To evaluate the association between secondhand smoke (SHS) exposure and depression. Tobacco smoking and depression are strongly associated, but the possible effects of SHS have not been evaluated.
...The 2005 to 2006 National Health and Nutrition Examination Survey (NHANES) is a cross-sectional sample of the noninstitutionalized civilian U.S. population. SHS exposure was measured in adults aged > or =20 years by serum cotinine and depressive symptoms by the Patient Health Questionnaire. Zero-inflated Poisson regression analyses were completed with adjustment for survey design and potential confounders.
Serum cotinine-documented SHS exposure was positively associated with depressive symptoms in never-smokers, even after adjustment for age, race/ethnicity, gender, education, alcohol consumption, and medical comorbidities. The association between SHS exposure and depressive symptoms did not vary by gender, nor was there any association between SHS smoke exposure and depressive symptoms in former smokers.
Findings from the present study suggest that SHS exposure is positively associated with depressive symptoms in never-smokers and highlight the need for further research to establish the mechanisms of association.
Sensory systems encode environmental information that is necessary for adaptive behavioural choices, and thus greatly influence the evolution of animal behaviour and the underlying neural circuits. ...Here, we evaluate how the quality of sensory information impacts the jamming avoidance response (JAR) in weakly electric fish. To sense their environment, these fish generate an oscillating electric field: the electric organ discharge (EOD). Nearby fish with similar EOD frequencies perform the JAR to increase the difference between their EOD frequencies, i.e. their difference frequency (DF). The fish determines the sign of the DF: when it has a lower frequency (DF > 0), EOD frequency is decreased and vice versa. We study the sensory basis of the JAR in two species: Apteronotus leptorhynchus have a high frequency (ca 1000 Hz), spatio-temporally heterogeneous electric field, whereas Eigenmannia sp. have a low frequency (ca 300 Hz), spatially uniform field. We show that the increased complexity of the Apteronotus field decreases the reliability of sensory cues used to determine the DF. Interestingly, Apteronotus responds to all JAR stimuli by increasing EOD frequency, having lost the neural pathway that produces JAR-related decreases in EOD frequency. Our results suggest that electric field complexity may have influenced the evolution of the JAR by degrading the related sensory information.
IntroductionHip fractures treated with total hip arthroplasty (THA) are at high risk of prosthesis instability, and dislocation is the most common indication for revision surgery. This study aims to ...determine whether dual mobility THA implants reduce the risk of dislocation compared with conventional THA in patients with hip fracture suitable to be treated with THA.Methods and analysisThis is a cluster-randomised, crossover, open-label trial nested within the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). The clusters will comprise hospitals that perform at least 12 THAs for hip fracture per annum. All adults age ≥50 years who meet the Australian and New Zealand Hip Fracture Registry guidelines for THA will be included. The intervention will be dual mobility THA and the comparator will be conventional THA. Each hospital will be allocated to two consecutive periods, one of dual mobility THA and the other of conventional THA in random order, aiming for an average of 16 patients eligible for the primary analysis per group (32 total per site), allowing different recruitment totals between sites. Data will be collected through the AOANJRR and linked with patient-level discharge data acquired through government agencies. The primary outcome is dislocation within 1 year. Secondary outcomes include revision surgery for dislocation and all-cause, complications and mortality at 1, 2 and 5 years. If dual mobility THA is found to be superior, a cost-effectiveness analysis will be conducted. The study will aim to recruit 1536 patients from at least 48 hospitals over 3 years.Ethics and disseminationEthics approval has been granted (Sydney Local Health District - Royal Prince Alfred Hospital Zone (approval X20-0162 and 2020/ETH00680) and site-specific approvals). Participant recruitment is via an opt-out consent process as both treatments are considered accepted, standard practice. The trial is endorsed by the Australia and New Zealand Musculoskeletal Clinical Trials Network.Trial registration numberACTRN12621000069853.
Heart rate variability (HRV) is an objective and sensitive measure of integrated physiological functioning reflective of heart rhythm responsivity to internal and external demands. Reduced HRV is ...associated with vulnerability to stress and deterioration of medical and/or psychiatric conditions, while increased HRV is associated with a favorable treatment response and recovery from various medical and/or psychiatric conditions. Our previous review found that acute alcohol consumption caused decreased parasympathetic and increased sympathetic HRV effects in both nonalcoholic and chronic alcohol users. This review investigates the effects of chronic alcohol consumption on HRV in alcohol‐dependent subjects and nondependent users. MEDLINE, Scopus, and PubMed were searched for human experimental and clinical trials that measured the effects of chronic alcohol use on HRV. Only publications that included a description of their study designs and clearly stated methodologies for data collections, and outcome measures were reviewed. We have reviewed a total of 24 articles. In nondependent users, low dose (approximating the recommended daily amount of 1 standard drink in women and 2 in men) use is associated with increased HRV parameters compared to those who drink less frequently or abstain altogether. A further increase in consumption is associated with decreased HRV compared to both abstainers and more moderate drinkers. HRV changes during withdrawal generally follow the same negative direction but are more complex and less understood. In dependent subjects, an improvement in HRV was seen following abstinence but remained reduced compared to nonalcoholic controls. This review demonstrates that HRV changes associated with chronic use follow a J‐shaped curve. It supports recommendations that limit daily alcohol intake to no more than 2 drinks for men and 1 drink for women. Future studies should investigate HRV as a biomarker of alcoholism development and treatment response as well as the physiological basis for alcohol effects on HRV.
The
genus includes opportunistic pathogens that can cause chronic infections in immunocompromised patients, especially in people with cystic fibrosis (CF). Treatment of
infections is complicated by ...antimicrobial resistance. In this study, a collection of
clinical isolates, from CF and non-CF sources, was investigated for polymyxin B (PmB) resistance. Additionally, the effect of PmB challenge in a subset of isolates was examined and the presence of PmB-resistant subpopulations within the isolates was described. Further, chemical and mass spectrometry analyses of the lipid A of
clinical isolates enabled the determination of the most common structures and showed that PmB challenge was associated with lipid A modifications that included the addition of glucosamine and palmitoylation and the concomitant loss of the free phosphate at the C-1 position. This study demonstrates that lipid A modifications associated with PmB resistance are prevalent in
and that subresistant populations displaying the addition of positively charged residues and additional acyl chains to lipid A can be selected for and isolated from PmB-sensitive
clinical isolates.
species can cause chronic and potentially severe infections in immunocompromised patients, especially in those with cystic fibrosis. Bacteria cannot be eradicated due to
's intrinsic multidrug resistance. We report that intrinsic resistance to polymyxin B (PmB), a last-resort antimicrobial peptide used to treat infections by multiresistant bacteria, is prevalent in
clinical isolates; many isolates also display increased resistance upon PmB challenge. Analysis of the lipopolysaccharide lipid A moiety of several
species reveals a penta-acylated lipid A, which in the PmB-resistant isolates was modified by the incorporation of glucosamine residues, an additional acyl chain, loss of phosphates, and hydroxylation of acyl chains, all of which can enhance PmB resistance in other bacteria. We conclude that PmB resistance, particularly in
isolates from chronic respiratory infections, is a common phenomenon, and that
lipid A displays modifications that may confer increased resistance to polymyxins and potentially other antimicrobial peptides.
Active sensory systems have evolved to properly encode natural stimuli including those created by conspecifics, yet little is known about the properties of such stimuli. We consider the ...electrosensory signal at the skin of a fixed weakly electric fish in the presence of a swimming conspecific. The dipole recordings are obtained in parallel with video tracking of the position of the animals. This enables the quantification of the relationships between the recording dipole and the positions of the head, midbody and tail of the freely swimming fish. The contrast of the signal at the skin is shown to be well-fitted by a decreasing exponential function of distance. It is thus anti-correlated with distance; it is also correlated with the second envelope (i.e., the envelope of the envelope) of the raw recorded signal. The variance of the contrast signal is highest at short range. However, the coefficient of variation (CV) of this signal increases with distance. We find a range of position and associated contrast patterns under quasi-2D swimming conditions. This is quantified using global measures of the visit times of the free fish within measurable range, with each visit causing a bump in contrast. The durations of these bumps as well as the times between these bumps are well reproduced by a doubly stochastic process formed by a dichotomous (two-state) noise with Poisson statistics multiplying a colored noise Ornstein-Uhlenbeck (OU) process. Certain rapid body movements such as bending or turning are seen to produce contrast drops that may be part of cloaking strategies.
Darwin's finches are a clade of 19 species of passerine birds native to the Galápagos Islands, whose biogeography, specialized beak morphologies, and dietary choices-ranging from seeds to blood-make ...them a classic example of adaptive radiation. While these iconic birds have been intensely studied, the composition of their gut microbiome and the factors influencing it, including host species, diet, and biogeography, has not yet been explored.
We characterized the microbial community associated with 12 species of Darwin's finches using high-throughput 16S rRNA sequencing of fecal samples from 114 individuals across nine islands, including the unusual blood-feeding vampire finch (Geospiza septentrionalis) from Darwin and Wolf Islands. The phylum-level core gut microbiome for Darwin's finches included the Firmicutes, Gammaproteobacteria, and Actinobacteria, with members of the Bacteroidetes at conspicuously low abundance. The gut microbiome was surprisingly well conserved across the diversity of finch species, with one exception-the vampire finch-which harbored bacteria that were either absent or extremely rare in other finches, including Fusobacterium, Cetobacterium, Ureaplasma, Mucispirillum, Campylobacter, and various members of the Clostridia-bacteria known from the guts of carnivorous birds and reptiles. Complementary stable isotope analysis of feathers revealed exceptionally high δ
N isotope values in the vampire finch, resembling top marine predators. The Galápagos archipelago is also known for extreme wet and dry seasons, and we observed a significant seasonal shift in the gut microbial community of five additional finch species sampled during both seasons.
This study demonstrates the overall conservatism of the finch gut microbiome over short (< 1 Ma) divergence timescales, except in the most extreme case of dietary specialization, and elevates the evolutionary importance of seasonal shifts in driving not only species adaptation, but also gut microbiome composition.
Background
Aberrant PI3K/AKT signaling in BRAF‐mutant cancers contributes to resistance to BRAF inhibitors. The authors examined dual MAPK and PI3K pathway inhibition in patients who had BRAF‐mutated ...solid tumors (ClinicalTrials.gov identifier NCT01902173).
Methods
Patients with BRAF V600E/V600K–mutant solid tumors received oral dabrafenib at 150 mg twice daily with dose escalation of oral uprosertib starting at 50 mg daily, or, in the triplet cohorts, with dose escalation of both oral trametinib starting at 1.5 mg daily and oral uprosertib starting at 25 mg daily. Dose‐limiting toxicities (DLTs) were assessed within the first 56 days of treatment. Radiographic responses were assessed at 8‐week intervals.
Results
Twenty‐seven patients (22 evaluable) were enrolled in parallel doublet and triplet cohorts. No DLTs were observed in the doublet cohorts (N = 7). One patient had a DLT at the maximum administered dose of triplet therapy (dabrafenib 150 mg twice daily and trametinib 2 mg daily plus uprosertib 75 mg daily). Three patients in the doublet cohorts had partial responses (including one who had BRAF inhibitor‐resistant melanoma). Two patients in the triplet cohorts had a partial response, and one patient had an unconfirmed partial response. Pharmacokinetic data suggested reduced dabrafenib and dabrafenib metabolite exposure in patients who were also exposed to both trametinib and uprosertib, but not in whose who were exposed to uprosertib without trametinib.
Conclusions
Concomitant inhibition of both the MAPK and PI3K‐AKT pathways for the treatment of BRAF‐mutated cancers was well tolerated, leading to objective responses, but higher level drug‐drug interactions affected exposure to dabrafenib and its metabolites.
A phase 1 trial of triplet‐targeted therapy demonstrates that a combination of dabrafenib, trametinib, and uprosertib (BRAF, MEK, and AKT inhibitors) is well tolerated, but higher order drug‐drug interactions affect drug exposures.
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In our continuing efforts to explore structure–activity relationships around the novel class of potent, isonicotinamide-based GSK3 inhibitors described in our previous report, we ...extensively explored structural variations around both 4/5-pyridine substitutions and the amide group. Some analogs were found to have greatly improved pTau lowering potency while retaining high kinase selectivity. In contrast to previous active compounds 1a-c, a close analog 3h did not show in vivo efficacy in a triple-transgenic mouse Alzheimer’s disease model. In general, these 2‑pyridinyl amide derivatives were prone to amidase mediated hydrolysis in mouse plasma.
D-glucosamine is a widely consumed dietary supplement used to promote joint health and treat osteoarthritis. It also stimulates intracellular hexosamine flux and increases transforming growth factor ...β1 (TGFβ1) mRNA expression and insulin resistance in animal studies. The effects of D-glucosamine exposure were investigated in obese Zucker rats. Male (leprfa/leprfa) Zucker rats were exposed to 30, 120, 300 and 600 mg D-glucosamine HCl per kg/day either alone or with chondroitin sulfate (24, 96, 240 and 480 mg/kg/day respectively) for 90 days. After 4 weeks exposure, these doses produced CmaxD-glucosamine concentrations of up to 24 μM in tail vein serum concurrent with a transient 30% increase in blood glucose concentration in the 600 mg/kg/day dose group. D-Glucosamine did not significantly alter body weight, blood glucose or serum insulin levels at any dose tested after 13 weeks exposure, but did increase urinary TGFβ1 concentrations. The Zucker rats developed nephropathy and scrotal sores that were related to their hyperglycemia and obesity, and D-glucosamine exposure exacerbated these conditions to a small extent. The incidence of pulmonary osseous metaplasia was increased in rats exposed to D-glucosamine and a single incidence of adrenal osseous metaplasia was noted in one animal exposed to 600/480 mg D-glucosamine HCl/chondroitin sulfate. These lesions may have been treatment related. These studies suggest that the risk of adverse effects of oral D-glucosamine is small compared to that of hyperglycemia in these animals, but the potential for TGFβ1-mediated pathologies, such as osseous metaplasia and renal nephropathy may be increased.
•90-day exposure to D-glucosamine HCl caused only transient increases in blood glucose.•Zucker rats developed dermal sores associated with obesity and hyperglycemia.•D-glucosamine exacerbated pathological effects of hyperglycemia in obese Zucker rats.•Risk of adverse effects due to D-glucosamine exposure less than that of hyperglycemia.
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