Recommendations for treatment of rifampicin-resistant tuberculosis (RR-TB) during pregnancy and post-partum now include Group A and B antituberculosis drugs. While pharmacokinetic data for most of ...these drugs among adults receiving treatment for RR-TB are limited, the data from pregnant patients and their infants are extremely scarce. Existing data suggest that fluoroquinolones, bedaquiline, clofazimine and terizidone may be used safely in pregnancy. Pharmacokinetic exposures, particularly between trimesters, are potentially sub-optimal; however, there is currently no evidence to support dose adjustment during pregnancy. Linezolid poses a potentially serious toxicity risk, particularly as exposures appear to be high in the later stages of pregnancy and post-partum following extended use, but this should be considered alongside the benefits of this extremely effective drug in the treatment of this life-threatening disease. While plenty of questions remain regarding the exposure to Group A and B antituberculosis drugs through breastmilk, existing literature suggests minimal harm to the breastfed infant. Pregnant patients and their infants should be included in therapeutic trials and pharmacokinetic studies of effective antituberculosis drugs.
Mammals have the oldest sex chromosome system known: the mammalian X and Y chromosomes evolved from ordinary autosomes beginning at least 180 million years ago. Despite their shared ancestry, ...mammalian Y chromosomes display enormous variation among species in size, gene content, and structural complexity. Several unique features of the Y chromosome-its lack of a homologous partner for crossing over, its functional specialization for spermatogenesis, and its high degree of sequence amplification-contribute to this extreme variation. However, amid this evolutionary turmoil many commonalities have been revealed that have contributed to our understanding of the selective pressures driving the evolution and biology of the Y chromosome. Two biological themes have defined Y-chromosome research over the past six decades: testis determination and spermatogenesis. A third biological theme begins to emerge from recent insights into the Y chromosome's roles beyond the reproductive tract-a theme that promises to broaden the reach of Y-chromosome research by shedding light on fundamental sex differences in human health and disease.
Suicide is a leading cause of death. New data indicate alarming increases in suicide death rates, yet no treatments with replicated efficacy or effectiveness exist for youths with self-harm ...presentations, a high-risk group for both fatal and nonfatal suicide attempts. We addressed this gap by evaluating Safe Alternatives for Teens and Youths (SAFETY), a cognitive-behavioral, dialectical behavior therapy-informed family treatment designed to promote safety.
Randomized controlled trial for adolescents (12-18 years of age) with recent (past 3 months) suicide attempts or other self-harm. Youth were randomized either to SAFETY or to treatment as usual enhanced by parent education and support accessing community treatment (E-TAU). Outcomes were evaluated at baseline, 3 months, or end of treatment period, and were followed up through 6 to 12 months. The primary outcome was youth-reported incident suicide attempts through the 3-month follow-up.
Survival analyses indicated a significantly higher probability of survival without a suicide attempt by the 3-month follow-up point among SAFETY youths (cumulative estimated probability of survival without suicide attempt = 1.00, standard error = 0), compared to E-TAU youths (cumulative estimated probability of survival without suicide attempt = 0.67, standard error = 0.14; z = 2.45, p = .02, number needed to treat = 3) and for the overall survival curves (Wilcoxon χ
= 5.81, p = .02). Sensitivity analyses using parent report when youth report was unavailable and conservative assumptions regarding missing data yielded similar results for 3-month outcomes.
Results support the efficacy of SAFETY for preventing suicide attempts in adolescents presenting with recent self-harm. This is the second randomized trial to demonstrate that treatment including cognitive-behavioral and family components can provide some protection from suicide attempt risk in these high-risk youths. Clinical trial registration information-Effectiveness of a Family-Based Intervention for Adolescent Suicide Attempters (The SAFETY Study); http://clinicaltrials.gov/; NCT00692302.
Sex differences abound in human health and disease, as they do in other mammals used as models. The extent to which sex differences are conserved at the molecular level across species and tissues is ...unknown. We surveyed sex differences in gene expression in human, macaque, mouse, rat, and dog, across 12 tissues. In each tissue, we identified hundreds of genes with conserved sex-biased expression-findings that, combined with genomic analyses of human height, explain ~12% of the difference in height between females and males. We surmise that conserved sex biases in expression of genes otherwise operating equivalently in females and males contribute to sex differences in traits. However, most sex-biased expression arose during the mammalian radiation, which suggests that careful attention to interspecies divergence is needed when modeling human sex differences.
The human X and Y chromosomes evolved from an ordinary pair of autosomes, but millions of years ago genetic decay ravaged the Y chromosome, and only three per cent of its ancestral genes survived. We ...reconstructed the evolution of the Y chromosome across eight mammals to identify biases in gene content and the selective pressures that preserved the surviving ancestral genes. Our findings indicate that survival was nonrandom, and in two cases, convergent across placental and marsupial mammals. We conclude that the gene content of the Y chromosome became specialized through selection to maintain the ancestral dosage of homologous X-Y gene pairs that function as broadly expressed regulators of transcription, translation and protein stability. We propose that beyond its roles in testis determination and spermatogenesis, the Y chromosome is essential for male viability, and has unappreciated roles in Turner's syndrome and in phenotypic differences between the sexes in health and disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The reference sequence of structurally complex regions can only be obtained through a highly accurate clone-based approach that we call Single-Haplotype Iterative Mapping and Sequencing (SHIMS). In ...recent years, improvements to SHIMS have reduced the cost and time required by two orders of magnitude, but internally repetitive clones still require extensive manual effort to transform draft assemblies into reference-quality finished sequences. Here we describe SHIMS 3.0, using ultra-long nanopore reads to augment the Illumina data from SHIMS 2.0 assemblies and resolve internally repetitive structures. This greatly minimizes the need for manual finishing of Illumina-based draft assemblies, allowing a small team with no prior finishing experience to sequence challenging targets with high accuracy. This protocol proceeds from clone-picking to finished assemblies in 2 weeks for about $80 (USD) per clone. We recently used this protocol to produce reference sequence of structurally complex palindromes on chimpanzee and rhesus macaque X chromosomes. Our protocol provides access to structurally complex regions that would otherwise be inaccessible from whole-genome shotgun data or require an impractical amount of manual effort to generate an accurate assembly.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Most caregivers of people with dementia (CPWD) experience a high degree of stress due to the demands of providing care, especially when addressing unpredictable behavioral and psychological symptoms ...of dementia. Such challenging responsibilities make caregivers susceptible to poor sleep quality with detrimental effects on their overall health. Hence, monitoring caregivers’ sleep quality can provide important CPWD stress assessment. Most current sleep studies are based on polysomnography, which is expensive and potentially disrupts the caregiving routine. To address these issues, we propose a clinical decision support system to predict sleep quality based on trends of physiological signals in the deep sleep stage. This system utilizes four raw physiological signals using a wearable device (E4 wristband): heart rate variability, electrodermal activity, body movement, and skin temperature. To evaluate the performance of the proposed method, analyses were conducted on a two-week period of sleep monitored on eight CPWD. The best performance is achieved using the random forest classifier with an accuracy of 75% for sleep quality, and 73% for restfulness, respectively. We found that the most important features to detect these measures are sleep efficiency (ratio of amount of time asleep to the amount of time in bed) and skin temperature. The results from our sleep analysis system demonstrate the capability of using wearable sensors to measure sleep quality and restfulness in CPWD.
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•Sleep efficiency and skin temperature play main roles in sleep quality assessment.•Random forest achieved the highest accuracy of 75% for sleep quality prediction.•Random forest scored the highest accuracy of 73% for measuring restfulness of sleep.•The easy-to-use E4 wristband can be used to predict the sleep quality of caregivers.
We sequenced the MSY (male-specific region of the Y chromosome) of the C57BL/6J strain of the laboratory mouse Mus musculus. In contrast to theories that Y chromosomes are heterochromatic and gene ...poor, the mouse MSY is 99.9% euchromatic and contains about 700 protein-coding genes. Only 2% of the MSY derives from the ancestral autosomes that gave rise to the mammalian sex chromosomes. Instead, all but 45 of the MSY's genes belong to three acquired, massively amplified gene families that have no homologs on primate MSYs but do have acquired, amplified homologs on the mouse X chromosome. The complete mouse MSY sequence brings to light dramatic forces in sex chromosome evolution: lineage-specific convergent acquisition and amplification of X-Y gene families, possibly fueled by antagonism between acquired X-Y homologs. The mouse MSY sequence presents opportunities for experimental studies of a sex-specific chromosome in its entirety, in a genetically tractable model organism.
In mammals, the Y chromosome plays the pivotal role in male sex determination and is essential for normal sperm production. Yet only three Y chromosomes have been completely sequenced to date-those ...of human, chimpanzee, and rhesus macaque. While Y chromosomes are notoriously difficult to sequence owing to their highly repetitive genomic landscapes, these dedicated sequencing efforts have generated tremendous yields in medical, biological, and evolutionary insight. Knowledge of the complex structural organization of the human Y chromosome and a complete catalog of its gene content have provided a deeper understanding of the mechanisms that generate disease-causing mutations and large-scale rearrangements. Variation among human Y-chromosome sequences has been an invaluable tool for understanding relationships among human populations. Comprehensive comparisons of the human Y-chromosome sequence with those of other primates have illuminated aspects of Y-chromosome evolutionary dynamics over much longer timescales (>25 million years compared with 100,000 years). The future sequencing of additional Y chromosomes will provide a basis for a more comprehensive understanding of the evolution of Y chromosomes and their roles in reproductive biology.
Sperm storage by females after mating for species-dependent periods is used widely among animals with internal fertilization to allow asynchrony between mating and ovulation. Many mammals store sperm ...in the lower oviduct where specific glycans on oviduct epithelial cells retain sperm to form a reservoir. Binding to oviduct cells suppresses sperm intracellular Ca2+ and increases sperm longevity. We investigated the mechanisms by which a specific oviduct glycan, 3-O-sulfated Lewis X trisaccharide (suLeX), prolongs the lifespan of porcine sperm. Using targeted metabolomics, we found that binding to suLeX diminishes the abundance of 4-hydroxybenzoic acid, the precursor to ubiquinone (also known as Coenzyme Q), 30 min after addition. Ubiquinone functions as an electron acceptor in the electron transport chain (ETC). 3-O-sulfated Lewis X trisaccharide also suppressed the formation of fumarate. A component of the citric acid cycle, fumarate is synthesized by succinate-coenzyme Q reductase, which employs ubiquinone and is also known as Complex II in the ETC. Consistent with the reduced activity of the ETC, the production of harmful reactive oxygen species (ROS) was diminished. The enhanced sperm lifespan in the oviduct may be because of suppressed ROS production because high ROS concentrations have toxic effects on sperm. Summary Sentence The binding of porcine sperm to an oviduct trisaccharide diminishes electron transport chain activity and reduces production of harmful reactive oxygen species. Graphical Abstract
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