In situ measurements of aerosol microphysical, chemical, and optical properties were made during global-scale flights from 2016-2018 as part of the Atmospheric Tomography Mission (ATom). The NASA ...DC-8 aircraft flew from â¼ 84.sup." N to â¼ 86.sup." S latitude over the Pacific, Atlantic, Arctic, and Southern oceans while profiling nearly continuously between altitudes of â¼ 160 m and â¼ 12 km. These global circuits were made once each season. Particle size distributions measured in the aircraft cabin at dry conditions and with an underwing probe at ambient conditions were combined with bulk and single-particle composition observations and measurements of water vapor, pressure, and temperature to estimate aerosol hygroscopicity and hygroscopic growth factors and calculate size distributions at ambient relative humidity. These reconstructed, composition-resolved ambient size distributions were used to estimate intensive and extensive aerosol properties, including single-scatter albedo, the asymmetry parameter, extinction, absorption, Ãngström exponents, and aerosol optical depth (AOD) at several wavelengths, as well as cloud condensation nuclei (CCN) concentrations at fixed supersaturations and lognormal fits to four modes. Dry extinction and absorption were compared with direct in situ measurements, and AOD derived from the extinction profiles was compared with remotely sensed AOD measurements from the ground-based Aerosol Robotic Network (AERONET); this comparison showed no substantial bias.
Canagliflozin, dapagliflozin, and empagliflozin, all recently approved for treatment of type 2 diabetes, were derived from the natural product phlorizin. They reduce hyperglycemia by inhibiting ...glucose reuptake by sodium/glucose cotransporter (SGLT) 2 in the kidney, without affecting intestinal glucose uptake by SGLT1. We now report that canagliflozin also activates AMPK, an effect also seen with phloretin (the aglycone breakdown product of phlorizin), but not to any significant extent with dapagliflozin, empagliflozin, or phlorizin. AMPK activation occurred at canagliflozin concentrations measured in human plasma in clinical trials and was caused by inhibition of Complex I of the respiratory chain, leading to increases in cellular AMP or ADP. Although canagliflozin also inhibited cellular glucose uptake independently of SGLT2, this did not account for AMPK activation. Canagliflozin also inhibited lipid synthesis, an effect that was absent in AMPK knockout cells and that required phosphorylation of acetyl-CoA carboxylase (ACC) 1 and/or ACC2 at the AMPK sites. Oral administration of canagliflozin activated AMPK in mouse liver, although not in muscle, adipose tissue, or spleen. Because phosphorylation of ACC by AMPK is known to lower liver lipid content, these data suggest a potential additional benefit of canagliflozin therapy compared with other SGLT2 inhibitors.
The British Association for Psychopharmacology guidelines for the treatment of substance abuse, harmful use, addiction and comorbidity with psychiatric disorders primarily focus on their ...pharmacological management. They are based explicitly on the available evidence and presented as recommendations to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback from participants. The guidelines primarily cover the pharmacological management of withdrawal, short- and long-term substitution, maintenance of abstinence and prevention of complications, where appropriate, for substance abuse or harmful use or addiction as well management in pregnancy, comorbidity with psychiatric disorders and in younger and older people.
BackgroundThe international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We ...analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them.MethodsWe analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES).Results997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported.ConclusionsOur findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.Clinical trial registrationID number NCT01193075.
Although the critical role for epigenetic mechanisms in development and cell differentiation has long been appreciated, recent evidence reveals that these mechanisms are also employed in postmitotic ...neurons as a means of consolidating and stabilizing cognitive-behavioral memories. In this review, we discuss evidence for an “epigenetic code” in the central nervous system that mediates synaptic plasticity, learning, and memory. We consider how specific epigenetic changes are regulated and may interact with each other during memory formation and how these changes manifest functionally at the cellular and circuit levels. We also describe a central role for mitogen-activated protein kinases in controlling chromatin signaling in plasticity and memory. Finally, we consider how aberrant epigenetic modifications may lead to cognitive disorders that affect learning and memory, and we review the therapeutic potential of epigenetic treatments for the amelioration of these conditions.
– Avulsion of permanent teeth is one of the most serious dental injuries, and a prompt and correct emergency management is very important for the prognosis. The International Association of Dental ...Traumatology (IADT) has developed a consensus statement after a review of the dental literature and group discussions. Experienced researchers and clinicians from various specialties were included in the task group. The guidelines represent the current best evidence and practice based on literature research and professionals’ opinion. In cases where the data did not appear conclusive, recommendations were based on the consensus opinion or majority decision of the task group. Finally, the IADT board members were giving their opinion and approval. The primary goal of these guidelines is to delineate an approach for the immediate or urgent care of avulsed permanent teeth.
Abstract
We present the localization and host galaxies of one repeating and two apparently nonrepeating fast radio bursts (FRBs). FRB 20180301A was detected and localized with the Karl G. Jansky Very ...Large Array to a star-forming galaxy at
z
= 0.3304. FRB20191228A and FRB20200906A were detected and localized by the Australian Square Kilometre Array Pathfinder to host galaxies at
z
= 0.2430 and
z
= 0.3688, respectively. We combine these with 13 other well-localized FRBs in the literature, and analyze the host galaxy properties. We find no significant differences in the host properties of repeating and apparently nonrepeating FRBs. FRB hosts are moderately star forming, with masses slightly offset from the star-forming main sequence. Star formation and low-ionization nuclear emission-line region emission are major sources of ionization in FRB host galaxies, with the former dominant in repeating FRB hosts. FRB hosts do not track stellar mass and star formation as seen in field galaxies (more than 95% confidence). FRBs are rare in massive red galaxies, suggesting that progenitor formation channels are not solely dominated by delayed channels which lag star formation by gigayears. The global properties of FRB hosts are indistinguishable from core-collapse supernovae and short gamma-ray bursts hosts, and the spatial offset (from galaxy centers) of FRBs is mostly inconsistent with that of the Galactic neutron star population (95% confidence). The spatial offsets of FRBs (normalized to the galaxy effective radius) also differ from those of globular clusters in late- and early-type galaxies with 95% confidence.
Primaquine radical cure is used to treat dormant liver-stage parasites and prevent relapsing Plasmodium vivax malaria but is limited by concerns of haemolysis. We undertook a systematic review and ...individual patient data meta-analysis to investigate the haematological safety of different primaquine regimens for P vivax radical cure.
For this systematic review and individual patient data meta-analysis, we searched MEDLINE, Web of Science, Embase, and Cochrane Central for prospective clinical studies of uncomplicated P vivax from endemic countries published between Jan 1, 2000, and June 8, 2023. We included studies if they had active follow-up of at least 28 days, if they included a treatment group with daily primaquine given over multiple days where primaquine was commenced within 3 days of schizontocidal treatment and was given alone or coadministered with chloroquine or one of four artemisinin-based combination therapies (ie, artemether–lumefantrine, artesunate–mefloquine, artesunate–amodiaquine, or dihydroartemisinin–piperaquine), and if they recorded haemoglobin or haematocrit concentrations on day 0. We excluded studies if they were on prevention, prophylaxis, or patients with severe malaria, or if data were extracted retrospectively from medical records outside of a planned trial. For the meta-analysis, we contacted the investigators of eligible trials to request individual patient data and we then pooled data that were made available by Aug 23, 2021. The main outcome was haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL by day 14. Haemoglobin concentration changes between day 0 and days 2–3 and between day 0 and days 5–7 were assessed by mixed-effects linear regression for patients with glucose-6-phosphate dehydrogenase (G6PD) activity of (1) 30% or higher and (2) between 30% and less than 70%. The study was registered with PROSPERO, CRD42019154470 and CRD42022303680.
Of 226 identified studies, 18 studies with patient-level data from 5462 patients from 15 countries were included in the analysis. A haemoglobin reduction of more than 25% to a concentration of less than 7 g/dL occurred in one (0·1%) of 1208 patients treated without primaquine, none of 893 patients treated with a low daily dose of primaquine (<0·375 mg/kg per day), five (0·3%) of 1464 patients treated with an intermediate daily dose (0·375 mg/kg per day to <0·75 mg/kg per day), and six (0·5%) of 1269 patients treated with a high daily dose (≥0·75 mg/kg per day). The covariate-adjusted mean estimated haemoglobin changes at days 2–3 were –0·6 g/dL (95% CI –0·7 to –0·5), –0·7 g/dL (–0·8 to –0·5), –0·6 g/dL (–0·7 to –0·4), and –0·5 g/dL (–0·7 to –0·4), respectively. In 51 patients with G6PD activity between 30% and less than 70%, the adjusted mean haemoglobin concentration on days 2–3 decreased as G6PD activity decreased; two patients in this group who were treated with a high daily dose of primaquine had a reduction of more than 25% to a concentration of less than 7 g/dL. 17 of 18 included studies had a low or unclear risk of bias.
Treatment of patients with G6PD activity of 30% or higher with 0·25–0·5 mg/kg per day primaquine regimens and patients with G6PD activity of 70% or higher with 0·25–1 mg/kg per day regimens were associated with similar risks of haemolysis to those in patients treated without primaquine, supporting the safe use of primaquine radical cure at these doses.
Australian National Health and Medical Research Council, Bill & Melinda Gates Foundation, and Medicines for Malaria Venture.
In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we ...carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.
Abstract Purpose Despite growing calls for team-based care, the current staff composition of primary care practices is unknown. We describe staffing patterns for primary care practices in the Centers ...for Medicare and Medicaid Services (CMS) Comprehensive Primary Care (CPC) initiative. Methods We undertook a descriptive analysis of CPC initiative practices' baseline staffing using data from initial applications and a practice survey. CMS selected 502 primary care practices (from 987 applicants) in 7 regions based on their health information technology, number of patients covered by participating payers, and other factors; 496 practices were included in this analysis. Results Consistent with the national distribution, most of the CPC initiative practices included in this study were small: 44% reported 2 or fewer full-time equivalent (FTE) physicians; 27% reported more than 4. Nearly all reported administrative staff (98%) and medical assistants (89%). Fifty-three percent reported having nurse practitioners or physician assistants; 47%, licensed practical or vocational nurses; 36%, registered nurses; and 24%, care managers/coordinators—all of these positions are more common in larger practices. Other clinical staff were reported infrequently regardless of practice size. Compared with other CPC initiative practices, designated patient-centered medical homes were more likely to have care managers/coordinators but otherwise had similar staff types. Larger practices had fewer FTE staff per physician. Conclusions At baseline, most CPC initiative practices used traditional staffing models and did not report having dedicated staff who may be integral to new primary care models, such as care coordinators, health educators, behavioral health specialists, and pharmacists. Without such staff and payment for their services, practices are unlikely to deliver comprehensive, coordinated, and accessible care to patients at a sustainable cost.
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