Daily consumption of ketone ester, bis-octanoyl (R)-1,3-butanediol, is safe and tolerable in healthy older adults, a randomized, parallel arm, double-blind, placebo-controlled, pilot study.

Objectives: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to determine tolerability and safety of KE ingestion in older adults. Design: Randomized, placebo-controlled, double-blinded, parallel-arm trial, with a 12-week intervention period ( NCT05585762 ). Setting: General community, Northern California, USA. Participants: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n=30) were randomized and n=23 (M= 14, F=9) completed the protocol. Intervention: Participants were randomly allocated to consume either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. Measurements: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events. Results: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n =2 (14.3% [90% CI = 2.6 - 38.5]); PLA n=1 (7.1% [90% CI = 0.4 - 29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 - 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group. Conclusions: This KE was safe and well-tolerated in healthy older adults. These results provide a foundation for use of KEs in aging research. Highlights: Ketones esters induce ketosis without dietary changes and may target aging biologyStudies of ketone esters were limited in duration and focused on younger adultsWe found ketone esters were safe and tolerable for 12 weeks in healthy older adults.

A randomized open-label, observational study of the novel ketone ester, bis octanoyl (R)-1,3-butanediol, and its acute effect on ß-hydroxybutyrate and glucose concentrations in healthy older adults.

Bis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentrations rapidly after ingestion. KE is hypothesized to have beneficial metabolic effects on health and performance, especially in older adults. Whilst many studies have investigated the ketogenic effect of KE in young adults, they have not been studied in an exclusively older adult population, for whom age-related differences in body composition and metabolism may alter the effects. This randomized, observational, open-label study in healthy older adults (n = 30, 50% male, age = 76.5 years, BMI = 25.2 kg/m2) aimed to elucidate acute tolerance, blood BHB and blood glucose concentrations for 4 hours following consumption of either 12.5 or 25 g of BO-BD formulated firstly as a ready-to-drink beverage (n = 30), then as a re-constituted powder (n = 21), taken with a standard meal. Both serving sizes and formulations of BO-BD were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥ 0.5mM) that lasted until the end of the study. Ketosis was dose responsive; peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 g compared to 12.5 g of BO-BD in both formulations. There were no significant differences in Cmax or iAUC between formulations. Blood glucose increased in all conditions following the meal; there were no consistent significant differences in glucose response between conditions. These results demonstrate that both powder and beverage formulations of the novel KE, BO-BD, induce ketosis in healthy older adults, facilitating future research on functional effects of this ingredient in aging.

Changes in Inhaled Nitric Oxide Use Across ICUs After Implementation of a Standard Pathway.

OBJECTIVES: Inhaled nitric oxide (iNO) is a selective pulmonary vasodilator. It is expensive, frequently used, and not without risk. There is limited evidence supporting a standard approach to initiation and weaning. Our objective was to optimize the use of iNO in the cardiac ICU (CICU), PICU, and neonatal ICU (NICU) by establishing a standard approach to iNO utilization. DESIGN: A quality improvement study using a prospective cohort design with historical controls. SETTING: Four hundred seven-bed free standing quaternary care academic children's hospital. PATIENTS: All patients on iNO in the CICU, PICU, and NICU from January 1, 2017 to December 31, 2022. INTERVENTIONS: Unit-specific standard approaches to iNO initiation and weaning. MEASUREMENTS AND MAIN RESULTS: Sixteen thousand eighty-seven patients were admitted to the CICU, PICU, and NICU with 9343 in the pre-iNO pathway era (January 1, 2017 to June 30, 2020) and 6744 in the postpathway era (July 1, 2020 to December 31, 2022). We found a decrease in the percentage of CICU patients initiated on iNO from 17.8% to 11.8% after implementation of the iNO utilization pathway. We did not observe a change in iNO utilization between the pre- and post-iNO pathway eras in either the PICU or NICU. Based on these data, we estimate 564 total days of iNO (-24%) were saved over 24 months in association with the standard pathway in the CICU, with associated cost savings. CONCLUSIONS: Implementation of a standard pathway for iNO use was associated with a statistically discernible reduction in total iNO usage in the CICU, but no change in iNO use in the NICU and PICU. These differential results likely occurred because of multiple contextual factors in each care setting.

Rationale and protocol for a safety, tolerability and feasibility randomized, parallel group, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms.

Background: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. Objectives: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. Methods: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. Conclusion: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.

Rhachiella malawica gen. nov., spec. nov. from Malawi-another beauty of the Afrotropics (Neuroptera: Rhachiberothidae).

A new species and a new genus of Rhachiberothidae, Rhachiella malawica gen. nov., spec. nov., are described from Malawi. The new species is characterized by a flat vertex, a long penisfilum in the male, and by a bifurcate pseudohypocauda in the female. This combination of characters requires the description of a new genus, which is the sister taxon of Mucroberotha Tjeder, 1959. This is the first record of Rhachiberothidae in Malawi. The distributions of all 14 species of Rhachiberothidae so far known are shown in three maps.

Neonatal Jaundice: Improved Quality and Cost Savings After Implementation of a Standard Pathway.

OBJECTIVES: Seattle Children's Hospital sought to optimize the value equation for neonatal jaundice patients by creating a standard care pathway. METHODS: An evidence-based pathway for management of neonatal jaundice was created. This included multidisciplinary team assembly, comprehensive literature review, creation of a treatment algorithm and computer order sets, formulation of goals and metrics, roll-out of an education program for end users, and ongoing pathway improvement. The pathway was implemented on May 31, 2012. Quality metrics before and after implementation were compared. External data were used to analyze cost impacts. RESULTS: Significant improvements were achieved across multiple quality dimensions. Time to recovery decreased: mean length of stay was 1.30 days for 117 prepathway patients compared with 0.87 days for 69 postpathway patients (P < .001). Efficiency was enhanced: mean time to phototherapy initiation was 101.26 minutes for 14 prepathway patients compared with 54.67 minutes for 67 postpathway patients (P = .03). Care was less invasive: intravenous fluid orders were reduced from 80% to 44% (P < .001). Inpatient use was reduced: 66% of prepathway patients were admitted from the emergency department to inpatient care, compared with 50% of postpathway patients (P = .01). There was no increase in the readmission rate. These achievements translated to statistically significant cost reductions in total charges, as well as in the following categories: intravenous fluids, laboratory, room cost, and emergency department charges. CONCLUSIONS: An evidence-based standard care pathway for neonatal jaundice can significantly improve multiple dimensions of value, including reductions in cost and length of stay.

Naturally occurring variation in tadpole morphology and performance linked to predator regime.

Divergent natural selection drives a considerable amount of the phenotypic and genetic variation observed in natural populations. For example, variation in the predator community can generate conflicting selection on behavioral, life-history, morphological, and performance traits. Differences in predator regime can subsequently increase phenotypic and genetic variations in the population and result in the evolution of reproductive barriers (ecological speciation) or phenotypic plasticity. We evaluated morphology and swimming performance in field collected Bronze Frog larvae (Lithobates clamitans) in ponds dominated by predatory fish and those dominated by invertebrate predators. Based on previous experimental findings, we hypothesized that tadpoles from fish-dominated ponds would have small bodies, long tails, and large tail muscles and that these features would facilitate fast-start speed. We also expected to see increased tail fin depth (i.e., the tail-lure morphology) in tadpoles from invertebrate-dominated ponds. Our results support our expectations with respect to morphology in affecting swimming performance of tadpoles in fish-dominated ponds. Furthermore, it is likely that divergent natural selection is playing a role in the diversification on morphology and locomotor performance in this system.

A new East-Asian species in the Chrysoperla carnea-group of cryptic lacewing species (Neuroptera: Chrysopidae) based on distinct larval morphology and a unique courtship song.

Larval morphology and substrate-borne vibrational courtship songs have been hypothesized to distinguish and isolate Chrysoperla 'nipponensis-B' from true 'Type A' Chrysoperla nipponensis (Okamoto), both of which occur sympatrically in eastern Asia. Here, we formally describe C. 'nipponensis-B' as Chrysoperla nigrocapitata sp.n., based on populations sampled throughout Japan and at two sites in South Korea. Behavioral playback experiments show that males and females of each species reject the duetting songs of non-conspecifics, supporting the existence in nature of strong premating reproductive isolation between the two species. Detailed morphological analysis substantiates that the adults of the two species are nearly identical. However, the dorsum of the larval head of C. nigrocapitata is usually darkly and heavily pigmented, in striking contrast to the condition seen in C. nipponensis; if available, it is probably the best trait for distinguishing the two species morphologically. Other aspects of life history, ecology, geographic distribution, and molecular systematics of the new species are briefly considered.

Sexual ornaments, body morphology, and swimming performance in naturally hybridizing swordtails (teleostei: xiphophorus).

Determining the costs of sexual ornaments is complicated by the fact that ornaments are often integrated with other, non-sexual traits, making it difficult to dissect the effect of ornaments independent of other aspects of the phenotype. Hybridization can produce reduced phenotypic integration, allowing one to evaluate performance across a broad range of multivariate trait values. Here we assess the relationship between morphology and performance in the swordtails Xiphophorus malinche and X. birchmanni, two naturally-hybridizing fish species that differ extensively in non-sexual as well as sexual traits. We took advantage of novel trait variation in hybrids to determine if sexual ornaments incur a cost in terms of locomotor ability. For both fast-start and endurance swimming, hybrids performed at least as well as the two parental species. The sexually-dimorphic sword did not impair swimming performance per se. Rather, the sword negatively affected performance only when paired with a sub-optimal body shape. Studies seeking to quantify the costs of ornaments should consider that covariance with non-sexual traits may create the spurious appearance of costs.

Obligatory duetting behaviour in the Chrysoperla carnea-group of cryptic species (Neuroptera: Chrysopidae): its role in shaping evolutionary history.

An unusual system of communication has evolved in green lacewings of the Chrysoperla carnea-group, triggering rapid proliferation of numerous cryptic species across all of the Northern Hemisphere and large portions of Africa. The system is based on sexually monomorphic, substrate-borne vibrational signals, produced by abdominal oscillation. These low-frequency signals are exchanged between courting individuals in a precise duetting format. The song of each of the more than 20 described species exhibits a unique acoustical phenotype that reproductively isolates the taxon from all other species with which it might come into contact. Here, we review what is known about duetting behaviour in the carnea-group, emphasizing the dominant role that duetting has played in the evolution, ecology, and speciation of the complex. Included are descriptions and discussions of song diversity and its impact on reproductive isolation among species, the genetic basis of interspecific song differences, partitioning of acoustic space among sympatric species, parallel song evolution in allopatric species pairs, and modes of speciation within the complex. We also emphasize the importance of correctly identifying by song all species of the carnea-group that are to be used either in experimental studies or programs of biological control, while acknowledging the continuing relevance of morphology to carnea-group systematics.

Surface stresses of mixed-mode grinding materials on borosilicate glass.

Mixed-mode grinding occurs when a bound abrasive works in both brittle and ductile regimes simultaneously. Substrates ground in a mixed-mode behavior show reduced curvature induced by compressive surface forces than loose abrasives as demonstrated by observing the Twyman effect. This reduction in bending corresponds to reduced subsurface damage. This is verified by controlled acid etching, which shows the exponential decay of the compressive force per unit length. Loose abrasive particles, added to maintain pad wear due to low pressures, have no effect on the measured stresses. If loose abrasive wear ceases, the pads glaze. Glazing creates near-specular surfaces while reducing measurable stress. These effects for borosilicate glass and Trizact grinding pads are explored and quantified.

Form, function, and fitness: pathways to survival.

Two hypotheses have been considered in the literature regarding how anuran morphology reduces predation risk: by (1) improving escape swimming performance, or (2) using the tail as a lure to draw predator strikes away from the body of the tadpole. We investigated these hypotheses using a modification of the morphology, performance, and fitness path analysis of Arnold (1983, Am. Zool. 23:347-361). Indirect effects of morphology on fitness, as mediated by burst swimming speed, as well as direct paths from morphology to survival with dragonfly larvae were included in the path model. Tadpole morphology did affect burst swimming speed, however, burst swimming speed did not influence survival. Fast tadpoles were larger overall, had long tails, deep tail muscles, and proportionally small bodies. In addition, a shape trait similar to published descriptions of the tail lure morphology had a direct relationship with survival. Thus, only the tail lure effect was supported. This study documents the utility of analyzing multiple trait effects and demonstrates that including direct paths between traits and fitness in the morphology, performance, and fitness path model allows evaluation of alternative hypothesis of selection.

Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma.

Asthma is an increasingly common disorder responsible for considerable morbidity and mortality. Although obesity is a risk factor for asthma and weight loss can improve symptoms, many patients do not adhere to low calorie diets and the impact of dietary restriction on the disease process is unknown. A study was designed to determine if overweight asthma patients would adhere to an alternate day calorie restriction (ADCR) dietary regimen, and to establish the effects of the diet on their symptoms, pulmonary function and markers of oxidative stress, and inflammation. Ten subjects with BMI>30 were maintained for 8 weeks on a dietary regimen in which they ate ad libitum every other day, while consuming less than 20% of their normal calorie intake on the intervening days. At baseline, and at designated time points during the 8-week study, asthma control, symptoms, and Quality of Life questionnaires (ACQ, ASUI, mini-AQLQ) were assessed and blood was collected for analyses of markers of general health, oxidative stress, and inflammation. Peak expiratory flow (PEF) was measured daily on awakening. Pre- and postbronchodilator spirometry was obtained at baseline and 8 weeks. Nine of the subjects adhered to the diet and lost an average of 8% of their initial weight during the study. Their asthma-related symptoms, control, and QOL improved significantly, and PEF increased significantly, within 2 weeks of diet initiation; these changes persisted for the duration of the study. Spirometry was unaffected by ADCR. Levels of serum beta-hydroxybutyrate were increased and levels of leptin were decreased on CR days, indicating a shift in energy metabolism toward utilization of fatty acids and confirming compliance with the diet. The improved clinical findings were associated with decreased levels of serum cholesterol and triglycerides, striking reductions in markers of oxidative stress (8-isoprostane, nitrotyrosine, protein carbonyls, and 4-hydroxynonenal adducts), and increased levels of the antioxidant uric acid. Indicators of inflammation, including serum tumor necrosis factor-alpha and brain-derived neurotrophic factor, were also significantly decreased by ADCR. Compliance with the ADCR diet was high, symptoms and pulmonary function improved, and oxidative stress and inflammation declined in response to the dietary intervention. These findings demonstrate rapid and sustained beneficial effects of ADCR on the underlying disease process in subjects with asthma, suggesting a novel approach for therapeutic intervention in this disorder.

The effect on health of alternate day calorie restriction: eating less and more than needed on alternate days prolongs life.

Restricting caloric intake to 60-70% of normal adult weight maintenance requirement prolongs lifespan 30-50% and confers near perfect health across a broad range of species. Every other day feeding produces similar effects in rodents, and profound beneficial physiologic changes have been demonstrated in the absence of weight loss in ob/ob mice. Since May 2003 we have experimented with alternate day calorie restriction, one day consuming 20-50% of estimated daily caloric requirement and the next day ad lib eating, and have observed health benefits starting in as little as two weeks, in insulin resistance, asthma, seasonal allergies, infectious diseases of viral, bacterial and fungal origin (viral URI, recurrent bacterial tonsillitis, chronic sinusitis, periodontal disease), autoimmune disorder (rheumatoid arthritis), osteoarthritis, symptoms due to CNS inflammatory lesions (Tourette's, Meniere's) cardiac arrhythmias (PVCs, atrial fibrillation), menopause related hot flashes. We hypothesize that other many conditions would be delayed, prevented or improved, including Alzheimer's, Parkinson's, multiple sclerosis, brain injury due to thrombotic stroke atherosclerosis, NIDDM, congestive heart failure. Our hypothesis is supported by an article from 1957 in the Spanish medical literature which due to a translation error has been construed by several authors to be the only existing example of calorie restriction with good nutrition. We contend for reasons cited that there was no reduction in calories overall, but that the subjects were eating, on alternate days, either 900 calories or 2300 calories, averaging 1600, and that body weight was maintained. Thus they consumed either 56% or 144% of daily caloric requirement. The subjects were in a residence for old people, and all were in perfect health and over 65. Over three years, there were 6 deaths among 60 study subjects and 13 deaths among 60 ad lib-fed controls, non-significant difference. Study subjects were in hospital 123 days, controls 219, highly significant difference. We believe widespread use of this pattern of eating could impact influenza epidemics and other communicable diseases by improving resistance to infection. In addition to the health effects, this pattern of eating has proven to be a good method of weight control, and we are continuing to study the process in conjunction with the NIH.

Cancer screening practices and attitudes: comparison of low-income women in three ethnic groups.

OBJECTIVE: Based on the Health Belief Model, this study investigates differences among ethnically diverse, low-income women in the USA to inform better outreach strategies to encourage participation in the Centers for Disease Control & Prevention (CDC)- sponsored breast and cervical cancer early detection program. DESIGN: Program-eligible, low-income, Hispanic, Vietnamese and Cambodian American women who were over the age of 40 volunteered to be interviewed in their first language for the study. A total of 78 women completed the interviews. RESULTS: All three samples of women were more likely to perceive barriers to having a mammogram performed compared to the non-minority normative group. Hispanic and Vietnamese women were more similar in their health beliefs and behaviors than Vietnamese and Cambodian women. CONCLUSION: This study supports other research on the barriers and health belief differences found among ethnic minority women in the USA. Further, these findings suggest that it is not advisable to collapse ethnic groups into general categories such as 'Asian' when planning cancer control strategies, as differences were found by country of origin.