Physiologic Adaptation to Macronutrient Change Distorts Findings from Short Dietary Trials: Reanalysis of a Metabolic Ward Study.

An influential 2-wk cross-over feeding trial without a washout period purported to show advantages of a low-fat diet (LFD) compared with a low-carbohydrate diet (LCD) for weight control. In contrast to several other macronutrient trials, the diet order effect was originally reported as not significant. In light of a new analysis by the original investigative group identifying an order effect, we aimed to examine, in a reanalysis of publicly available data (16 of 20 original participants; 7 female; mean BMI, 27.8 kg/m2), the validity of the original results and the claims that trial data oppose the carbohydrate-insulin model of obesity (CIM). We found that energy intake on the LCD was much lower when this diet was consumed first compared with second (a difference of -1164 kcal/d, P = 3.6 × 10-13); the opposite pattern was observed for the LFD (924 kcal/d, P = 2.0 × 10-16). This carry-over effect was significant (P interaction = 0.0004) whereas the net dietary effect was not (P = 0.4). Likewise, the between-arm difference (LCD - LFD) was -320 kcal/d in the first period and +1771 kcal/d in the second. Body fat decreased with consumption of the LCD first and increased with consumption of this diet second (-0.69 ± 0.33 compared with 0.57 ± 0.32 kg, P = 0.007). LCD-first participants had higher ß-hydroxybutyrate levels while consuming the LCD and lower respiratory quotients while consuming LFD when compared with LFD-first participants on their respective diets. Change in insulin secretion as assessed by C-peptide in the first diet period predicted higher energy intake and less fat loss in the second period. These findings, which tend to support rather than oppose the CIM, suggest that differential (unequal) carry-over effects and short duration, with no washout period, preclude causal inferences regarding chronic macronutrient effects from this trial.

Albuminuria, Disease Duration, and Glycated Hemoglobin Are Related With Bone Mineral Density in Type 1 Diabetes: A Cross-sectional Study.

OBJECTIVE: Studies have found a significant decrease in bone mineral density (BMD) in individuals with type 1 diabetes (T1D) compared to healthy controls. Factors associated with this phenomenon have yet to be defined; therefore, this study aimed to explore the association of glycated hemoglobin (HbA1c), disease duration, albuminuria, and glomerular filtration rate with BMD in adults with T1D. METHODS: A cross-sectional study was carried out in tertiary care center. BMD analysis was performed by dual x-ray absorptiometry. Linear models were constructed considering variables associated with BMD. Approval from the ethics committees and informed consent were obtained. RESULTS: We included 128 participants, of whom 59% were women, and 16% had menopause. The median age was 33 (26-42) years. The average age of diabetes diagnosis was 15.3 ± 6.3 years, and the median disease duration was 19.5 (12-27) years. In the adjusted analysis, higher albuminuria (P < .01) and disease duration (P < .05) were associated with a lower BMD in the femoral neck and total hip, independently of age, sex, and body mass index (BMI). Higher HbA1c (P < .01) was associated with a lower spine BMD after adjustment for age, sex, and BMI. CONCLUSION: Studied factors specific to T1D, including albuminuria, disease duration, and HbA1c have an association with BMD regardless of BMI, age, and sex.

Ketosis Suppression and Ageing (KetoSAge): The Effects of Suppressing Ketosis in Long Term Keto-Adapted Non-Athletic Females.

Most studies on ketosis have focused on short-term effects, male athletes, or weight loss. Hereby, we studied the effects of short-term ketosis suppression in healthy women on long-standing ketosis. Ten lean (BMI 20.5 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9) maintaining nutritional ketosis (NK) for > 1 year (3.9 years ± 2.3) underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Adherence to each phase was confirmed with daily capillary D-beta-hydroxybutyrate (BHB) tests (P1 = 1.9 ± 0.7; P2 = 0.1 ± 0.1; and P3 = 1.9 ± 0.6 pmol/L). Ageing biomarkers and anthropometrics were evaluated at the end of each phase. Ketosis suppression significantly increased: insulin, 1.78-fold from 33.60 (± 8.63) to 59.80 (± 14.69) pmol/L (p = 0.0002); IGF1, 1.83-fold from 149.30 (± 32.96) to 273.40 (± 85.66) µg/L (p = 0.0045); glucose, 1.17-fold from 78.6 (± 9.5) to 92.2 (± 10.6) mg/dL (p = 0.0088); respiratory quotient (RQ), 1.09-fold 0.66 (± 0.05) to 0.72 (± 0.06; p = 0.0427); and PAI-1, 13.34 (± 6.85) to 16.69 (± 6.26) ng/mL (p = 0.0428). VEGF, EGF, and monocyte chemotactic protein also significantly increased, indicating a pro-inflammatory shift. Sustained ketosis showed no adverse health effects, and may mitigate hyperinsulinemia without impairing metabolic flexibility in metabolically healthy women.

Ketones: potential to achieve brain energy rescue and sustain cognitive health during ageing.

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.

Evaluation of statistical illiteracy in Latin American clinicians and the piloting evaluation of a short course across multiple timepoints.

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 < 0.01). However, scores dropped after one and 2 months to 7.7/10, IQR:1.6 and 6.1 / 10, IQR:2.2, respectively. 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.

Evaluation of the usefulness of vitamin D as a predictor of mortality in patients with COVID-19.

INTRODUCTION: One of the functions of vitamin D is to regulate respiratory epithelium inflammatory response; therefore, deficiency of this vitamin in the context of COVID-19 could constitute a predictive biomarker of the disease outcome. OBJECTIVE: To evaluate the usefulness of vitamin D for predicting mortality in patients with COVID-19. METHODS: Observational, retrospective study in which 154 patients diagnosed with COVID-19 were included, out of whom 111 survived and 43 died. Vitamin D concentration was determined in all of them. RESULTS: A log-rank p-value < 0.032 was obtained for survival when vitamin D concentration was used as a categorical variable (≤ 20 ng/mL and > 20 ng/mL). On Cox proportional analysis, age and vitamin D concentration were shown to be risk factors associated with mortality in patients with COVID-19 (age: HR = 1.036, 95% CI = 1.016-1.058, p < 0.001; vitamin D: HR (≤ 20 ng/mL and > 20 ng/mL) = 0.478, 95% CI = 0.237-0.966, p < 0.040). CONCLUSION: Age and vitamin D concentration were predictive factors for mortality in COVID-19-infected patients.

INTRODUCCIÓN: Una de las funciones de la vitamina D es regular la respuesta inflamatoria del epitelio respiratorio; por ello, la deficiencia de esa vitamina en el contexto de COVID-19 podría constituir un biomarcador preditivo del desenlace de COVID-19. OBJETIVO: Evaluar la utilidad de la vitamina D para predecir la mortalidad en pacientes con COVID-19. MÉTODOS: Estudio observacional y retrospectivo en el que se incluyeron 154 pacientes con diagnóstico de COVID-19, de los cuales 111 sobrevivieron y 43 fallecieron. En todos se determinó la concentración de vitamina D. RESULTADOS: Se obtuvo un valor log-rank de p < 0.032 para la supervivencia al utilizar la concentración de vitamina D como variable categórica (≤ 20 ng/mL y > 20 ng/mL). Mediante análisis proporcional de Cox se encontró que la edad y concentración de vitamina D mostraron ser factores de riesgo asociados a la mortalidad en pacientes con COVID-19 (edad: HR = 1.036, IC 95 % = 1.016-1.058, p < 0.001; vitamina D: HR ≤ 20 ng/mL y > 20 ng/mL = 0.478, IC 95 % = 0.237-0.966, p < 0.040). CONCLUSIÓN: La edad y la concentración de vitamina D constituyeron factores predictivos de mortalidad en pacientes infectados por COVID-19.

Why a d-ß-hydroxybutyrate monoester?

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-ß-hydroxybutyrate (ßHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate ßHB 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 ßHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The ßHB monoester is a salt-free ßHB 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 ßHB 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 ßHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.

Safety and tolerability of sustained exogenous ketosis using ketone monoester drinks for 28 days in healthy adults.

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-ß-hydroxybutyrate (ßHB) to similar concentrations within minutes, with ßHB 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 ßHB 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.

Increased low-density lipoprotein cholesterol on a low-carbohydrate diet in adults with normal but not high body weight: A meta-analysis.

BACKGROUND: Low-density lipoprotein (LDL) cholesterol change with consumption of a low-carbohydrate diet (LCD) is highly variable. Identifying the source of this heterogeneity could guide clinical decision-making. OBJECTIVES: To evaluate LDL cholesterol change in randomized controlled trials involving LCDs, with a focus on body mass index (BMI) in kg/m2. METHODS: Three electronic indexes (Pubmed, EBSCO, and Scielo) were searched for studies between 1 January, 2003 and 20 December, 2022. Two independent reviewers identified randomized controlled trials involving adults consuming <130 g/d carbohydrate and reporting BMI and LDL cholesterol change or equivalent data. Two investigators extracted relevant data, which were validated by other investigators. Data were analyzed using a random-effects model and contrasted with results of pooled individual participant data. RESULTS: Forty-one trials with 1379 participants and a mean intervention duration of 19.4 wk were included. In a meta-regression accounting for 51.4% of the observed variability on LCDs, mean baseline BMI had a strong inverse association with LDL cholesterol change [ß = -2.5 mg/dL/BMI unit, 95% confidence interval (CI): -3.7, -1.4], whereas saturated fat amount was not significantly associated with LDL cholesterol change. For trials with mean baseline BMI <25, LDL cholesterol increased by 41 mg/dL (95% CI: 19.6, 63.3) on the LCD. By contrast, for trials with a mean of BMI 25-<35, LDL cholesterol did not change, and for trials with a mean BMI ≥35, LDL cholesterol decreased by 7 mg/dL (95% CI: -12.1, -1.3). Using individual participant data, the relationship between BMI and LDL cholesterol change was not observed on higher-carbohydrate diets. CONCLUSIONS: A substantial increase in LDL cholesterol is likely for individuals with low but not high BMI with consumption of an LCD, findings that may help guide individualized nutritional management of cardiovascular disease risk. As carbohydrate restriction tends to improve other lipid and nonlipid risk factors, the clinical significance of isolated LDL cholesterol elevation in this context warrants investigation. This trial was registered at PROSPERO as CRD42022299278.

Impact of healthcare strain on access to mechanical ventilation and mortality of hospitalized COVID-19 patients: a retrospective cohort study.

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.

Evaluation of the safety and tolerability of exogenous ketosis induced by orally administered free beta-hydroxybutyrate in healthy adult subjects.

Beta-hydroxybutyrate (D-BHB) is a metabolite with intrinsic signalling activity that has gained attention as a potentially clinically useful supplement. There are available supplements for inducing ketosis: ketone salts, ketone esters and medium-chain triglycerides. Even when all of them raise D-BHB in the blood and all are safe and well tolerated, they significantly differ in their safety profile, their palatability and their price. A fourth and potentially interesting option is to use biologically identical D-BHB, which it is already commercially available in the USA (American Ketone) and Greater China (MedPHA). However, its safety and tolerability had not yet been documented in the scientific literature. We evaluated the safety and tolerability of orally administered free D-BHB in a gender and age-balanced sample of 24 asymptomatic and overtly healthy adults. No participant showed acid-base abnormalities or electrolyte abnormalities. Secondary symptoms were reported after only 6.2% of all drink takes and none of the reports described the symptom as 'severe'. The most frequently reported secondary effects (19/720 or 2.6%) were gastrointestinal discomfort, headache (7/720 or 1%) and loss of appetite (7/720 or 1%). No correlation between weight-adjusted dose and frequency of secondary symptoms was observed. Free D-BHB was a safe and well-tolerated intervention for inducing sustained exogenous ketosis. Being bioidentical, salt-free and lacking intermediate metabolites, this form of supplementation could have a larger safety spectrum than salt or alcohol-based exogenous ketones. More research is warranted to assess its clinical efficacy in those clinical scenarios in which achieving ketosis rapidly could be beneficial.

Evidence for the carbohydrate-insulin model in a reanalysis of the Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial.

BACKGROUND: The Diet Intervention Examining The Factors Interacting with Treatment Success (DIETFITS) trial demonstrated that meaningful weight loss can be achieved with either a "healthy low-carbohydrate diet" (LCD) or "healthy low-fat diet" (LFD). However, because both diets substantially decreased glycemic load (GL), the dietary factors mediating weight loss remain unclear. OBJECTIVES: We aimed to explore the contribution of macronutrients and GL to weight loss in DIETFITS and examine a hypothesized relationship between GL and insulin secretion. DESIGN: This study is a secondary data analysis of the DIETFITS trial, in which participants with overweight or obesity (aged 18-50 y) were randomized to a 12-mo LCD (N = 304) or LFD (N = 305). RESULTS: Measures related to carbohydrate intake (total amount, glycemic index, added sugar, and fiber) showed strong associations with weight loss at 3-, 6-, and 12-mo time points in the full cohort, whereas those related to total fat intake showed weak to no associations. A biomarker of carbohydrate (triglyceride/HDL cholesterol ratio) predicted weight loss at all time points (3-mo: ß [kg/biomarker z-score change] = 1.1, P = 3.5 × 10-9; 6-mo: ß = 1.7, P = 1.1 × 10-9; and 12-mo: ß = 2.6, P = 1.5 × 10-15), whereas that of fat (low-density lipoprotein cholesterol + HDL cholesterol) did not (all time points: P = NS). In a mediation model, GL explained most of the observed effect of total calorie intake on weight change. Dividing the cohort into quintiles of baseline insulin secretion and GL reduction revealed evidence of effect modification for weight loss, with P = 0.0009 at 3 mo, P = 0.01 at 6 mo, and P = 0.07 at 12 mo. CONCLUSIONS: As predicted by the carbohydrate-insulin model of obesity, weight loss in both diet groups of DIETFITS seems to have been driven by the reduction of GL more so than dietary fat or calories, an effect that may be most pronounced among those with high insulin secretion. These findings should be interpreted cautiously in view of the exploratory nature of this study. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01826591).

Defining metabolic migraine with a distinct subgroup of patients with suboptimal inflammatory and metabolic markers.

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.

Dermatoscopic Patterns in Childhood Vitiligo and Their Association With Reflectance Confocal Microscopy Findings.

INTRODUCTION: The diagnosis of vitiligo is mainly based on clinical findings. However, dermoscopy or reflectance confocal microscopy (RCM) could be useful for assessing its progression (stability, pigmen-tation, or depigmentation). OBJECTIVES: To evaluate the correlation of dermatological findings by dermoscopy and RCM in pediatric vitiligo. METHODS: We conducted a cross-sectional, descriptive, and analytical clinical study. Pediatric patients with vitiligo of both sexes, aged > 1 year and < 18 years, with all spectrums of the disease were includ-ed. Vitiligo lesions were evaluated clinically, by dermoscopy, and microscopy. RESULTS: A total of 40 patients with vitiligo were included. Eight dermoscopic patterns were found: reduced/absent pigment network, perifollicular pigmentation, trichromic, tapioca sago, perifollicular depigmentation, starburst, leukotrichia, and erythema. Skin with a normal pigment network showed complete dermal papillary rings and half-rings. Skin with reduced/absent pigment network also had an absence of papillary rings or only showed half-rings and was more common in unstable vitiligo. The trichrome pattern only showed half-rings. The Tapioca sago pattern showed complete papillary rings and appeared in younger patients. Perifollicular pigmentation showed half-rings and complete rings and did not show associations. The diffuse borders did not present complete papillary structures. It was found that vitiligo duration time of fewer than 24 months (Odds Ratio 4.56, CI 1.09-18.99) and absent papillary rings (OR 2.75, CI 1.01-7.51) are associated with unstable prognosis. CONCLUSIONS: Certain dermatoscopic and microscopic findings, such as the reduction/absence of the pigment network, tapioca sago pattern, and absence of papillary rings, can be used to assess the stabil-ity of the disease and provide insight into the clinical behaviour of vitiligo.

Thyroid markers and body composition predict LDL-cholesterol change in lean healthy women on a ketogenic diet: experimental support for the lipid energy model.

Introduction: There is a large heterogeneity in LDL-cholesterol change among individuals adopting ketogenic diets. Interestingly, lean metabolically healthy individuals seem to be particularly susceptible, with an inverse association between body mass index and LDL-cholesterol change. The lipid energy model proposes that, in lean healthy individuals, carbohydrate restriction upregulates systemic lipid trafficking to meet energy demands. To test if anthropometric and energy metabolism markers predict LDL-cholesterol change during carbohydrate restriction. Methods: Ten lean, healthy, premenopausal women who habitually consumed a ketogenic diet for ≥6 months were engaged in a three-phase crossover study consisting of continued nutritional ketosis, suppression of ketosis with carbohydrate reintroduction, and return to nutritional ketosis. Each phase lasted 21 days. The predictive performance of all available relevant variables was evaluated with the linear mixed-effects models. Results: All body composition metrics, free T3 and total T4, were significantly associated with LDL-cholesterol change. In an interaction model with BMI and free T3, both markers were significant independent and interacting predictors of LDL-cholesterol change. Neither saturated fat, HOMA-IR, leptin, adiponectin, TSH, nor rT3 was associated with LDL-cholesterol changes. Discussion: Among lean, healthy women undergoing carbohydrate restriction, body composition and energy metabolism markers are major drivers of LDL-cholesterol change, not saturated fat, consistent with the lipid energy model.