RESUMO
In the period between 5,300 and 4,900 calibrated years before present (cal. BP), populations across large parts of Europe underwent a period of demographic decline1,2. However, the cause of this so-called Neolithic decline is still debated. Some argue for an agricultural crisis resulting in the decline3, others for the spread of an early form of plague4. Here we use population-scale ancient genomics to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist. We find that the Neolithic plague was widespread, detected in at least 17% of the sampled population and across large geographical distances. We demonstrate that the disease spread within the Neolithic community in three distinct infection events within a period of around 120 years. Variant graph-based pan-genomics shows that the Neolithic plague genomes retained ancestral genomic variation present in Yersinia pseudotuberculosis, including virulence factors associated with disease outcomes. In addition, we reconstruct four multigeneration pedigrees, the largest of which consists of 38 individuals spanning six generations, showing a patrilineal social organization. Lastly, we document direct genomic evidence for Neolithic female exogamy in a woman buried in a different megalithic tomb than her brothers. Taken together, our findings provide a detailed reconstruction of plague spread within a large patrilineal kinship group and identify multiple plague infections in a population dated to the beginning of the Neolithic decline.
Assuntos
Fazendeiros , Genômica , Linhagem , Peste , Dinâmica Populacional , Yersinia pestis , Feminino , Humanos , Masculino , Cemitérios/história , Fazendeiros/história , Genoma Bacteriano/genética , História Antiga , Filogenia , Peste/epidemiologia , Peste/história , Peste/microbiologia , Peste/mortalidade , Países Escandinavos e Nórdicos/epidemiologia , Fatores de Tempo , Fatores de Virulência/genética , Yersinia pestis/genética , Yersinia pestis/isolamento & purificaçãoRESUMO
Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.
Assuntos
Genoma Humano , Genômica , Migração Humana , Populações Escandinavas e Nórdicas , Humanos , Dinamarca/etnologia , Emigrantes e Imigrantes/história , Genótipo , Populações Escandinavas e Nórdicas/genética , Populações Escandinavas e Nórdicas/história , Migração Humana/história , Genoma Humano/genética , História Antiga , Pólen , Dieta/história , Caça/história , Fazendeiros/história , Cultura , Fenótipo , Conjuntos de Dados como AssuntoRESUMO
Hepatitis B virus (HBV) is a major cause of human hepatitis. There is considerable uncertainty about the timescale of its evolution and its association with humans. Here we present 12 full or partial ancient HBV genomes that are between approximately 0.8 and 4.5 thousand years old. The ancient sequences group either within or in a sister relationship with extant human or other ape HBV clades. Generally, the genome properties follow those of modern HBV. The root of the HBV tree is projected to between 8.6 and 20.9 thousand years ago, and we estimate a substitution rate of 8.04 × 10-6-1.51 × 10-5 nucleotide substitutions per site per year. In several cases, the geographical locations of the ancient genotypes do not match present-day distributions. Genotypes that today are typical of Africa and Asia, and a subgenotype from India, are shown to have an early Eurasian presence. The geographical and temporal patterns that we observe in ancient and modern HBV genotypes are compatible with well-documented human migrations during the Bronze and Iron Ages1,2. We provide evidence for the creation of HBV genotype A via recombination, and for a long-term association of modern HBV genotypes with humans, including the discovery of a human genotype that is now extinct. These data expose a complexity of HBV evolution that is not evident when considering modern sequences alone.
Assuntos
Evolução Molecular , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B/virologia , Filogenia , África , Animais , Ásia , Europa (Continente) , Genótipo , Vírus da Hepatite B/classificação , História Antiga , História Medieval , Hominidae/virologia , Migração Humana/história , Humanos , Recombinação GenéticaRESUMO
In Fig. 2 of this Letter, the 'E' and 'G' clade labels were inadvertently reversed, and in Table 2 the genotype of DA27 was 'D1' instead of 'D5'. These have been corrected online.
RESUMO
Archaeological dental calculus, or mineralized plaque, is a key tool to track the evolution of oral microbiota across time in response to processes that impacted our culture and biology, such as the rise of farming during the Neolithic. However, the extent to which the human oral flora changed from prehistory until present has remained elusive due to the scarcity of data on the microbiomes of prehistoric humans. Here, we present our reconstruction of oral microbiomes via shotgun metagenomics of dental calculus in 44 ancient foragers and farmers from two regions playing a pivotal role in the spread of farming across Europe-the Balkans and the Italian Peninsula. We show that the introduction of farming in Southern Europe did not alter significantly the oral microbiomes of local forager groups, and it was in particular associated with a higher abundance of the species Olsenella sp. oral taxon 807. The human oral environment in prehistory was dominated by a microbial species, Anaerolineaceae bacterium oral taxon 439, that diversified geographically. A Near Eastern lineage of this bacterial commensal dispersed with Neolithic farmers and replaced the variant present in the local foragers. Our findings also illustrate that major taxonomic shifts in human oral microbiome composition occurred after the Neolithic and that the functional profile of modern humans evolved in recent times to develop peculiar mechanisms of antibiotic resistance that were previously absent.
Assuntos
Agricultura/história , DNA Antigo , Cálculos Dentários/genética , Cálculos Dentários/microbiologia , Microbiota/genética , Bactérias/genética , Península Balcânica , Cálculos Dentários/química , Resistência Microbiana a Medicamentos/genética , Europa (Continente) , História Antiga , História Medieval , Humanos , Filogenia , Plantas/químicaRESUMO
OBJECTIVES: To compare the incidence, epidemiology, testing patterns, treatment, and outcomes of Clostridioides difficile infection (CDI) among hospitalized pediatric patients from 2013 to 2019. STUDY DESIGN: The Pediatric Health Information System database was queried for patient admissions (age 0-17 years) with International Classification of Diseases, 9th and 10th edition, codes for diagnoses of CDI with a billing code for a CDI-related antibiotic treatment. RESULTS: We identified 17â142 pediatric patients, representing 23â052 admissions, with CDI. The adjusted annual CDI incidence decreased over the study period from 7.09 cases per 10â000 patient-days (95% CI, 6.15-8.18) in 2013 to 4.89 cases per 10â000 patient-days (95% CI, 4.03-5.93) in 2019 (P < .001). C difficile-specific testing also decreased during the study period (P < .001). Chronic gastrointestinal conditions (36%) and malignancy (32%) were the most common comorbidities in CDI encounters. Oral metronidazole use decreased during the study period (P < .01) and oral vancomycin use increased (P < .001). CONCLUSIONS: Our study demonstrates a decrease in CDI incidence in hospitalized pediatric patients, a notable change from prior studies, although this may have been influenced by altered testing patterns. We found a high incidence of CDI in patients with cancer and gastrointestinal conditions: groups that warrant targeted evaluation of CDI prevention and treatment.
Assuntos
Clostridioides difficile , Infecções por Clostridium , Neoplasias , Humanos , Criança , Recém-Nascido , Lactente , Pré-Escolar , Adolescente , Infecções por Clostridium/diagnóstico , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/epidemiologia , Metronidazol , Antibacterianos/uso terapêutico , Incidência , Neoplasias/complicaçõesRESUMO
Individualized, precision feeding of dairy cattle may contribute to profitable and sustainable dairy production. Feeding strategies targeted at optimizing efficiency of individual cows, rather than groups of animals with similar characteristics, is a logical goal of individualized precision feeding. However, algorithms designed to make feeding recommendations for specific animals are scarce. The objective of this study was to develop and test 2 algorithms designed to improve feed efficiency of individual cows by supplementing total mixed rations (TMR) with varying types and amounts of top-dressed feedstuffs. Twenty-four Holstein dairy cows were assigned to 1 of 3 treatment groups as follows: a control group fed a common TMR ad libitum, a group fed individually according to algorithm 1, and a group fed individually according to algorithm 2. Algorithm 1 used a mixed-model approach with feed efficiency as the response variable and automated measurements of production parameters and top-dress type as dependent variables. Cow was treated as a random effect, and cow by top-dress interactions were included if significant. Algorithm 2 grouped cows based on top-dress response efficiency structure using a principal components and k-means clustering. Both algorithms were trained over a 36-d experimental period immediately before testing, and were updated weekly during the 35-d testing period. Production performance responses for dry matter intake (DMI), milk yield, milk fat percentage and yield, milk protein percentage and yield, and feed efficiency were analyzed using a mixed-effects model with fixed effects for feeding algorithm, top dress, week, and the 2- and 3-way interactions among these variables. Milk protein percentage and feed efficiency were significantly affected by the 3-way interaction of top dress, algorithm, and week, and DMI tended to be affected by this 3-way interaction. Feeding algorithm did not affect milk yield, milk fat yield, or milk protein yield. However, feeding costs were reduced, and hence milk revenue increased on the algorithm-fed cows. The efficacy of feeding algorithms differed by top dress and time, and largely relied on DMI shifts to modulate feed efficiency. The net result, for the cumulative feeding groups, was that cows in the algorithm 1 and 2 groups earned over $0.45 and $0.70 more per head per day in comparison to cows on the TMR control, respectively. This study yielded 2 candidate approaches for efficiency-focused, individualized feeding recommendations. Refinement of algorithm selection, development, and training approaches are needed to maximize production parameters through individualized feeding.
Assuntos
Lactação , Rúmen , Algoritmos , Ração Animal/análise , Animais , Bovinos , Dieta/veterinária , Feminino , Lactação/fisiologia , Proteínas do Leite/metabolismo , Rúmen/metabolismoRESUMO
PURPOSE: We compared urinary tract infection (UTI) symptom resolution rates at 7-10 days in symptomatic women randomized to treatment based on standard urine culture (SUC) versus expanded quantitative urine culture (EQUC) results. MATERIALS AND METHODS: Women ≥18 years old who responded "yes" to "do you feel you have a UTI?" agreed to urethral catheterization and followup. Symptoms were assessed using the validated UTI Symptom Assessment (UTISA) questionnaire. Culture method was randomized 2:1 (SUC:EQUC); antibiotics were prescribed to women with positive cultures. The primary outcome, UTI symptom resolution, was determined 7-10 days following enrollment on all participants regardless of treatment. RESULTS: Demographic data were similar between groups. Of the SUC and EQUC groups 63% and 74% had positive cultures (p=0.10), respectively. Of participants with positive cultures 97% received antibiotics. Primary outcome data were provided by 215 of 225 participants (SUC 143 [95%], EQUC 72 [97%]). At the primary outcome assessment, 64% and 69% in the SUC and EQUC groups, respectively, reported UTI symptom resolution (p=0.46); UTISA scores improved from baseline in the EQUC arm compared to the SUC arm (p=0.04). In the subset of women predominated by non-Escherichia coli (76), there was a trend toward more symptom resolution in the EQUC arm (21%, p=0.08). CONCLUSIONS: Symptom resolution was similar for the overall population (E. coli and non-E. coli) of women treated for UTI symptoms based on SUC or EQUC. Although the sample size limits conclusions regarding the utility of EQUC in women with non-E. coli uropathogens, the detected trend indicates that this understudied clinical subset warrants further study.
Assuntos
Antibacterianos/uso terapêutico , Técnicas Bacteriológicas/métodos , Bacteriúria/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacologia , Bacteriúria/diagnóstico , Bacteriúria/microbiologia , Bacteriúria/urina , Feminino , Humanos , Testes de Sensibilidade Microbiana/métodos , Pessoa de Meia-Idade , Autorrelato , Resultado do TratamentoRESUMO
The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought.
Assuntos
Povo Asiático/genética , Evolução Cultural/história , Fósseis , Genoma Humano/genética , Genômica , Idioma/história , População Branca/genética , Arqueologia/métodos , Ásia/etnologia , DNA/genética , DNA/isolamento & purificação , Europa (Continente)/etnologia , Frequência do Gene/genética , Genética Populacional , História Antiga , Migração Humana/história , Humanos , Intolerância à Lactose/genética , Polimorfismo de Nucleotídeo Único/genética , Pigmentação da Pele/genéticaRESUMO
The early stages of the metagenomics era produced countless observational studies linking various human diseases to alterations in the gut microbiota. Only recently have we begun to decipher the causal roles that gut microbes play in many of these conditions. Despite an incomplete understanding of how gut microbes influence pathophysiology, clinical trials have tested empirically numerous microbiota-targeting therapies to prevent or treat disease. Unsurprisingly, these trials have yielded mixed results. Nonetheless, the consumer market for probiotics, prebiotics, and synbiotics continues to grow. This theme paper highlights recent discoveries of mechanisms underlying diet-microbial-host interactions as they pertain to growth and metabolism and discusses current and future applications of microbiota-targeting therapies in the context of child malnutrition as well as obesity and its metabolic comorbidities, including nonalcoholic fatty liver disease and cardiovascular disease. We also highlight current challenges and identify future directions to facilitate a more efficient and direct path to clinical impact.
Assuntos
Fenômenos Fisiológicos do Sistema Digestório/genética , Microbioma Gastrointestinal/fisiologia , Trato Gastrointestinal/fisiologia , Prebióticos , Probióticos/uso terapêutico , Simbióticos , Gastroenteropatias/prevenção & controle , Trato Gastrointestinal/crescimento & desenvolvimento , Genômica , HumanosRESUMO
OBJECTIVE: To characterise the bladder microbiota of continent adult women. DESIGN: Cross-sectional study of adult women who contributed catheterised urine samples, completed validated symptom questionnaires, and provided demographic data. SETTING: US academic medical centre. POPULATION: Well-characterised continent adult women. METHODS: Participants contributed symptoms questionnaires, demographic data, and catheterised urine samples that were analysed by enhanced urine culture methodology and 16S rRNA gene sequencing. MAIN OUTCOME MEASURES: Associations between demographics and microbial community state structures (urotypes, defined by the dominant taxon of each specimen). RESULTS: The bladder microbiota (urobiome) of a control group of 224 continent women were characterised, demonstrating variability in terms of urotype. The most common urotype was Lactobacillus (19%), which did not differ with any demographic. In contrast, the Gardnerella (P < 0.001) and Escherichia (P = 0.005) urotypes were more common in younger and older women, respectively. CONCLUSIONS: For urobiome research, enhanced culture methods and/or DNA sequencing are the preferred techniques for bacterial detection. The interpretation of clinical tests, such as the standard urine culture, should incorporate the knowledge that some women have Gardnerella or Escherichia urotypes without evidence of any clinical disorder. Clinical care strategies should preserve or restore the beneficial effects of the native urobiome, as disruption of that microbial community could result in unintended vulnerability to uropathogen invasion or opportunistic pathogen overgrowth. Longitudinal studies of urobiome responses to therapies should be encouraged. TWEETABLE ABSTRACT: In continent adult women bladder microbiome composition differs by age, with relevance for clinical practice.
Assuntos
Microbiota/genética , Bexiga Urinária/microbiologia , Sistema Urinário/microbiologia , Urina/microbiologia , Adulto , Estudos Transversais , Estudos de Avaliação como Assunto , Feminino , Humanos , Lactobacillus/genética , Microbiota/fisiologia , Pessoa de Meia-Idade , RNA Ribossômico 16S , Análise de Sequência de DNA , Bexiga Urinária/fisiologiaRESUMO
Gene drive is a naturally occurring phenomenon in which selfish genetic elements manipulate gametogenesis and reproduction to increase their own transmission to the next generation. Currently, there is great excitement about the potential of harnessing such systems to control major pest and vector populations. If synthetic gene drive systems can be constructed and applied to key species, they may be able to rapidly spread either modifying or eliminating the targeted populations. This approach has been lauded as a revolutionary and efficient mechanism to control insect-borne diseases and crop pests. Driving endosymbionts have already been deployed to combat the transmission of dengue and Zika virus in mosquitoes. However, there are a variety of barriers to successfully implementing gene drive techniques in wild populations. There is a risk that targeted organisms will rapidly evolve an ability to suppress the synthetic drive system, rendering it ineffective. There are also potential risks of synthetic gene drivers invading non-target species or populations. This Special Feature covers the current state of affairs regarding both natural and synthetic gene drive systems with the aim to identify knowledge gaps. By understanding how natural drive systems spread through populations, we may be able to better predict the outcomes of synthetic drive release.
Assuntos
Vetores de Doenças , Tecnologia de Impulso Genético , Aedes , Animais , Evolução Biológica , Culicidae , Dengue , Mosquitos Vetores , Reprodução , Wolbachia , Zika virus , Infecção por Zika virusRESUMO
Selfish genetic elements such as selfish chromosomes increase their transmission rate relative to the rest of the genome and can generate substantial cost to the organisms that carry them. Such segregation distorters are predicted to either reach fixation (potentially causing population extinction) or, more commonly, promote the evolution of genetic suppression to restore transmission to equality. Many populations show rapid spread of segregation distorters, followed by the rapid evolution of suppression. However, not all drivers display such flux, some instead persisting at stable frequencies in natural populations for decades, perhaps hundreds of thousands of years, with no sign of suppression evolving or the driver spreading to fixation. This represents a major evolutionary paradox. How can drivers be maintained in the long term at stable frequencies? And why has suppression not evolved as in many other gene drive systems? Here, we explore potential factors that may explain the persistence of drive systems, focusing on the ancient sex-ratio driver in the fly Drosophila pseudoobscura. We discuss potential solutions to the evolutionary mystery of why suppression does not appear to have evolved in this system, and address how long-term stable frequencies of gene drive can be maintained. Finally, we speculate whether ancient drivers may be functionally and evolutionarily distinct to young drive systems.
Assuntos
Evolução Biológica , Tecnologia de Impulso Genético , Animais , Drosophila , Sequências Repetitivas de Ácido Nucleico , Razão de MasculinidadeRESUMO
Functional diversity is an important aspect of biodiversity, but its relationship to species diversity in time and space is poorly understood. Here we compare spatial patterns of functional and taxonomic diversity across marine and terrestrial systems to identify commonalities in their respective ecological and evolutionary drivers. We placed species-level ecological traits into comparable multi-dimensional frameworks for two model systems, marine bivalves and terrestrial birds, and used global species-occurrence data to examine the distribution of functional diversity with latitude and longitude. In both systems, tropical faunas show high total functional richness (FR) but low functional evenness (FE) (i.e. the tropics contain a highly skewed distribution of species among functional groups). Functional groups that persist toward the poles become more uniform in species richness, such that FR declines and FE rises with latitude in both systems. Temperate assemblages are more functionally even than tropical assemblages subsampled to temperate levels of species richness, suggesting that high species richness in the tropics reflects a high degree of ecological specialization within a few functional groups and/or factors that favour high recent speciation or reduced extinction rates in those groups.
Assuntos
Biodiversidade , Aves , Bivalves , Ecossistema , Animais , Geografia , Modelos BiológicosRESUMO
OBJECTIVES: The ancient city of Chichén Itzá in the northern Yucatán of Mexico was one of the most important in the Maya area, but its origins and history are poorly understood. A major question concerns the origins of the peoples who founded and later expanded the ancient city. Hundreds of people were ritually executed and their bodies thrown into the waters of the Sacred Cenote at Chichén. MATERIALS AND METHODS: In this study, we use strontium and oxygen isotopes to study the place of origin of a large sample of these individuals. Isotopes are deposited in human tooth enamel. Enamel forms during the first years of life, remains largely unchanged long past death, and can provide a signature of the place of birth. If the isotope ratios in enamel are different from the place of death, the individual must have moved during his/her lifetime. RESULTS: Comparison of our results from the cenote with information on isotope ratios across the Maya region and elsewhere suggests that the individuals in the cenote came from a number of different parts of Mexico and possibly beyond. DISCUSSION: It is not known if all of the sacrificial victims resided in Chichén Itzá, but their suggested origins likely reflect patterns of population movement and social networks that existed between Chichén Itzá and both neighboring and distant regions. Various lines of evidence point to places in the Yucatán, along the Gulf Coast, Central America, or even in the Central Highlands of Mexico.
Assuntos
Comportamento Ritualístico , Indígenas Norte-Americanos/etnologia , Indígenas Norte-Americanos/história , Adulto , Antropologia Física , Criança , Pré-Escolar , Feminino , História Medieval , Humanos , Masculino , México/etnologia , Isótopos de Oxigênio/análise , Crânio/química , Crânio/lesões , Crânio/patologia , Isótopos de Estrôncio/análiseRESUMO
Oligogenic inheritance implies a role for several genetic factors in disease etiology. We studied oligogenic inheritance in Parkinson's (PD) by assessing the potential burden of additional rare variants in established Mendelian genes and/or GBA, in individuals with and without a primary pathogenic genetic cause in two large independent cohorts totaling 7,900 PD cases and 6,166 controls. An excess (≥30%) of cases with a recognised primary genetic cause had ≥1 additional rare variants in Mendelian PD genes, as compared with no known mutation PD cases (17%) and unaffected controls (16%), supporting our hypothesis. Carriers of additional Mendelian gene variants have younger ages at onset (AAO). The effect of additional Mendelian variants in LRRK2 G2019S mutation carriers, of which ATP13A2 variation is particularly common, may account for some of the variation in penetrance. About 10% of No Known Mutation-PD cases harbour a rare GBA variant compared to known pathogenic mutation PD cases (8%) and controls (5%), with carriers having earlier AAOs. Together, the data suggest that the oligogenic inheritance of rare Mendelian variants may be important in patient with a primary pathogenic cause, whereas GBA increases risk across all forms of PD. This study highlights the potential genetic complexity of Mendelian PD. The identification of potential modifying variants provides new insights into disease mechanisms by potentially separating relevant from benign variants and by the interaction between genes in specific pathways. In the future this may be relevant to genetic testing and counselling of patients with PD and their families.
Assuntos
Predisposição Genética para Doença , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Herança Multifatorial/genética , Doença de Parkinson/genética , Idade de Início , Feminino , Genótipo , Humanos , Masculino , Mutação , Doença de Parkinson/patologia , Fatores de RiscoRESUMO
Forced expiratory volume in 1 second (FEV1 ) from spirometry is the most commonly used parameter to detect early allograft dysfunction after lung transplantation (LTx). There are concerns regarding its sensitivity. Nitrogen-multiple breath washout (N2 -MBW) is sensitive at detecting early global (lung clearance index [LCI]) and acinar (Sacin ) airway inhomogeneity. We investigated whether N2 -MBW indices indicate small airways pathology after LTx in children with stable spirometry. Thirty-seven children without bronchiolitis obliterans syndrome [BOS] at a median of 1.6 (0.6-3.0) years after LTx underwent N2 -MBW and spirometry, 28 of those on 2 occasions (≤6 months apart) during clinically stable periods. Additional longitudinal data (11 and 8 measurements, respectively) are provided from 2 patients with BOS. In patients without BOS, LCI and Sacin were significantly elevated compared with healthy controls. LCI was abnormal at the 2 test occasions in 81% and 71% of patients, respectively, compared with 30% and 39% of patients with abnormal FEV1 /forced vital capacity (FVC). Correlations of LCI with FEV1 /FVC (r = 0.1, P = .4) and FEV1 (r = -0.1, P = .6) were poor. N2 -MBW represents a sensitive and reproducible tool for the early detection of airways pathology in stable transplant recipients. Moreover, indices were highly elevated in both patients with BOS. Spirometry and LCI showed poor correlation, indicating distinct and complementary physiologic measures.
Assuntos
Testes Respiratórios/métodos , Bronquiolite Obliterante/complicações , Volume Expiratório Forçado , Rejeição de Enxerto/diagnóstico , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias , Adolescente , Adulto , Bronquiolite Obliterante/fisiopatologia , Estudos de Casos e Controles , Criança , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Estudos Longitudinais , Masculino , Nitrogênio , Prognóstico , Testes de Função Respiratória , Fatores de Risco , Espirometria , Transplantados , Adulto JovemRESUMO
Background: The consensus molecular subtypes (CMS) is a transcriptome-based classification of colorectal cancer (CRC) initially described in early-stage cohorts, but the associations of CMS with treatment outcomes in the metastatic setting are yet to be established. This study aimed to evaluate the prognostic impact of CMS classification and its predictive effects for bevacizumab benefit in metastatic CRC by correlative analysis of the AGITG MAX trial. Patients and methods: The MAX trial previously reported improved progression-free survival (PFS) for the addition of bevacizumab (B) to chemotherapy [capecitabine (C)±mitomycin (M)]. Archival primary tumours from 237 patients (50% of trial population) underwent gene expression profiling and classification into CMS groups. CMS groups were correlated to PFS and overall survival (OS). The interaction of CMS with treatment was assessed by proportional hazards model. Results: The distribution of CMS in MAX were CMS1 18%, CMS2 47%, CMS3 12%, CMS4 23%. CMS1 was the predominant subtype in right-sided primary tumours, while CMS2 was the predominant subtype in left-sided. CMS was prognostic of OS (P = 0.008), with CMS2 associated with the best outcome and CMS1 the worst. CMS remained an independent prognostic factor in a multivariate analysis. There was a significant interaction between CMS and treatment (P-interaction = 0.03), for PFS, with hazard ratios (95% CI) for CB+CBM versus C arms in CMS1, 2, 3 and 4: 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25), respectively. Conclusions: This exploratory study found that CMS stratified OS outcomes in metastatic CRC regardless of first-line treatment, with prognostic effects of CMS groups distinct from those previously reported in early-stage cohorts. In CMS associations with treatment, CMS2 and possibly CMS3 tumours may preferentially benefit from the addition of bevacizumab to first-line capecitabine-based chemotherapy, compared with other CMS groups. Validation of these findings in additional cohorts is warranted. Clinical trial number: This is a molecular sub-study of MAX clinical trial (NCT00294359).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Transcriptoma/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Capecitabina/uso terapêutico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mitomicina/uso terapêutico , Prognóstico , Intervalo Livre de ProgressãoRESUMO
We report quantum-mechanical and semiclassical WKB calculations for energies and wave functions of high-lying 2Σ states of H2+ in atomic units. The high-lying states we present lie in an unexplored regime, corresponding asymptotically to H ( n ≤ 146) plus a proton, with R ≤ 120â¯000 a0. We compare quantum-mechanical energies, spectroscopic constants, dipole matrix elements, and phases with semiclassical results and demonstrate a high level of agreement. Our quantum-mechanical phases were determined by using Milne's phase-amplitude procedure. We compare our semiclassical energies for low-lying states with those of other researchers.
RESUMO
Recent quantum calculations of rotationally inelastic collisions of NaK (A1Σ+) with He or Ar in a cell experiment are analyzed using semiclassical approximations valid for large quantum numbers. The results suggest a physical interpretation of jm â j'm' transitions based on the vector model and lead to expressions that explicitly involve the initial and final polar angles of the angular momentum of the target molecule. The relation between the polar angle θ and the azimuthal quantum number m links the semiclassical results for the change in polar angle (θ â θ') to quantum results for an m â m' transition. Analytic formulas are derived that relate the location and width of peaks in the final polar angle distribution (PAD) to the K-dependence of the coefficients dK(j, j'), which are proportional to tensor cross sections σK(j â j'). Several special cases are treated that lead to final PADs that are approximately Lorentzian or sinc functions centered at θ' = θ. Another interesting case, "angular momentum reversal," was observed in the calculations for He. This phenomenon, which involves a reversal of the direction of the target's angular momentum, is shown to be associated with oscillatory behavior of the dK for certain transitions. Finally, several strategies for obtaining the dK coefficients from experimental data are discussed.