Neanderthal behaviour, diet, and disease inferred from ancient DNA in dental calculus.

Recent genomic data have revealed multiple interactions between Neanderthals and modern humans, but there is currently little genetic evidence regarding Neanderthal behaviour, diet, or disease. Here we describe the shotgun-sequencing of ancient DNA from five specimens of Neanderthal calcified dental plaque (calculus) and the characterization of regional differences in Neanderthal ecology. At Spy cave, Belgium, Neanderthal diet was heavily meat based and included woolly rhinoceros and wild sheep (mouflon), characteristic of a steppe environment. In contrast, no meat was detected in the diet of Neanderthals from El Sidrón cave, Spain, and dietary components of mushrooms, pine nuts, and moss reflected forest gathering. Differences in diet were also linked to an overall shift in the oral bacterial community (microbiota) and suggested that meat consumption contributed to substantial variation within Neanderthal microbiota. Evidence for self-medication was detected in an El Sidrón Neanderthal with a dental abscess and a chronic gastrointestinal pathogen (Enterocytozoon bieneusi). Metagenomic data from this individual also contained a nearly complete genome of the archaeal commensal Methanobrevibacter oralis (10.2× depth of coverage)-the oldest draft microbial genome generated to date, at around 48,000 years old. DNA preserved within dental calculus represents a notable source of information about the behaviour and health of ancient hominin specimens, as well as a unique system that is useful for the study of long-term microbial evolution.

Reconstructing Neanderthal diet: The case for carbohydrates.

Evidence for plants rarely survives on Paleolithic sites, while animal bones and biomolecular analyses suggest animal produce was important to hominin populations, leading to the perspective that Neanderthals had a very-high-protein diet. But although individual and short-term survival is possible on a relatively low-carbohydrate diet, populations are unlikely to have thrived and reproduced without plants and the carbohydrates they provide. Today, nutritional guidelines recommend that around half the diet should be carbohydrate, while low intake is considered to compromise physical performance and successful reproduction. This is likely to have been the same for Paleolithic populations, highlighting an anomaly in that the basic physiological recommendations do not match the extensive archaeological evidence. Neanderthals had large, energy-expensive brains and led physically active lifestyles, suggesting that for optimal health they would have required high amounts of carbohydrates. To address this anomaly, we begin by outlining the essential role of carbohydrates in the human reproduction cycle and the brain and the effects on physical performance. We then evaluate the evidence for resource availability and the archaeological evidence for Neanderthal diet and investigate three ways that the anomaly between the archaeological evidence and the hypothetical dietary requirements might be explained. First, Neanderthals may have had an as yet unidentified genetic adaptation to an alternative physiological method to spare blood glucose and glycogen reserves for essential purposes. Second, they may have existed on a less-than-optimum diet and survived rather than thrived. Third, the methods used in dietary reconstruction could mask a complex combination of dietary plant and animal proportions. We end by proposing that analyses of Paleolithic diet and subsistence strategies need to be grounded in the minimum recommendations throughout the life course and that this provides a context for interpretation of the archaeological evidence from the behavioral and environmental perspectives.

A novel nutritional intervention improves lung function in overweight/obese adolescents with poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study.

Asthma in the obese is often severe, difficult to treat, and characterized by less eosinophilic inflammation than asthma in the nonobese. Obesity-associated metabolic dysregulation may be a causal factor. We previously reported that a nutrient- and fiber-dense bar [Children's Hospital Oakland Research Institute (CHORI)-bar], which was designed to fill gaps in poor diets, improved metabolism in healthy overweight/obese (OW/OB) adults. In this pilot trial, OW/OB adolescents with poorly controlled asthma were randomized to weekly nutrition/exercise classes with or without twice-daily CHORI-bar consumption. Intent-to-treat analysis did not indicate CHORI-bar-specific effects. However, restricting the analysis to participants with acceptable compliance and a relatively low fraction of exhaled nitric oxide (FENO; <50/ ppb, a surrogate for noneosinophilic asthma; study participants: CHORI-bar, n = 16; controls, n = 15) indicated that CHORI-bar-specific, significant improvements in lung function (forced vital capacity, percent-predicted forced expiratory volume in 1 s, and percent-predicted forced expiratory flow between 25 and 75% of forced vital capacity), primarily in participants with low chronic inflammation (high-sensitivity C-reactive protein <1.5 mg/L). (We previously observed that chronic inflammation blunted CHORI-bar-induced metabolic improvements in healthy OW/OB adults.) Lung function improvement occurred without weight loss and was independent of improvements in metabolic and anthropometric end points and questionnaire-based measures of asthma control and quality of life. This study suggests that a nutritional intervention can improve lung function in OW/OB adolescents with asthma and relatively low FENO without requiring major changes in dietary habits, lifestyle, or weight loss and that this effect is blunted by chronic inflammation.-Bseikri, M., McCann, J. C., Lal, A., Fong, E., Graves, K., Goldrich, A., Block, D., Gildengoren, G. L., Mietus-Snyder, M., Shigenaga, M., Suh, J., Hardy, K., Ames, B. N. A novel nutritional intervention improves lung function in overweight/obese adolescents with poorly controlled asthma: the Supplemental Nutrition in Asthma Control (SNAC) pilot study.

Paleomedicine and the use of plant secondary compounds in the Paleolithic and Early Neolithic.

Reconstructing plant use before domestication is challenging due to a lack of evidence. Yet, on the small number of sites with assemblages, the wide range of different plant species cannot be explained simply in terms of nutrition. Assemblages from the Lower Paleolithic to the Early Neolithic were examined to investigate the relative edible and medicinal properties of the plants. The assemblages contain a mixture of edible species, plants that are both edible and medicinal, and plants with only medicinal properties. The proportion of medicinal plants at all sites is well above the natural average and increases over time. Mechanisms for preventing intestinal parasitic infections are common among animals and together with chimpanzees' preventative and curative self-medication practices suggest an evolutionary context for this behavior. A broad-spectrum approach to plant collection is likely to have been in place throughout the Paleolithic driven, in part, by the need for medicinal compounds.

Pleistocene dental calculus: Recovering information on Paleolithic food items, medicines, paleoenvironment and microbes.

Dental calculus is now widely used to recover information on items ingested in the past. It is particularly valuable in the earlier Paleolithic, where recovered data may represent the only evidence for plant use. Several recovery methods are used and each one produces different results. Biomolecular markers and genetic material recovered from dental calculus is providing new data on identifiable dietary and medicinal items and human microbial communities. The recovery of microfossils, in particular, starch granules, has triggered a new awareness of the role of plants in the diet throughout the Paleolithic. However, the minute amount of material recovered has little relationship with food eaten during a person's life, while salivary amylase breaks down cooked starch. Therefore, broader dietary interpretations and detection of cooked food are problematic. The study of ancient dental calculus holds great potential to recover information about past lives, within realistic parameters.

Diet and environment 1.2 million years ago revealed through analysis of dental calculus from Europe's oldest hominin at Sima del Elefante, Spain.

Sima del Elefante, Atapuerca, Spain contains one of the earliest hominin fragments yet known in Europe, dating to 1.2 Ma. Dental calculus from a hominin molar was removed, degraded and analysed to recover entrapped remains. Evidence for plant use at this time is very limited and this study has revealed the earliest direct evidence for foods consumed in the genus Homo. This comprises starchy carbohydrates from two plants, including a species of grass from the Triticeae or Bromideae tribe, meat and plant fibres. All food was eaten raw, and there is no evidence for processing of the starch granules which are intact and undamaged. Additional biographical detail includes fragments of non-edible wood found adjacent to an interproximal groove suggesting oral hygiene activities, while plant fibres may be linked to raw material processing. Environmental evidence comprises spores, insect fragments and conifer pollen grains which are consistent with a forested environment.

Beyond food: The multiple pathways for inclusion of materials into ancient dental calculus.

Dental calculus (mineralized dental plaque) was first recognised as a potentially useful archaeological deposit in the 1970s, though interest in human dental calculus as a resource material has increased sharply in the past few years. The majority of recent research has focused on the retrieval of plant microfossils embedded in its matrix and interpretation of these finds as largely the result of deliberate consumption of plant-derived food. However, while most of the material described in published works does represent food, dental calculus is in fact a "depositional environment" as material can enter the mouth from a range of sources. In this respect, it therefore represents an archaeological deposit that can also contain extensive non-dietary debris. This can comprise a wide variety of cultural and environmental material which reaches the mouth and can become embedded in dental calculus through alternative pathways. Here, we explore the human behaviors and activities besides eating that can generate a flux of particles into the human mouth, the broad range of additional cultural and environmental information that can be obtained through the analysis and contextualisation of this material, and the implications of the additional pathways by which material can become embedded in dental calculus.

Respiratory and sleep disorders in mucopolysaccharidosis.

MPS encompasses a group of rare lysosomal storage disorders that are associated with the accumulation of glycosaminoglycans (GAG) in organs and tissues. This accumulation can lead to the progressive development of a variety of clinical manifestations. Ear, nose, throat (ENT) and respiratory problems are very common in patients with MPS and are often among the first symptoms to appear. Typical features of MPS include upper and lower airway obstruction and restrictive pulmonary disease, which can lead to chronic rhinosinusitis or chronic ear infections, recurrent upper and lower respiratory tract infections, obstructive sleep apnoea, impaired exercise tolerance, and respiratory failure. This review provides a detailed overview of the ENT and respiratory manifestations that can occur in patients with MPS and discusses the issues related to their evaluation and management.

Human consumption of seaweed and freshwater aquatic plants in ancient Europe.

During the Mesolithic in Europe, there is widespread evidence for an increase in exploitation of aquatic resources. In contrast, the subsequent Neolithic is characterised by the spread of farming, land ownership, and full sedentism, which lead to the perception of marine resources subsequently representing marginal or famine food or being abandoned altogether even at the furthermost coastal limits of Europe. Here, we examine biomarkers extracted from human dental calculus, using sequential thermal desorption- and pyrolysis-GCMS, to report direct evidence for widespread consumption of seaweed and submerged aquatic and freshwater plants across Europe. Notably, evidence of consumption of these resources extends through the Neolithic transition to farming and into the Early Middle Ages, suggesting that these resources, now rarely eaten in Europe, only became marginal much more recently. Understanding ancient foodstuffs is crucial to reconstructing the past, while a better knowledge of local, forgotten resources is likewise important today.

Minimum Core Data Elements for Transcatheter Mitral Therapies: Scientific Statement by PASSION CV, HVC, and TVTR.

Mitral regurgitation is the most common valvular disease and is estimated to affect over 5 million Americans. Real-world data collection contributes to safety and effectiveness evidence for the U.S. Food and Drug Administration, quality evaluation for the Centers for Medicare and Medicaid Services and hospitals, and clinical best practice research. We aimed to establish a minimum core data set in mitral interventions to promote efficient, reusable real-world data collection for all of these purposes. Two expert task forces separately evaluated and reconciled a list of candidate elements derived from: 1) 2 ongoing transcatheter mitral trials; and 2) a systemic literature review of high-impact mitral trials and U.S multicenter, multidevice registries. From 703 unique data elements considered, unanimous consensus agreement was achieved on 127 "core" data elements, with the most common reasons for exclusion from the minimum core data set being burden or difficulty in accurate assessment (41.2%), duplicative information (25.0%), and low likelihood of affecting outcomes (19.6%). After a systematic review and extensive discussions, a multilateral group of academicians, industry representatives, and regulators established and implemented into the national Society of Thoracic Surgery/American College of Cardiology Transcatheter Valve Therapies Registry 127 interoperable, reusable core data elements to support more efficient, consistent, and informative transcatheter mitral device evidence for regulatory submissions, safety surveillance, best practice development, and hospital quality assessments.

Neanderthal medics? Evidence for food, cooking, and medicinal plants entrapped in dental calculus.

Neanderthals disappeared sometime between 30,000 and 24,000 years ago. Until recently, Neanderthals were understood to have been predominantly meat-eaters; however, a growing body of evidence suggests their diet also included plants. We present the results of a study, in which sequential thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) and pyrolysis-gas chromatography-mass spectrometry (Py-GC-MS) were combined with morphological analysis of plant microfossils, to identify material entrapped in dental calculus from five Neanderthal individuals from the north Spanish site of El Sidrón. Our results provide the first molecular evidence for inhalation of wood-fire smoke and bitumen or oil shale and ingestion of a range of cooked plant foods. We also offer the first evidence for the use of medicinal plants by a Neanderthal individual. The varied use of plants that we have identified suggests that the Neanderthal occupants of El Sidrón had a sophisticated knowledge of their natural surroundings which included the ability to select and use certain plants.

Minimum Core Data Elements for Evaluation of TAVR: A Scientific Statement by PASSION CV, HVC, and TVT Registry.

Transcatheter aortic valve replacement (TAVR) is the standard of care for severe, symptomatic aortic stenosis. Real-world TAVR data collection contributes to benefit/risk assessment and safety evidence for the U.S. Food and Drug Administration, quality evaluation for the Centers for Medicare and Medicaid Services and hospitals, as well as clinical research and real-world implementation through appropriate use criteria. The essential minimum core dataset for these purposes has not previously been defined but is necessary to promote efficient, reusable real-world data collection supporting quality, regulatory, and clinical applications. The authors performed a systematic review of the published research for high-impact TAVR studies and U.S. multicenter, multidevice registries. Two expert task forces, one from the Predictable and Sustainable Implementation of National Cardiovascular Registries/Heart Valve Collaboratory and another from The Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry convened separately and then met to reconcile a final list of essential data elements. From 276 unique data elements considered, unanimous consensus agreement was achieved on 132 "core" data elements, with the most common reasons for exclusion from the minimum core dataset being burden or difficulty in accurate assessment (36.9%), duplicative information (33.3%), and low likelihood of affecting outcomes (10.7%). After a systematic review and extensive discussions, a multilateral group of academicians, industry representatives, and regulators established 132 interoperable, reusable essential core data elements essential to supporting more efficient, consistent, and informative TAVR device evidence for regulatory submissions, safety surveillance, best practice, and hospital quality assessments.

Minimum Core Data Elements for Evaluation of TAVR: A Scientific Statement by PASSION CV, HVC, and TVT Registry.

Transcatheter aortic valve replacement (TAVR) is the standard of care for severe, symptomatic aortic stenosis. Real-world TAVR data collection contributes to benefit/risk assessment and safety evidence for the U.S. Food and Drug Administration, quality evaluation for the Centers for Medicare and Medicaid Services and hospitals, as well as clinical research and real-world implementation through appropriate use criteria. The essential minimum core dataset for these purposes has not previously been defined but is necessary to promote efficient, reusable real-world data collection supporting quality, regulatory, and clinical applications. The authors performed a systematic review of the published research for high-impact TAVR studies and U.S. multicenter, multidevice registries. Two expert task forces, one from the Predictable and Sustainable Implementation of National Cardiovascular Registries/Heart Valve Collaboratory and another from The Society of Thoracic Surgeons/American College of Cardiology TVT (Transcatheter Valve Therapy) Registry convened separately and then met to reconcile a final list of essential data elements. From 276 unique data elements considered, unanimous consensus agreement was achieved on 132 "core" data elements, with the most common reasons for exclusion from the minimum core dataset being burden or difficulty in accurate assessment (36.9%), duplicative information (33.3%), and low likelihood of affecting outcomes (10.7%). After a systematic review and extensive discussions, a multilateral group of academicians, industry representatives, and regulators established 132 interoperable, reusable essential core data elements essential to supporting more efficient, consistent, and informative TAVR device evidence for regulatory submissions, safety surveillance, best practice, and hospital quality assessments.

Transcatheter Mitral Valve Therapy in the United States: A Report from the STS/ACC TVT Registry.

Data for nearly all patients undergoing transcatheter edge-to-edge repair (TEER) and transcatheter mitral valve replacement (TMVR) with an approved device in the United States is captured in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. All data submitted for TEER or TMVR between 2014 and March 31, 2020, are reported. A total of 37,475 patients underwent a mitral transcatheter procedure, including 33,878 TEER and 3,597 TMVR. Annual procedure volumes for TEER have increased from 1,152 per year in 2014 to 10,460 per year in 2019 at 403 sites and for TMVR from 84 per year to 1,120 per year at 301 centers. Mortality rates have decreased for TEER at 30 days (5.6%-4.1%) and 1 year (27.4%-22.0%). Early off-label use data on TMVR in mitral valve-in-valve therapy led to approval by the U.S. Food and Drug Administration in 2017, and the 2019 30-day mortality rate was 3.9%. Overall improvements in outcomes over the last 6 years are apparent. (STS/ACC TVT Registry Mitral Module; NCT02245763).

Asthma in sickle cell disease.

In recent years, evidence has increased that asthma predisposes to complications of sickle cell disease (SCD), such as pain crises, acute chest syndrome, pulmonary hypertension, and stroke, and is associated with increased mortality. An obstructive pattern of pulmonary function, along with a higher-than-expected prevalence of airway hyper-responsiveness (AHR) when compared to the general population, has led some researchers to suspect that underlying hemolysis may contribute to the development of a pulmonary disease similar to asthma in patients with SCD. While the pathophysiologic mechanism in atopic asthma involves up-regulation of Th2 cytokines, mast cell- and eosinophil-driven inflammation, plus increased activity of inducible nitric oxide synthase (iNOS) and arginase in airway epithelium resulting in obstructive changes and AHR, the exact mechanisms of AHR, obstructive and restrictive lung disease in SCD is unclear. It is known that SCD is associated with a proinflammatory state and an enhanced inflammatory response is seen during vaso-occlusive events (VOE). Hemolysis-driven acute-on-chronic inflammation and dysregulated arginine-nitric oxide metabolism are potential mechanisms by which pulmonary dysfunction could occur in patients with SCD. In patients with a genetic predisposition of atopic asthma, these changes are probably more severe and result in increased susceptibility to sickle cell complications. Early recognition and aggressive management of asthma based on established National Institutes of Health asthma guidelines is recommended in order to minimize morbidity and mortality.

Paleomedicine and the Evolutionary Context of Medicinal Plant Use.

Modern human need for medicines is so extensive that it is thought to be a deep evolutionary behavior. There is abundant evidence from our Paleolithic and later prehistoric past, of survival after periodontal disease, traumas, and invasive medical treatments including trepanations and amputations, suggesting a detailed, applied knowledge of medicinal plant secondary compounds. Direct archeological evidence for use of plants in the Paleolithic is rare, but evidence is growing. An evolutionary context for early human use of medicinal plants is provided by the broad evidence for animal self-medication, in particular, of non-human primates. During the later Paleolithic, there is evidence for the use of poisonous and psychotropic plants, suggesting that Paleolithic humans built on and expanded their knowledge and use of plant secondary compounds.

Transcatheter Mitral Valve Therapy in the United States: A Report From the STS-ACC TVT Registry.

Data for nearly all patients undergoing transcatheter edge-to-edge repair (TEER) and transcatheter mitral valve replacement (TMVR) with an approved device in the United States is captured in the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. All data submitted for TEER or TMVR between 2014 and March 31, 2020, are reported. A total of 37,475 patients underwent a mitral transcatheter procedure, including 33,878 TEER and 3,597 TMVR. Annual procedure volumes for TEER have increased from 1,152 per year in 2014 to 10,460 per year in 2019 at 403 sites and for TMVR from 84 per year to 1,120 per year at 301 centers. Mortality rates have decreased for TEER at 30 days (5.6%-4.1%) and 1 year (27.4%-22.0%). Early off-label use data on TMVR in mitral valve-in-valve therapy led to approval by the U.S. Food and Drug Administration in 2017, and the 2019 30-day mortality rate was 3.9%. Overall improvements in outcomes over the last 6 years are apparent. (STS/ACC TVT Registry Mitral Module; NCT02245763).

Pulmonary, gonadal, and central nervous system status after bone marrow transplantation for sickle cell disease.

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

Enzyme replacement therapy for mucopolysaccharidosis VI: evaluation of long-term pulmonary function in patients treated with recombinant human N-acetylgalactosamine 4-sulfatase.

Pulmonary function is impaired in untreated mucopolysaccharidosis type VI (MPS VI). Pulmonary function was studied in patients during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB; rhN-acetylgalactosamine 4-sulfatase). Pulmonary function tests prior to and for up to 240 weeks of weekly infusions of rhASB at 1 mg/kg were completed in 56 patients during Phase 1/2, Phase 2, Phase 3 and Phase 3 Extension trials of rhASB and the Survey Study. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and, in a subset of patients, maximum voluntary ventilation (MVV), were analyzed as absolute volume in liters. FEV1 and FVC showed little change from baseline during the first 24 weeks of ERT, but after 96 weeks, these parameters increased over baseline by 11% and 17%, respectively. This positive trend compared with baseline continued beyond 96 weeks of treatment. Improvements from baseline in pulmonary function occurred along with gains in height in the younger group (5.5% change) and in the older patient group (2.4% change) at 96 weeks. Changes in MVV occurred earlier within 24 weeks of treatment to approximately 15% over baseline. Model results based on data from all trials showed significant improvements in the rate of change in pulmonary function during 96 weeks on ERT, whereas little or no improvement was observed for the same time period prior to ERT. Thus, analysis of mean percent change data and longitudinal modeling both indicate that long-term ERT resulted in improvement in pulmonary function in MPS VI patients.