommendation. In addition to providing definitions, the framework addresses several processes. The planning process should address the organization's adoption of the living methodology as well as each specific guideline project. The production process consists of initiation, maintenance, and retirement phases. The reporting should cover the evidence surveillance time stamp, the outcome of reassessment of the body of evidence (when applicable), and the outcome of revisiting a recommendation (when applicable). The dissemination process may necessitate the use of different venues, including one for formal publication. LIMITATION: This study does not provide detailed or practical guidance for how the described concepts would be best implemented. CONCLUSION: The framework will help guideline developers in planning, producing, reporting, and disseminating living guideline projects. It will also help research methodologists study the processes of living guidelines. PRIMARY FUNDING SOURCE: None.

The link between COVID-19 and VItamin D (VIVID): A systematic review and meta-analysis.

BACKGROUND: Disease severity and mortality rates due to COVID-19 infection are greater in the elderly and chronically ill patients, populations at high risk for vitamin D deficiency. Vitamin D plays an important role in immune function and inflammation. This systematic review and meta-analysis assesses the impact of vitamin D status and supplementation on COVID-19 related mortality and health outcomes. METHODS: We searched four databases until December 18th 2020, and trial registries until January 20th 2021. Two reviewers screened the studies, collected data, assessed the risk of bias, and graded the evidence for each outcome across studies, independently and in duplicate. Pre-specified outcomes of interest were mortality, ICU admission, invasive and non-invasive ventilation, hospitalization, time of hospital stay, disease severity and SARS-CoV-2 positivity. We only included data from peer-reviewed articles in our primary analyses. RESULTS: We identified 31 peer-reviewed observational studies. In our primary analysis, there was a positive trend between serum 25(OH)D level <20 ng/ml and an increased risk of mortality, ICU admission, invasive ventilation, non-invasive ventilation or SARS-CoV-2 positivity. However, these associations were not statistically significant. Mean 25(OH)D levels was 5.9 ng/ml (95% CI [-9.5, -2.3]) significantly lower in COVID-19 positive, compared to negative patients. The certainty of the evidence was very low. We identified 32 clinical trial protocols, but only three have published results to-date. The trials administer vitamin D doses of 357 to 60,000 IU/day, from one week to 12 months. Eight megatrials investigate the efficacy of vitamin D in outpatient populations. A pilot trial revealed a significant decrease in ICU admission with calcifediol, compared to placebo (OR = 0.003), but the certainty of the evidence was unclear. Another small trial showed that supplementation with cholecalciferol, 60,000 IU/day, decreased fibrinogen levels, but did not have an effect on D-dimer, procalcitonin and CRP levels, compared to placebo. The third trial did not find any effect of vitamin D supplementation on COVID-19 related health outcomes. CONCLUSION: While the available evidence to-date, from largely poor-quality observational studies, may be viewed as showing a trend for an association between low serum 25(OH)D levels and COVID-19 related health outcomes, this relationship was not found to be statistically significant. Calcifediol supplementation may have a protective effect on COVID-19 related ICU admissions. The current use of high doses of vitamin D in COVID-19 patients is not based on solid evidence. It awaits results from ongoing trials to determine the efficacy, desirable doses, and safety, of vitamin D supplementation to prevent and treat COVID-19 related health outcomes.

The Appearance of a Leptin Effect on Glucose Absorption in Caco2 Cells Depends on Their Differentiation Level.

UNLABELLED: Backdround/Aims: The aim of this work was to study the effect and mechanism of action of leptin added apically, on glucose absorption, using Caco-2 cells as a model. METHODS: Cells were grown on inserts and treated with leptin, at different time points after confluence. Radiolabelled glucose was added to the upper chamber and samples from the lower chamber were collected and assayed for radioactivity. RESULTS: Glucose absorption increased with an increase in the level of differentiation and was associated with an increase in the protein expression level of glucose transporters. Leptin reduced glucose absorption only by day 16 after confluence, the time at which apical leptin receptors started appearing. This inhibitory effect became higher the longer the post confluence period, and was prominent on day 23. The hormone effect was found to be mediated via a decrease in the number of glucose transporters (SGLT1 and GLUT2) and a decrease in the activity of the Na+/K+ ATPase which was assayed by measuring the amount of inorganic phosphate liberated in presence and absence of enzyme activators. CONCLUSION: It was concluded that by day 23 post confluence, Caco-2 cells are differentiated and are appropriate to use as a model for intestinal transport studies.

Leptin inhibits the Na(+)/K(+) ATPase in Caco-2 cells via PKC and p38MAPK.

We demonstrated previously an inhibitory effect of luminal leptin on glucose absorption in differentiated Caco-2 cells. Since this process is dependent on the Na(+) gradient established by the Na(+)/K(+)ATPase this work was undertaken to investigate if the ATPase is one of the hormone's targets. Fully differentiated Caco-2 cells were incubated with 10nM luminal leptin and the activity of the Na(+)/K(+) ATPase was assayed by measuring the amount of inorganic phosphate liberated. To elucidate the signaling pathway involved, the suspected mediators, namely PKC, p38MAPK, ERK and PI3K, were inhibited with specific pharmacological inhibitors and their implication was confirmed by determining changes in the protein expression of their active phosphorylated forms by Western blot analysis. Leptin reduced significantly the activity of the Na(+)/K(+) ATPase, by activating p38MAPK via inhibition of PKC, an upstream inhibitor of the kinase. ERK and PI3K are modulators of the pump and are not along the pathway activated by leptin but cross talk with it at the level of p38MAPK.

Leptin inhibits glucose intestinal absorption via PKC, p38MAPK, PI3K and MEK/ERK.

The role of leptin in controlling food intake and body weight is well recognized, but whether this is achieved by modulating nutrient absorption is still a controversial issue. The aim of this work was to investigate the direct effect of luminal leptin on glucose intestinal absorption and elucidate for the first time its signaling pathway. Fully differentiated Caco-2 cells grown on transwell filters were used for glucose transport studies. Leptin caused a significant reduction in glucose absorption. Individual and simultaneous inhibition of ERK, p38MAPK, PI3K or PKC abrogated completely the inhibitory effect of leptin. Activating PKC, lead to a stimulatory effect that appeared only when ERK, p38MAPK, or PI3K was inactive. Moreover, leptin increased the phosphorylation of ERK, Akt and p38MAPK. This increase changed into a decrease when p38MAPK and PKC were inactivated individually. Inhibiting ERK maintained the leptin-induced up-regulation of p-Akt and p-p38MAPK while inhibiting PI3K reduced the level of p-ERK and p-Akt but maintained the increase in p-p38MAPK. These results suggest that leptin reduces glucose absorption by activating PKC. Although the latter modulates glucose absorption via a stimulatory and an inhibitory pathway, only the latter is involved in leptin's action. Active PKC leads to a sequential activation of p38MAPK, PI3K and ERK which exerts an inhibitory effect on glucose absorption. The results reveal a modulatory role of leptin in nutrient absorption in addition to its known satiety inducing effect.

Anti-hyperglycemic effect of the aqueous extract of banana infructescence stalks in streptozotocin-induced diabetic rats.

Water extract of banana (Musa sapientum) infructescence stalks has been used in folk medicine in the treatment of diabetes mellitus. This work aims at verifying the claimed effect and elucidating its possible mode of action. The extract was given in replacement of drinking water to diabetic rats, and its mechanism of action was studied by investigating its involvement in glucose transport in Caco-2 monolayers, and in rat jejuna using an in situ perfusion technique. Its effect on the Na(+)/K(+) ATPase was studied by measuring the amount of inorganic phosphate liberated. The extract reduced significantly blood glucose levels in diabetic rats and glucose transport across rat jejuna and Caco-2 monolayers, and induced a 50 % decrease in their Na(+)/K(+) ATPase activity. The extract did not induce any further decrease in jejunal glucose uptake in the simultaneous presence of phloridzin and phloretin, respective inhibitors of SGLT1 and GLUT2 transporters nor did it induce a change in the protein expression of SGLT1 and GLUT2. It was concluded that the extract acts by reducing the Na(+)/K(+) ATPase activity of enterocytes and consequently the sodium gradient required for sugar transport by SGLT1, which leads to down-regulation of GLUT2 and contributes to the observed anti-hyperglycemic effect.

Pine bark extract inhibits glucose transport in enterocytes via mitogen-activated kinase and phosphoinositol 3-kinase.

OBJECTIVE: Pine bark extract (PBE) has been reported to have hypoglycemic effects but its mode of action is still unclear. This work studied the effect of PBE on glucose uptake by Caco-2 cells in isolation of its effect on insulin, which may appear if ingested by the animal. METHODS: Caco-2 cells were incubated in the presence of PBE and [(14)C] 3-O-methyl-D-glucose as a tracer and the change in radioactivity of the incubation medium was taken as a measurement of glucose uptake. To determine the mechanism of action of the extract and type of transporters involved, Na(+)-coupled glucose transporter-1 (SGLT1) and glucose transporter-2 (GLUT2) and different signaling mediators known to be involved in glucose transport were inactivated by specific inhibitors. Changes in the protein expression of glucose transporters were studied by western blotting. RESULTS: The extract significantly decreased glucose transport but did not affect the activity or expression of Na(+)/K(+) adenosine triphosphatase. It was concluded that PBE affects the number of glucose transporters in the brush-border membrane. This conclusion was confirmed by western blot analysis. The results showed that the extract acts by activating p38 mitogen-activated kinase, which in turn activates SGLT1 transporters and two different pathways that target GLUT2: an inhibitory pathway involving phosphoinositol 3-kinase and a stimulatory pathway involving mitogen activated protein kinase/extracellular signal-regulated kinase kinase. The activity of the two pathways is orchestrated by SGLT1. CONCLUSION: Pine bark extract inhibits glucose absorption by p38 mitogen-activated kinase and constitutes a potential complementary therapeutic or prophylactic agent for diabetes and its complications.