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.

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.

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.

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.

Acute Leukemia Relapse after Hematopoietic Stem Cell Transplantation: The Good, the Bad, and the Ugly of Isolated Extramedullary Relapse in a Latin American Population.

Hematopoietic stem cell transplantation (HSCT) is an effective therapy for acute leukemia (AL). Relapse represents the main cause of mortality. Isolated extramedullary relapse (iEMR) is atypical and has been related to better outcomes. Here we describe the clinical characteristics and outcomes of AL relapse after HSCT in our study population and analyze the impacts of different types of relapse on survival outcomes. This retrospective, multicenter study included 124 patients age ≥15 years with AL who underwent HSCT between 2004 and 2019. At diagnosis, 66.1% of the patients had lymphocytic AL, 19.7% presented with high-risk features, and 18.5% had extramedullary disease (EMD). At HSCT, 83.1% of the patients were in complete remission (CR), and 44.8% had negative measurable residual disease (MRD). The vast majority of donors were related (96%), including 48.4% HLA-matched and 47.6% haploidentical. Myeloablative conditioning was provided to 80.6% of patients. The median overall survival (OS) was 15 months (95% confidence interval [CI] 9.9 to 20.1 months). Factors associated with improved OS were adolescent and young adult (AYA) patient (P = .035), first or second CR (P = .026), and chronic graft-versus-host disease (GVHD) (P < .001). Acute GVHD grade III-IV (P = .009) was associated with increased mortality. The median relapse-free survival was 13 months (95% CI, 7.17 to 18.8 months); early disease status (P = .017) and chronic GVHD (P < .001) had protective roles. Sixty-eight patients (55%) relapsed after HSCT, with a median time to relapse of 6 months (95% CI, 3.6 to 8.4 months). iEMR was reported in 16 patients (23.5%). The most commonly involved extramedullary sites were the central nervous system and skin. Compared to patients with bone marrow relapse, all patients with iEMR had a diagnosis of acute lymphoid leukemia (P = .008), and 93.8% belonged to the AYA group; regarding pre-HSCT characteristics, iEMR patients had higher rates of negative MRD (P = .06) and a history of EMD (P = .009). Seventy-seven percent of relapsed patients received additional treatment with curative intent. The median OS after relapse (OSr) was 4 months (95% CI, 2.6 to 5.4 months). Factors related to increased OSr included lymphoid phenotype (P = .03), iEMR (P = .0042), late relapse (≥6 months) (P = .014), receipt of systemic therapy including second HSCT (P < .001), and response to therapy (P < .001). Rates of relapse and iEMR were higher than those previously reported in other studies. Advanced disease, reduced-intensity conditioning, and a diminished graft-versus-leukemia effect were factors influencing these findings. At relapse, presenting with iEMR after 6 months and receiving intensive therapy with adequate response were associated with better outcomes. Our results strongly suggest that a personalized approach to treating patients with HSCT is needed to counterbalance specific adverse factors and can positively impact clinical outcomes.

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.

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.

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).

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.

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.