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Emerging evidence suggest migraine is a response to cerebral energy deficiency or oxidative stress in the brain. Beta-hydroxybutyrate (BHB) is likely able to circumvent some of the meta-bolic abnormalities reported in migraine. Exogenous BHB was given to test this assumption and, in this post-hoc analysis, multiple metabolic biomarkers were identified to predict clinical improvements. A randomized clinical trial, involving 41 patients with episodic migraine. Each treatment period was 12 weeks long, followed by eight weeks of washout phase / second run-in phase before entering the corresponding second treatment period. The primary endpoint was the number of migraine days in the last 4 weeks of treatment adjusted for baseline. BHB re-sponders were identified (those with at least a 3-day reduction in migraine days over placebo) and its predictors were evaluated using Akaike’s Information Criterion (AIC) stepwise boot-strapped analysis and logistic regression. Responder analysis showed that metabolic markers could identify a “metabolic migraine” subgroup, which responded to BHB with a 5.7 migraine days reduction compared to the placebo. This analysis provides further support for a “metabolic migraine” subtype. Additionally, these analyses identified low-cost and easily accessible biomarkers that could guide recruitment in future research on this subgroup of patients.This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233

Background: A notable pandemic arisen during the COVID-19 pandemic has developed globally in intensive care units, with patients developing pressure ulcers (PUs) after being ventilated mechanically in the prone position. Objectives: The aim was to identify risk factors independently predictive of the development of PUs in adult patient populations treated with prone positioning and to evaluate a possible epidemiological association between the prevalence of PUs and specific clinical characteristics so as to develop clinical indicators for the prevention of PUs. Finally, the aim was to examine our study participants against the incidence of PUs with respect to the length of their stay. Methods: : This retrospective study enrolled patients hospitalized during the period of May 2020 through January 2021. Data was collected from 299 patients hospitalized and having required prone positioning ventilatory therapy in critical care areas (short-stay units, emergency units, and intensive care units), all of which had developed Pus of at least grade two according to the classification system proposed by the NPUAP/EPUAP. Results: : Patients who had developed PUs had a longer hospitalization stay overall and were more prone to die during hospitalization. Patients who developed Pus were more frequently males, with higher initial levels of CPK and ferritin. Conclusions: The study reveals valuable information on the most important risk factors in the development of PUs due to prone positioning. We have described how the total number of days of hospitalization is significantly related to the development of PUs. Even a PU is not a life-threatening lesion, the implementation of improved positioning protocols may enhance results in critical patient care. We believe that this is a current, globally underestimated problem as the incidence of COVID-19 patients requiring prone positioning—and, therefore, at risk for PUs—is increasing daily.

Alzheimer’s disease (AD) is the most common major neurocognitive disorder of ageing. Although largely ignored until about a decade ago, accumulating evidence suggests that deteriorating brain energy metabolism plays a key role in the development and/or progression of AD-associated cognitive decline. Brain glucose hypometabolism is a well-established biomarker in AD but was mostly assumed to be a consequence of neuronal dysfunction and death. However, its presence in cognitively asymptomatic populations at higher risk of AD strongly suggests that it is actually a pre-symptomatic component in the development of AD. The question then arises as to whether progressive AD-related cognitive decline could be prevented or slowed down by correcting or bypassing this progressive ‘brain energy gap’. In this review, we provide an overview of research on brain glucose and ketone metabolism in AD and its prodromal condition – mild cognitive impairment (MCI) – to provide a clearer basis for proposing keto-therapeutics as a strategy for brain energy rescue in AD. We also discuss studies using ketogenic interventions and their impact on plasma ketone levels, brain energetics and cognitive performance in MCI and AD. Given that exercise has several overlapping metabolic effects with ketones, we propose that in combination these two approaches might be synergistic for brain health during ageing. As cause-and-effect relationships between the different hallmarks of AD are emerging, further research efforts should focus on optimising the efficacy, acceptability and accessibility of keto-therapeutics in AD and populations at risk of AD.

Background The gut has been hypothesized to be a protagonist tissue in multiple organ dysfunction syndrome (MODS) for the past three decades. Gastric reactance (XL) is a potential perfusion marker derived from gastric impedance spectroscopy (GIS), which is an emerging tool through which living tissue can be continuously measured to determine its pathophysiological evolution. This study aimed to compare the performance of XL [positive predictive values (PPV), negative predictive values (NPV), and area under the curve (AUC)] against commonly used perfusion markers before and during hypovolemic shock in swine subjects. Methods Prospective, controlled animal trial with two groups, control group (CG) N = 5 and shock (MAP ≤ 48 mmHg) group (SG) N = 16. Comparison time points were defined as T-2 (2 h before shock), T-1 (1 h before shock), T0 (shock), T1 (1 h after shock), and T2 (2 h after shock). Shock severity was assessed through blood gases, systemic and hemodynamic variables, and via histological examination for assessing inflammation-edema and detachment in the gastric mucosa. Macroscopic assessment of the gastric mucosa was defined in five levels (0—normal mucosa, 1—stippling or epithelial hemorrhage, 2—pale mucosa, 3—violet mucosa, and 4—marmoreal mucosa). Receiver Operating Characteristic (ROC) curves of perfusion markers and XL were calculated to identify optimal cutoff values and their individual ability to predict hypovolemic shock. Results Comparison among the CG and the SG showed statistically significant differences in XL measurements at T-1, T0, T1, and T2, while lactate showed statistically significant differences until T1 and T2. Statistically significant differences were detected in mucosa class (p p = 0.021 and p = 0.043). The performance of the minimum XL value per subject per event (XL_Min) was better (0.81 ≤ AUC ≤ 0.96, 0.93 ≤ PPV ≤ 1.00, 0.45 ≤ NPV ≤ 0.83) than maximum lactate value (Lac_Max) per subject per event (0.29 ≤ AUC ≤ 0.82, 0.82 ≤ PPV ≤ 0.91, 0.24 ≤ NPV ≤ 0.82). Cutoff values for XL_Min show progressive increases at each time point, while cutoff values for Lac_Max increase only at T2. Conclusions XL proved to be an indirect and consistent marker of inadequate gastric mucosal perfusion, which shows significant and detectable changes before commonly used markers of global perfusion under the hypovolemic shock conditions outlined in this work.

Objective Healthcare saturation has been a prominent worry during the COVID-19 pandemic. Increase of hospital beds with mechanical ventilators has been central in Mexico's approach, but it is not known whether this actually improves access to care and the resulting quality of it. This study aimed to determine the impact of healthcare strain and other pre-specified variables on dying from coronavirus disease 2019 (COVID-19) without receiving invasive mechanical ventilation (IMV). Methods A retrospective cohort study was conducted using open data from Mexico City between 8 May 2020 and 5 January 2021. We performed Cox proportional hazards models to identify the strength of the association between proposed variables and the outcomes. Results Of 33 797 hospitalized patients with suspected or confirmed COVID-19, 19 820 (58.6%) did not require IMV and survived, 5414 (16.1%) required IMV and were intubated and 8563 (25.3%) required IMV but died without receiving it. A greater occupation of IMV-capable beds increased the hazard of death without receiving IMV (hazard ratio [HR] 1.56, comparing 90% with 50% occupation). Private healthcare was the most protective factor for death without IMV (HR 0.14). Conclusions Higher hospital bed saturation increased the hazard of dying without being intubated and worsened the outcomes among mechanically ventilated patients. Older age also increased the hazard of the outcomes, while private healthcare dramatically decreased them.

When lean people adopt carbohydrate-restricted diets (CRDs), they may develop a lipid profile consisting of elevated LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) with low triglycerides (TGs). The magnitude of this lipid profile correlates with BMI such that those with lower BMI exhibit larger increases in both LDL-C and HDL-C. The inverse association between BMI and LDL-C and HDL-C change on CRD contributed to the discovery of a subset of individuals—termed Lean Mass Hyper-Responders (LMHR)—who, despite normal pre-diet LDL-C, as compared to non-LMHR (mean levels of 148 and 145 mg/dL, respectively), exhibited a pronounced hyperlipidemic response to a CRD, with mean LDL-C and HDL-C levels increasing to 320 and 99 mg/dL, respectively, in the context of mean TG of 47 mg/dL. In some LMHR, LDL-C levels may be in excess of 500 mg/dL, again, with relatively normal pre-diet LDL-C and absent of genetic findings indicative of familial hypercholesterolemia in those who have been tested. The Lipid Energy Model (LEM) attempts to explain this metabolic phenomenon by positing that, with carbohydrate restriction in lean persons, the increased dependence on fat as a metabolic substrate drives increased hepatic secretion and peripheral uptake of TG contained within very low-density lipoproteins (VLDL) by lipoprotein lipase, resulting in marked elevations of LDL-C and HDL-C, and low TG. Herein, we review the core features of the LEM. We review several existing lines of evidence supporting the model and suggest ways to test the model’s predictions.

Emerging evidence suggests that “leanness” and good metabolic health markers may predict larger increases in LDL cholesterol (LDL-C) in response to carbohydrate restriction. Specifically, a recent cohort study demonstrated an inverse association between BMI and LDL-C change among individuals on carbohydrate-restricted diets and identified a subgroup of “Lean Mass Hyper-Responders” (LMHR) who exhibit exceptional increases in LDL-C, in the context of low triglycerides and high HDL-C. We present the case of one subject, LM, who adopted a ketogenic diet for management of ulcerative colitis. He subsequently experienced an increase in LDL-C from 95 to 545 mg/dl, at peak, in association with HDL-C >100 mg/dl and triglycerides ~40 mg/dl, typical of the emergent LMHR phenotype. Assessments of LM’s dietary intake, lipid panels, and BMI are consistent with prior data and suggest that the LMHR phenomenon is not dependent on saturated fat intake but inversely associates with BMI changes. Finally, computed tomography angiography conducted on LM after over 2 years of hypercholesterolemia revealed no evidence of calcified or non-calcified plaque.

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (31P-MRS) before and after ingestion of a ketone ester drink. We recruited 28 healthy individuals: 12 aged 23-70 years for cardiac 31P-MRS, and 16 aged 60-75 years for skeletal muscle 31P-MRS. Baseline and post-intervention resting cardiac and dynamic skeletal muscle 31P-MRS scans were performed in one visit, where 25 g of the ketone monoester, deltaG®, was administered after the baseline scan. Administration was timed so that post-intervention 31P-MRS would take place 30 min after deltaG® ingestion. The deltaG® ketone drink was well-tolerated by all participants. In participants who provided blood samples, post-intervention blood glucose, lactate and non-esterified fatty acid concentrations decreased significantly (-28.8%, p ≪ 0.001; -28.2%, p = 0.02; and -49.1%, p ≪ 0.001, respectively), while levels of the ketone body D-beta-hydroxybutyrate significantly increased from mean (standard deviation) 0.7 (0.3) to 4.0 (1.1) mmol/L after 30 min (p ≪ 0.001). There were no significant changes in cardiac PCr/ATP or skeletal muscle metabolic parameters between baseline and post-intervention. Acute ketone supplementation caused mild ketosis in blood, with drops in glucose, lactate, and free fatty acids; however, such changes were not associated with changes in 31P-MRS measures in the heart or in skeletal muscle. Future work may focus on the effect of longer-term ketone supplementation on tissue energetics in groups with compromised mitochondrial function., This study was funded by a combination of seed funding awarded to D.C. by Norwich Medical School, University of East Anglia, and funding from TdeltaS., Ltd. L.V is a Sir Henry Dale Fellow supported jointly by the Wellcome Trust and the Royal Academy (#221805/Z/20/Z), and he also acknowledges the support of the Slovak Grant Agencies VEGA (#2/0003/20) and APVV (#19-0032). A.I.S. was supported by The Austrian Science Fund (FWF) Schrödinger Fellowship (J 4043). C.T.R. is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (#098436/Z/12/B) and acknowledges support from the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. J.E. was funded by the Medical Research Council.

STUDY QUESTION What was the effect of the coronavirus disease 2019 (COVID-19) pandemic on healthcare and quality of life in those suffering from endometriosis? SUMMARY ANSWER Our study reveals a clear correlation between the deterioration of the reported physical and mental state and impaired medical care for patients suffering from endometriosis during the COVID-19 pandemic. WHAT IS KNOWN ALREADY The quality of life of patients suffering from endometriosis is compromised in a variety of aspects. In response to the ongoing COVID-19 pandemic, self-isolation practices aimed at curbing the spread of COVID-19 have severely complicated the availability of proper medical care worldwide. STUDY DESIGN, SIZE, DURATION The study involved a cross-sectional international self-reported online survey. Responses were accepted between November 2020 and January 2021. The survey was prepared by the Department of Obstetrics and Gynaecology in a medical university setting. The survey contained 17 questions and was placed online. Cooperation with different endometriosis organizations around the world enabled distribution of the survey through their social media platforms. PARTICIPANTS/MATERIALS, SETTING, METHODS The study participants (n = 3024 replies) originated from 59 countries. The questionnaire was created after a literature review and is partially based on the validated quality of life questionnaires, adjusted to the study question. The survey was then translated to 15 other languages following World Health Organization recommendations as closely as possible. Chi-square tests for independence were carried out for the analysis of the two variables: suspension of health services, and the patients mental and physical well-being. MAIN RESULTS AND THE ROLE OF CHANCE Out of 3024 participants from 59 countries who submitted the questionnaire between November 2020 and January 2021, 2964 (98.01%) provided information that enabled a full analysis. For the 1174 participants who had their medical appointments cancelled, 43.7% (n = 513) reported that their symptoms had been aggravated, and 49.3% (n = 579) reported that their mental state had worsened. In comparison, of the 1180 participants who kept their appointments, only 29.4% (n = 347) stated that their symptoms had been aggravated, and 27.5% (n = 325) stated their mental health had worsened. The results showed that there was a significant link between the reported deterioration of mental and physical wellbeing and impaired medical care (cancellation) (P ≪ 0.001). A total of 610 participants did not have medical appointments scheduled, and these participants followed a similar pattern as the participants who kept their appointments, with 29.0% (n = 177) reporting aggravation of symptoms and 28.2% (n = 172) reporting that their mental state had worsened. LIMITATIONS, REASONS FOR CAUTION Cultural differences among international participants are to be expected and this may have affected how participants from different countries interpreted and answered the questionnaire. Translating the questionnaire into 15 different languages, even though incorporating backwards translation, could possibly lead to different interpretations of given questions, simply based on different wording in the languages. The majority of respondents (around 90%) were from Europe and South America and therefore the findings may not be generalizable to other locations. WIDER IMPLICATIONS OF THE FINDINGS Further research is needed to assess the true impact and long-term consequences of the COVID-19 pandemic for patients living with endometriosis. STUDY FUNDING/COMPETING INTEREST(S) This study received no funding and the authors declare they have no relevant conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Background All clinicians require statistical interpretation skills to keep up to date with evidence-based recommendations in their field. However, statistical illiteracy among clinicians is a highly prevalent problem with far-reaching consequences. The few available that report statistical literacy improvements after educational interventions do not measure for how long these benefits last. To estimate statistical illiteracy among Latin-American clinicians across multiple levels of training and to evaluate a 10-h course at multiple timepoints. Methods Using an online questionnaire, we evaluated; self-perceived statistical proficiency, scientific literature reading habits and statistical literacy (using an adaptation of the Quick Risk Test). Separately, we evaluated statistical proficiency after a 10-h statistics course in a group of Internal Medicine residents at a tertiary center in Mexico City across multiple time points between November 2020 and February 2021. Results Data from 392 clinicians from 9 Latin American countries were analyzed. Most clinicians (85%) failed our adaptation of the Quick Risk Test (mean score = 2.6/10, IQR:1.4). The 10-h course significantly improved the scores of the Internal Medicine Residents (n = 16) from 3.8/10, IQR:1.8 to 8.3/10, IQR:1.4 (p Conclusion Statistical Illiteracy is highly prevalent among Latin American clinicians. Short-term educational interventions are effective but, their benefits quickly fade away. Medical boards and medical schools need to periodically teach and evaluate statistical proficiency to ameliorate these issues.

Background Interventions that induce ketosis simultaneously lower blood glucose and the explanation for this phenomenon is unknown. Additionally, the glucose‐lowering effect of acute ketosis is greater in people with type 2 diabetes (T2D). On the contrary, L‐alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D and infusing of ketones lower circulating L‐alanine blood levels. In this study, we sought to determine whether supplementation with L‐alanine would attenuate the glucose‐lowering effect of exogenous ketosis using a ketone ester (KE). Methods This crossover study involved 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) in the form of a KE drink (ΔG®) on two separate visits. During one of the visits, participants additionally ingested 2 g of L‐alanine to see whether L‐alanine supplementation would attenuate the glucose‐lowering effect of the KE drink. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured for 120 min after ingestion of the KE, with or without L‐alanine. Findings The KE drinks elevated blood βHB concentrations from negligible levels to 4.52 ± 1.23 mmol/L, lowered glucose from 4.97 ± SD 0.39 to 3.77 ± SD 0.40 mmol/L, and lowered and L‐alanine from 0.56 ± SD 0.88 to 0.41 ± SD 0.91 mmol/L. L‐alanine in the KE drink elevated blood L‐Alanine by 0.68 ± SD 0.15 mmol/L, but had no significant effect on blood βHB, L‐glutamine, FFA, lactate, nor C‐peptide concentrations. By contrast, L‐alanine supplementation significantly attenuated the ketosis‐induced drop in glucose from 28% ± SD 8% to 16% ± SD 7% (p, This was crossover study involved two separate visits for 10 healthy human volunteers who fasted for 24 h prior to the ingestion of 25 g of d‐β‐hydroxybutyrate (βHB) monoester (ΔG®). During one of the visits, participants ingested 2 g of L‐alanine. Blood L‐alanine, L‐glutamine, glucose, βHB, free fatty acids (FFA), lactate and C‐peptide were measured. Demonstrating that ketosis induces hypoglycemia, in part, by limiting L‐alanine availability for gluconeogenesis.

In this acute intervention study, we investigated the potential benefit of ketone supplementation in humans by studying cardiac phosphocreatine to adenosine-triphosphate ratios (PCr/ATP) and skeletal muscle PCr recovery using phosphorus magnetic resonance spectroscopy (

BackgroundMost COVID-19 mortality scores were developed in the early months of the pandemic and now available evidence-based interventions have helped reduce its lethality. It has not been evaluated if the original predictive performance of these scores holds true nor compared it against Clinical Gestalt predictions. We tested the current predictive accuracy of six COVID-19 scores and compared it with Clinical Gestalt predictions.Methods200 COVID-19 patients were enrolled in a tertiary hospital in Mexico City between September and December 2020. Clinical Gestalt predictions of death (as a percentage) and LOW-HARM, qSOFA, MSL-COVID-19, NUTRI-CoV and NEWS2 were obtained at admission. We calculated the AUC of each score and compared it against Clinical Gestalt predictions and against their respective originally reported value.Results106 men and 60 women aged 56+/-9 and with confirmed COVID-19 were included in the analysis. The observed AUC of all scores was significantly lower than originally reported; LOW-HARM 0.96 (0.94-0.98) vs 0.76 (0.69-0.84), qSOFA 0.74 (0.65-0.81) vs 0.61 (0.53-0.69), MSL-COVID-19 0.72 (0.69-0.75) vs 0.64 (0.55-0.73) NUTRI-CoV 0.79 (0.76-0.82) vs 0.60 (0.51-0.69), NEWS2 0.84 (0.79-0.90) vs 0.65 (0.56-0.75), Neutrophil-Lymphocyte ratio 0.74 (0.62-0.85) vs 0.65 (0.57-0.73). Clinical Gestalt predictions were non-inferior to mortality scores (AUC=0.68 (0.59-0.77)). Adjusting the LOW-HARM score with locally derived likelihood ratios did not improve its performance. However, some scores performed better than Clinical Gestalt predictions when clinician’s confidence of prediction was ConclusionNo score was significantly better than Clinical Gestalt predictions. Despite its subjective nature, Clinical Gestalt has relevant advantages for predicting COVID-19 clinical outcomes.

ObjectiveTo compare hypoxemia severity of patients with COVID-19 pneumonia that arrive at an emergency department as classified by three oxygenation indexes.DesignRetrospective analysis of pulse oximeter saturation and arterial blood gas analysis obtained at arrival.SettingTertiary referral hospital in Mexico City converted early in the pandemic to a COVID-19 center.Patients and measurementsA total of 2,960 patients with suspected COVID-19 pneumonia were admitted to the emergency department from April 2020 until March 2021. Pulse oximeter saturation and arterial blood gas analysis was obtained in all of them. Pulse oximeter saturation (SpO2) to inspired oxygen fraction ratio (FiO2), oxygen saturation in arterial blood (SatO2) to FiO2 ratio, and oxygen pressure in arterial blood to FiO2 ratio were calculated for every patient.InterventionsNone.Main ResultsA strong correlation was seen between PaO2/FiO2 & SpO2/FiO2 (rho = 0.6, p < 0.001), and SatO2/FiO2 & SpO2/FiO2 (rho = 0.65, p < 0.001), while a very strong correlation was seen between PaO2/FiO2 & SatO2/FiO2 (rho = 0.88, p < 0.001). When classifying severity by quantiles, considerable cross-over was observed when comparing oxygenation indexes, as only 785 (26.5%) patients were in the same quintile across the three indexes.ConclusionsHypoxemia severity is heterogeneous according to the oxygenation index utilized. This limits their usefulness as sole markers of severity, as inter-observer variability, especially on FiO2 estimation, and different practices limit consistent follow up and treatment decisions.

Introduction Ketogenic diets have shown to improve glycaemic control in patients with type 2 diabetes. This study investigated the safety, tolerability, and effects on glycaemic control in patients with type 2 diabetes of an exogenous ketone monoester (KE) capable of inducing fasting‐like elevations in serum β‐hydroxybutyrate (βHB) without the need for caloric or carbohydrate restriction. Methods Twenty one participants (14 men and 7 women, aged 45 ± 11 years) with insulin‐independent type 2 diabetes, and unchanged hypoglycaemic medication for the previous 6 months, were recruited for this non‐randomised interventional study. Participants wore intermittent scanning glucose monitors (IS‐GM) for a total of 6 weeks and were given 25 ml of KE 3 times daily for 4 weeks. Serum electrolytes, acid‐base status, and βHB concentrations were measured weekly and cardiovascular risk markers were measured before and after the intervention. The primary endpoints were safety and tolerability, with the secondary endpoint being glycaemic control. Results The 21 participants consumed a total of 1,588 drinks (39.7 litres) of KE over the course of the intervention. Adverse reactions were mild and infrequent, including mild nausea, headache, and gastric discomfort following fewer than 0.5% of the drinks. Serum electrolyte concentrations, acid‐base status, and renal function remained normal throughout the study. Compared to baseline, exogenous ketosis induced a significant decrease in all glycaemic control markers, including fructosamine (335 ± 60 μmol/L to 290 ± 49 μmol/L, p, This study involved a month of closely supervised exogenous ketosis using a ketone monoester. Additionally, it involved six weeks of continuous glucose monitorization to compare glucose control before, during and after exogenous ketosis. Exogenous ketosis was safe, well‐tolerated and improved glucose control.

BackgroundPneumonia is the hallmark of severe COVID-19, with supplemental oxygen requirement being the main indication for hospitalization. Refractory hypoxemia in these patients requires invasive mechanical ventilation (IMV) otherwise, death is imminent. In places with a high disease burden, availability of critical care experts, beds, or resources is challenged and many patients could die without receiving them.MethodsWe performed a retrospective cohort study using open databases from Mexico City about suspected or confirmed COVID-19 patients, health system saturation, and deaths between May 8th, 2020, and January 5th, 2021. After building a directed acyclic graph, we performed a binary logistic regression to identify the association between proposed causal variables and dying without receiving IMV (the outcome).ResultsWe included 33 805 hospitalized patients with suspected or confirmed COVID-19, of which 19 820 (58.6%) did not require IMV and survived, 5416 (16.1%) required and received IMV, and 8569 (25.3%) required IMV but died without receiving it. Saturation of IMV-capable beds did not increase the odds of the outcome (odds ratio 1.07, 95% confidence interval 0.94-1.22 of 90%vs50% occupancy), while general bed saturation (2, 1.86-2.14 of 90%vs50% occupancy) and IMV-capable to general bed ratio (1.64, 1.52-1.77 for a ratio of 2vs0.5) did. Private healthcare decreased the odds of the outcome (0.12, 0.08-0.17) and dyspnea increased them (1.33, 1.19-1.9).ConclusionsIn Mexico City, increased general hospital bed saturation and IMV-capable to general bed ratio were associated with a higher risk of dying without receiving IMV. Private healthcare was the most protective factor.Key messagesHospital saturation has been a central feature of public health messaging, but it is not known how outcomes relate to hospital saturation or capacity.In Mexico City, 90% of COVID-19 patients requiring mechanical ventilation died but less than half received it.Higher general bed saturation and an increased ratio of IMV-capable beds to general beds increased the probability of dying without being intubated while receiving private healthcare decreased this probability.Having available beds to intubate patients is possible thanks to the conversion of general beds, however, still yields suboptimal critical care.

There are two proven dietary approaches to shift type 2 diabetes (T2D) into remission: low energy diets (LED) and low carbohydrate diets (LCD). These approaches differ in their rationale and application yet both involve carbohydrate restriction, either as an explicit goal or as a consequence of reducing overall energy intake. The aims of this systematic review were to identify, characterise and compare existing clinical trials that utilised ‘low carbohydrate’ interventions with differing energy intakes. Electronic databases CENTRAL, CINAHL, Embase, MEDLINE and Scopus were searched to identify controlled clinical trials in adults with T2D involving low carbohydrate intake (defined as ad libitum) energy intakes produced clinically significant weight loss and reduction in HbA1c at study end-points. Trials that restricted energy intake were not superior to those that allowed ad libitum low carbohydrate feeding at 12 and 24 months. An association was observed across studies between average weight loss and reduction in HbA1c, which strengthened with trial length, indicating that sustained weight loss is key to T2D remission. Further research is needed to specifically ascertain the weight-independent effects of carbohydrate restriction on glycemic control in T2D.Graphical abstract

BackgroundInterventions that acutely increase blood ketone concentrations simultaneously lower blood glucose levels, although the explanation for this phenomenon is unknown. The hypoglycaemic effect of acute ketosis is greater in people with type 2 diabetes (T2D) in whom gluconeogenesis contributes significantly to hyperglycaemia. L-alanine is a gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D. As infusion of ketones lower circulating L-alanine blood levels, we sought to determine whether supplementation with L-alanine would attenuate the hypoglycaemic effect of an exogenous ketone ester (KE) supplement.MethodsThis crossover study involved 10 healthy human volunteers who fasted for 24 hours prior to the ingestion of 25 g of D-β-hydroxybutyrate (βHB) in the form of a KE drink (ΔG®) on two separate visits. During one of the visits participants additionally ingested 2 g of L-alanine to see if L-alanine supplementation would attenuate the hypoglycaemic effect of the KE drink. Blood L-alanine, L-glutamine, glucose, βHB, free fatty acids (FFA), lactate, and C-peptide were measured every fifteen minutes for 120 minutes after ingestion of the KE, with or without L-alanine.FindingsThe KE drinks elevated blood βHB concentrations from negligible levels to 4.5 ± 1.24 mmol/L, lowered glucose from 4.97 to 3.77 ± 0.4 mmol/L, and lowered and L-alanine from 0.56 to 0.41 ± 0.9 mmol/L. L-alanine in the KE drink elevated blood L-Alanine to 0.68 ± mmol/L, but had no significant effect on blood βHB, L-glutamine, FFA, lactate, nor C-peptide concentrations. By contrast, L-alanine supplementation significantly attenuated the ketosis-induced drop in glucose from 28% to 16% (pConclusionsThe hypoglycaemic effect of acutely elevated βHB is partially due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.

BackgroundInterventions that acutely increase blood ketone concentrations simultaneously lower blood glucose levels, although the explanation for this phenomenon is unknown. The hypoglycaemic effect of acute ketosis is greater in people with type 2 diabetes (T2D) in whom gluconeogenesis contributes significantly to their hyperglycaemia. One gluconeogenic substrate secreted by skeletal muscle at higher levels in people with T2D is L-alanine. Infusion of ketones lowers circulating L-alanine blood levels, so here we sought to determine whether supplementation with L-alanine would attenuate the hypoglycaemic effect of a ketone ester (KE) drink. MethodsThis crossover study involved two separate visits for 10 healthy human volunteers who fasted for 24 hours prior to the ingestion of 25 g of d-β-hydroxybutyrate (βHB) monoester (ΔG®). During one of the visits participants ingested 2 g of L-alanine. Blood L-alanine, L-glutamine, glucose, βHB, free fatty acids (FFA), lactate, and C-peptide were measured. FindingsThe KE drinks elevated blood βHB concentrations from negligible to 4.5 ± 1.24 mM/l, and lowered both glucose, from 4.97 to 3.77 ± 0.4 mM/l, and L-alanine from 0.56 to 0.41 ± 0.9 mM/l. L-alanine in the KE drink elevated blood L-Alanine to 0.56 ± mM/l, but had no significant effect on blood βHB, L-glutamine, FFA, lactate, or C-peptide concentrations. Preventing the KE-induced decrease in L-alanine by supplementing it significantly attenuated the glucose drop from mean 28% to 16% (pConclusionsThe hypoglycaemic effect of acutely elevated βHB is, at least partially, due to βHB decreasing L-alanine availability as a substrate for gluconeogenesis.

ImportanceMany COVID-19 prognostic factors for disease severity have been identified and many scores have already been proposed to predict death and other outcomes. However, hospitals in developing countries often cannot measure some of the variables that have been reported as useful.- ObjectiveTo assess the sensitivity, specificity, and predictive values of the novel LOW-HARM score (Lymphopenia, Oxygen saturation, White blood cells, Hypertension, Age, Renal injury, and Myocardial injury).- DesignThe score was designed using data from already published cohorts of patients diagnosed with COVID-19. Afterwards, it was calculated it in 438 consecutive hospital admissions at twelve different institutions in ten different cities in Mexico.- SettingTwelve hospitals in ten different cities in Mexico.- ParticipantsData from 438 patients was collected. Data from 400 patients (200 deaths and 200 survivors) was included in the analysis.- ExposureAll patients had an infection with SARS-CoV-2 confirmed by PCR.- Main OutcomeThe sensitivity, specificity, and predictive values of different cut-offs of the LOW-HARM score to predict death.- ResultsMean scores at admission and their distributions were significantly lower in patients who were discharged compared to those who died during their hospitalization 10 (SD: 17) vs 70 (SD: 28). The overall AUC of the model was 95%. A cut-off > 65 points had a specificity of 98% and a positive predictive value of 96%. More than a third of the cases (36%) in the sample had a LOW-HARM score > 65 points.- Conclusions and relevanceThe LOW-HARM score measured at admission is highly specific and useful for predicting mortality. It is easy to calculate and can be updated with individual clinical progression.KEY POINTSQuestionIs it possible to predict mortality in patients diagnosed with COVID-19 using easy-to-access and easy-to-measure variables?FindingsThe LOW-HARM score (Lymphopenia, Oxygen saturation, White blood cells, Hypertension, Age, Renal injury, and Myocardial injury) is a one-hundred-point score that, when measured at admission, had an overall AUC of 95% for predicting mortality. A cut-off of ≥ 65 points had a specificity of 98% and a positive predictive value of 96%.MeaningThe LOW-HARM score measured at admission is highly specific and useful for predicting mortality in patients diagnosed with COVID-19. In our sample, more than a third of patients met the proposed cut-off.

Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-β-hydroxybutyrate (βHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate βHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible βHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The βHB monoester is a salt-free βHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the βHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the βHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.

People commencing a carbohydrate-restricted diet (CRD) experience markedly heterogenous responses in LDL cholesterol, ranging from extreme elevations to reductions.The aim was to elucidate possible sources of heterogeneity in LDL cholesterol response to a CRD and thereby identify individuals who may be at risk for LDL cholesterol elevation.Hypothesis-naive analyses were conducted on web survey data from 548 adults consuming a CRD. Univariate and multivariate regression models and regression trees were built to evaluate the interaction between body mass index (BMI) and baseline lipid markers. Data were also collected from a case series of five clinical patients with extremely high LDL cholesterol consuming a CRD.BMI was inversely associated with LDL cholesterol change. Low triglyceride (TG) to HDL cholesterol ratio, a marker of good metabolic health, predicted larger LDL cholesterol increases. A subgroup of respondents with LDL cholesterol ≥200 mg/dL, HDL cholesterol ≥80 mg/dL, and TG ≤70 mg/dL were characterized as "lean mass hyper-responders." Respondents with this phenotype (These data suggest that, in contrast to the typical pattern of dyslipidemia, greater LDL cholesterol elevation on a CRD tends to occur in the context of otherwise low cardiometabolic risk.

Throughout history, the only way humans could raise their blood ketone levels was by several days of fasting or by following a strict low-carb, high-fat diet. A recently developed, dietary source of ketones, a ketone monoester, elevates d -β-hydroxybutyrate (βHB) to similar concentrations within minutes, with βHB remaining raised for several hours. To date, the longest human safety study of the exogenous ketone ester was for 5 days, but longer consumption times may be desired. Here we report results for 24 healthy adults, aged 18–70 years, who drank 25 ml (26.8 g) of the ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, three times a day for 28 days (a total of 2.1 L). Anthropomorphic measurements, plus fasting blood and urine analyses were made weekly. It was found that elevating blood βHB concentrations from 0.1 to 4.1 (±1.1) mM three times a day for 28 days had no effect on body weights or composition, fasting blood glucose, cholesterol, triglyceride or electrolyte concentrations, nor blood gases or kidney function, which were invariably normal. Mild nausea was reported following 6 of the 2,016 drinks consumed. We conclude that sustained exogenous ketosis using a ketone monoester is safe and well-tolerated by healthy adults.

As the prevalence of Alzheimer disease (AD) continues to rise unabated, new models have been put forth to improve our understanding of this devastating condition. Although individual models may have their merits, integrated models may prove more valuable. Indeed, the reliable failures of monotherapies for AD, and the ensuing surrender of major drug companies, suggests that an integrated perspective may be necessary if we are to invent multifaceted treatments that could ultimately prove more successful. In this review article, we discuss the Wnt/Glycogen Synthase Kinase 3β (GSK3β), α-synuclein, and type 3 diabetes hypotheses of AD, and their deep interconnection, in order to foster the integrative thinking that may be required to reach a solution for the coming neurological epidemic.

Particulate matter air pollution has considerably increased during the last decades; vanadium is a transition element adhered to this particulate matter, and the combustion of fossil fuels is the main source in the atmosphere. It has been reported that air pollution and specifically vanadium exposure increases the probability of suffering arrhythmias; however the biological mechanism of such a relationship remains unknown. It has been established that a diminished presence of N-Cadherin alters the Connexin-43 arrangement, and the consequent altered presence of these proteins predisposes to ventricular heart rate problems. We analyzed myocardial histology and the expression of N-Cadherin and Connexin-43 by immunohistochemistry in mouse that inhaled vanadium. Our results showed a significant and progressive reduction in both N-Cadherin and Connexin-43, as well as the presence of meganucleus; myofibrils disruption, and clumping in the exposed groups were also observed. Our findings add more information about a possible explanation for the arrythmogenic effect observed in dwellers of cities with high particulate matter atmospheric pollution.