BackgroundEfavirenz and nelfinavir are metabolized by cytochrome P-450 (CYP) 2B6 and CYP2C19, respectively, with some involvement by CYP3A. Nelfinavir is a substrate for P-glycoprotein, which is ...encoded by MDR1. The present study examined associations between genetic variants and long-term responses to treatment MethodsAdult AIDS Clinical Trials Group study 384 randomized antiretroviral-naive subjects to receive efavirenz and/or nelfinavir plus 2 nucleoside analogues, with follow-up lasting up to 3 years. Population pharmacokinetics were estimated from a nonlinear mixed-effects model. Polymorphisms in CYP2B6, CYP2C19, CYP3A4, CYP3A5 and MDR1 were characterized ResultsThe 504 participants in the genetic study included 340 efavirenz recipients and 348 nelfinavir recipients (184 of the 504 participants received both efavirenz and nelfinavir). Of the participants, 49% were white, 31% were black, and 19% were Hispanic. Plasma exposure to efavirenz and nelfinavir in each population was significantly associated with the polymorphisms CYP2B6 516G→T and CYP2C19 681G→A, respectively. Among efavirenz recipients, the MDR1 position 3435 TT genotype was associated with decreased likelihood of virologic failure and decreased emergence of efavirenz-resistant virus but not with plasma efavirenz exposure. Among nelfinavir recipients, a trend toward decreased virologic failure was associated with the polymorphism CYP2C19 681G→A ConclusionsGenetic variants predict plasma exposure to efavirenz and nelfinavir, and they may predict virologic failure and/or emergence of drug-resistant virus. These associations with treatment responses must be validated in other studies
Abstract The striatum, which processes cortical information for behavioral output, is a key target of Huntington's disease (HD), an autosomal dominant condition characterized by cognitive decline and ...progressive loss of motor control. Increasing evidence implicates deficient glutamate uptake caused by a down-regulation of GLT1, the primary astroglial glutamate transporter. To test this hypothesis, we administered ceftriaxone, a β-lactam antibiotic known to elevate GLT1 expression (200 mg/kg, i.p., for 5 days), to symptomatic R6/2 mice, a widely studied transgenic model of HD. Relative to vehicle, ceftriaxone attenuated several HD behavioral signs: paw clasping and twitching were reduced, while motor flexibility, as measured in a plus maze, and open-field climbing were increased. Assessment of GLT1 expression in striatum confirmed a ceftriaxone-induced increase relative to vehicle. To determine if the change in behavior and GLT1 expression represented a change in striatal glutamate handling, separate groups of behaving mice were evaluated with no-net-flux microdialysis. Vehicle treatment revealed a glutamate uptake deficit in R6/2 mice relative to wild-type controls that was reversed by ceftriaxone. Vehicle-treated animals, however, did not differ in GLT1 expression, suggesting that the glutamate uptake deficit in R6/2 mice reflects dysfunctional rather than missing GLT1. Our results indicate that impaired glutamate uptake is a major factor underlying HD pathophysiology and symptomology. The glutamate uptake deficit, moreover, is present in symptomatic HD mice and reversal of this deficit by up-regulating the functional expression of GLT1 with ceftriaxone attenuates the HD phenotype.
Zoonosis-based epidemics are inevitable unless we revisit our relationship with the natural world, protect habitats, and regulate wildlife trade, including live animals and non-sustenance products. ...To prevent future zoonoses, governments must establish effective legislation addressing wildlife trade, protection of habitats, and reduction of the wildlife–livestock–human interface.
Abstract
We have studied radio haloes and relics in nine merging galaxy clusters using the Murchison Widefield Array (MWA). The images used for this study were obtained from the GaLactic and ...Extragalactic All-sky MWA (GLEAM) Survey which was carried out at five frequencies, viz. 88, 118, 154, 188 and 215 MHz. We detect diffuse radio emission in eight of these clusters. We have estimated the spectra of haloes and relics in these clusters over the frequency range 80–1400 MHz; the first such attempt to estimate their spectra at low frequencies. The spectra follow a power law with a mean value of α = −1.13 ± 0.21 for haloes and α = −1.2 ± 0.19 for relics, where S ∝ να. We reclassify two of the cluster sources as radio galaxies. The low-frequency spectra are thus an independent means of confirming the nature of cluster sources. Five of the nine clusters host radio haloes. For the remaining four clusters, we place upper limits on the radio powers of possible haloes in them. These upper limits are a factor of 2–20 below those expected from the LX–P1.4 relation. These limits are the lowest ever obtained and the implications of these limits to the hadronic model of halo emission are discussed.
Abstract
Background
Because of critical shortage of physician anaesthesiologists, the government of Tanzania adopted a task shifting strategy for provision of anaesthesia services. This paper ...describes the results of an operational study designed to increase the number of anaesthesia providers for emergency obstetric surgeries in order to reduce maternal and perinatal mortality in underserved rural Tanzania.
Methods
In 2016 a before-after cohort study was conducted in seven health centres in rural Tanzania. Five health centres received an intervention and two were selected to track secular trends (control group). Ten associate clinicians, i.e. assistant medical officers, clinical officers, and nurse midwives, from five health centres were trained in anaesthesia skills for emergency obstetric surgeries for three months followed by quarterly supportive supervision, mentoring and teleconsultation to reinforce skills. Primary and secondary outcome measures included Caesarean delivery (CD) rate, quality and safety of anaesthesia, and uptake of the educational program for anaesthesia.
Results
Out of the 2,179 CDs performed in the intervention facilities from 2016 to 2019, two women died from complications of anaesthesia. The risk of death from anaesthetic complications was 0.9 per 1000 CD (95% CI 0.1–3.3. The risk of death was not established in the control group because of inadequate documentation and records keeping. The proportion of CD performed under spinal anaesthesia in intervention facilities doubled from 28% (60/214 with 95% CI 22–35) at baseline (July 2014 – June 2016) to 57% (558/971 with 95% CI of 54–61) in year three (July 2018 - June 2019), while in the control group increased by only 40% from 19% (92/475 with 95% CI of 16–23) at baseline and 27% (68/251 with 95% CI of 22–33) in year three. In 2020I, this educational training program was then adopted by the government with minor content changes and increasing duration of training to six months.
Conclusions
This three month educational training program for associate clinicians in anaesthesia, complemented by supportive supervision, can increase the CD rate to one that fills the “unmet need” and the proportion of operations performed under spinal anaesthesia, the gold standard technique for CD. The program can be used to meet the urgent demand for anaesthesia services in other underserved areas in Africa.
Within bioethics as well as in broader clinical practice, support for transgender and gender‐questioning adolescent access to pubertal suppression has often relied heavily on the desire to prevent ...risky, self‐destructive, and suicidal behavior. We argue that framing justifications for access to puberty suppression in this way can actually be harmful to both individual patients as well as to the broader trans population. This justification for access to care makes such access precarious, limits its scope, and introduces perverse incentives to the patient population that is being served. We go on to offer an alternative, positive defense of access to puberty‐blocking treatment for transgender youth grounded in the child's right to an open future. We argue that decisions related to pubertal suppression are both importantly weighty and potentially irreversible, and show why this justification is preferable to so‐called “informed consent” approaches.
Thermal ablation is a well‐established successful treatment for cardiac arrhythmia, but it still presents limitations that require further studies and developments. In the rotor‐driven functional ...re‐entry arrhythmia, tissue heterogeneity results on the generation of spiral/scroll waves and wave break dynamics that may cause dangerous sustainable fibrillation. The selection of the target region to perform thermal ablation to mitigate this type of arrhythmia is challenging, since it considerably affects the local electrophysiology dynamics. This work deals with the numerical simulation of the thermal ablation of a cardiac muscle tissue and its effects on the dynamics of rotor‐driven functional re‐entry arrhythmia. A non‐homogeneous two‐dimensional rectangular region is used in the present numerical analysis, where radiofrequency ablation is performed. The electrophysiology problem for the propagation of the action potential in the cardiac tissue is simulated with the Fenton–Karma model. Thermal damage caused to the tissue by the radiofrequency heating is modeled by the Arrhenius equation. The effects of size and position of a heterogeneous region in the original muscle tissue were first analyzed, in order to verify the possible existence of the functional re‐entry arrhythmia during the time period considered in the simulations. For each case that exhibited re‐entry arrhythmia, six different ablation procedures were analyzed, depending on the position of the radiofrequency electrode and heating time. The obtained results revealed the effects of different model parameters on the existence and possible mitigation of the functional re‐entry arrhythmia.
The figure shows how the S3 wave went around the thermally damaged region (red lines are contours of the fraction of damaged tissue) and then connected back to the top boundary. The reconnection of the wavefront to the boundary before the rotor tip was formed then reshaped the S3 wave, which continued to propagate downstream and the rotor generation was avoided by the thermally damaged region.
Brain cannabinoid CB1 receptors contribute to alcohol-related behaviors in experimental animals, but their potential role in humans with alcohol dependence is poorly understood. We measured CB1 ...receptors in alcohol dependent patients in early and protracted abstinence, and in comparison with control subjects without alcohol use disorders, using positron emission tomography and (18)FFMPEP-d2, a radioligand for CB1 receptors. We scanned 18 male in-patients with alcohol dependence twice, within 3-7 days of admission from ongoing drinking, and after 2-4 weeks of supervised abstinence. Imaging data were compared with those from 19 age-matched healthy male control subjects. Data were also analyzed for potential influence of a common functional variation (rs2023239) in the CB1 receptor gene (CNR1) that may moderate CB1 receptor density. On the first scan, CB1 receptor binding was 20-30% lower in patients with alcohol dependence than in control subjects in all brain regions and was negatively correlated with years of alcohol abuse. After 2-4 weeks of abstinence, CB1 receptor binding remained similarly reduced in these patients. Irrespective of the diagnostic status, C allele carriers at rs2023239 had higher CB1 receptor binding compared with non-carriers. Alcohol dependence is associated with a widespread reduction of cannabinoid CB1 receptor binding in the human brain and this reduction persists at least 2-4 weeks into abstinence. The correlation of reduced binding with years of alcohol abuse suggests an involvement of CB1 receptors in alcohol dependence in humans.
Human height is a classic, highly heritable quantitative trait. To begin to identify genetic variants influencing height, we examined genome-wide association data from 4,921 individuals. Common ...variants in the HMGA2 oncogene, exemplified by rs1042725, were associated with height (P = 4 × 10−8). HMGA2 is also a strong biological candidate for height, as rare, severe mutations in this gene alter body size in mice and humans, so we tested rs1042725 in additional samples. We confirmed the association in 19,064 adults from four further studies (P = 3 × 10−11, overall P = 4 × 10−16, including the genome-wide association data). We also observed the association in children (P = 1 × 10−6, N = 6,827) and a tall/short case-control study (P = 4 × 10−6, N = 3,207). We estimate that rs1042725 explains ∼0.3% of population variation in height (∼0.4 cm increased adult height per C allele). There are few examples of common genetic variants reproducibly associated with human quantitativetraits; these results represent, to our knowledge, the first consistently replicated association with adult and childhood height.
•Twitter facilitated thousands of #OBAnes discussions during the pandemic onset.•The top three #OBAnes tweeted topics were neuraxial, COVID-19, and general anesthesia.•Doctors were the most common ...Twitter users of the #OBAnes hashtag.
#OBAnes is the most used hashtag in obstetric anesthesiology. The primary objective of the study was to characterize #OBAnes tweets at the onset of the COVID-19 pandemic.
Observational study of all tweets using #OBAnes between June 30, 2019 and October 19, 2020. A list of 19 topics was compiled to categorize each tweet. All Twitter users were manually assigned into one of 19 Symplur Healthcare Stakeholder categories.
There were 12 431 tweets with #OBAnes during the study period, posted by 1704 unique users. The top user category was Doctor (n = 1211, 71%) with 9665 (78%) tweets. The top three topics identified within Twitter conversations were neuraxial anesthesia, COVID-19, and general anesthesia.
Twitter facilitated thousands of obstetric anesthesia-related discussions during the onset of the COVID-19 pandemic, with most conversations centering on anesthesia type (neuraxial or general anesthesia).
PDF
