Cervical cancer screening in Brazilian Amazon Indigenous women: Towards the intensification of public policies for prevention.
Indigenous women are vulnerable to cervical cancer. Screening is a strategy to reduce the burden of the disease. To evaluate the prevalence profile of cervical cancer screening cytological results in Brazilian indigenous women by age and frequency of tests compared to non-indigenous women. A cross-sectional study evaluating the prevalences of screening test results in indigenous women assisted in the Brazilian Amazon from 2007 to 2019 (3,231 tests), compared to non-indigenous women (698,415 tests). The main outcome was the cytological result. Other variables were frequency, age groups, and population. The frequency was categorized as "1st test", the first test performed by the women in their lifetime, or "screening test," tests from women who had previously participated in screening. Analyzes were based on prevalences by age group and population. We used Prevalence Ratios (PR) and 95% Confidence Intervals for risks and linear regression for trends. Data from the 1st test showed a higher prevalence of Low-grade Squamous Intraepithelial Lesion (LSIL) in indigenous women. Peaks were observed in indigenous under 25, 35 to 39, 45 to 49, and 60 to 64. The prevalence of High-grade Squamous Intraepithelial Lesion or more severe (HSIL+) was low in both groups in women younger than 25. The indigenous HSIL+ prevalence curve showed a rapid increase, reaching peaks in women from 25 to 34 years, following a slight decrease and a plateau. In screening tests, HSIL+ was more prevalent in indigenous from 25 to 39 (PR 4.0,2.3;6.8) and 40 to 64 (PR 3.8,1.6;9.0). In indigenous, the PR of HSIL+ results in screening tests over 1st tests showed no screening effect in all age groups. In non-indigenous, there was a significant effect toward protection in the age groups over 25. This screening study of indigenous women from diverse ethnicities showed a higher prevalence of cytological LSIL and HSIl+ than in non-indigenous women. The protective screening effect in reducing HSIL+ prevalence was not observed in indigenous.


Low mortality in ulcerative colitis and Crohn's disease in three regional centers in England.
Recent epidemiological studies suggest that mortality rates for inflammatory bowel disease (IBD) are similar to those of the general population. However, most of this work has been done in referred populations or larger urban centers. We intended to estimate mortality rates for ulcerative colitis (UC) and Crohn's disease (CD) in three British district general hospital practices in Wolverhampton, Salisbury, and Swindon. Consecutive patients with CD or UC were identified from 1978 to 1986 and followed prospectively. Demographic data, date and cause of death or health status at December 31, 1993 were used to estimate standardized mortality ratios (SMRs) and 95% confidence intervals. Sixty-four deaths occurred in 552 patients (UC 41 of 356; CD 23 of 196). The overall SMRs were 103 [95% confidence interval (CI): 79-140] for UC and 94 (95% CI: 59-140) for CD. The respective SMRs were higher only in the first year after diagnosis at 223 (95% CI: 99-439; p = 0.02) and 229 (74-535; p = 0.056), and even then, most subjects died from non-IBD causes (5 of 13). Nonsurvivors were significantly older than survivors in both UC and CD (p < 0.01). The SMR was also significantly greater during a severe first attack of UC at 310 (95% CI: 84-793; p = 0.04). Patients with perianal or colonic CD had an increased SMR [396 (95% CI: 108-335; p = 0.02) and 164 (95% CI: 82-335; p = 0.02)] respectively, partly related to the older mean age (52 vs 32 yr, p < 0.001). Mortality rates are not increased in IBD compared with the general population. However, older patients may be at increased risk of dying from other causes early in the disease clinical course.


Docking of verapamil in a synthetic Ca2+ channel: formation of a ternary complex involving Ca2+ ions.
The mechanism by which diverse drugs modulate voltage-dependent Ca2+ channels is ill-understood. We have approached this problem by examining the interaction of verapamil with a 97-residue synthetic channel peptide (SCP) that exhibits functional similarities to authentic L-type Ca2+ channels in terms of cation selectivity and permeation as well as interaction with channel-activating and blocking drugs (Grove et al. (1991) Proc. Natl. Acad. Sci. USA 88, 6418). Different possibilities of binding of verapamil inside the Ca(2+)-bound SCP were simulated using the Monte Carlo-with-energy-minimization method. In the optimal mode of the binding, verapamil adopted a folded conformation and fit snugly in the pore. The dimethoxyphenyl groups of the drug interacted with two Ca2+ ions coordinated to the acidic residues of SCP, thus forming a ternary complex of the drug, Ca2+, and channel. The isopropyl group of verapamil abetted a ring of four Ile residues constituting the putative SCP gate. The occlusion of this gate by verapamil in this manner was strikingly similar to that accomplished by the methyl group of dihydropyridine drugs. In conjunction with an earlier study on SCP bound to dihydropyridine drugs (Zhorov and Ananthanarayanan (1996) Biophys. J. 70, 22), our data suggest that, in general, drug modulation of SCP would involve the interaction of the ligands with the pore-bound Ca2+ and with the hydrophobic gate. In light of the functional similarity between SCP and L-type Ca2+ channel, it is likely that the latter would also interact with drugs in a similar fashion.


Bucindolol for the Maintenance of Sinus Rhythm in a Genotype-Defined HF Population: The GENETIC-AF Trial.
The purpose of this study was to compare the effectiveness of bucindolol with that of metoprolol succinate for the maintenance of sinus rhythm in a genetically defined heart failure (HF) population with atrial fibrillation (AF). Bucindolol is a beta-blocker whose unique pharmacologic properties provide greater benefit in HF patients with reduced ejection fraction (HFrEF) who have the beta1-adrenergic receptor (ADRB1) Arg389Arg genotype. A total of 267 HFrEF patients with a left ventricular ejection fraction (LVEF) <0.50, symptomatic AF, and the ADRB1 Arg389Arg genotype were randomized 1:1 to receive bucindolol or metoprolol therapy and were up-titrated to target doses. The primary endpoint of AF or atrial flutter (AFL) or all-cause mortality (ACM) was evaluated by electrocardiogram (ECG) during a 24-week period. The hazard ratio (HR) for the primary endpoint was 1.01 (95% confidence interval [CI]: 0.71 to 1.42), but trends for bucindolol benefit were observed in several subgroups. Precision therapeutic phenotyping revealed that a differential response to bucindolol was associated with the interval of time from the initial diagnoses of AF and HF to randomization and with the onset of AF relative to that of the initial HF diagnosis. In a cohort whose first AF and HF diagnoses were <12 years prior to randomization, in which AF onset did not precede HF by more than 2 years (n = 196), the HR was 0.54 (95% CI: 0.33 to 0.87; p = 0.011). Pharmacogenetically guided bucindolol therapy did not reduce the recurrence of AF/AFL or ACM compared to that of metoprolol therapy in HFrEF patients, but populations were identified who merited further investigation in future phase 3 trials.


Motor-Cognitive Virtual Reality Training to Improve Gait and Balance in Young Adults with TBI.
Traumatic Brain Injury (TBI) is one of the leading causes of motor and cognitive deficits in adults, and often results in motor control and balance impairments. Motor deficits include gait dysfunction and decreased postural control & coordination; leading to compromised functional ambulation and reduced quality of life. Research has shown that cognitive (attention and executive) function contributes to motor deficits and recovery. Hence, targeting the motor and the cognitive domains simultaneously by increasing cognitive and motor effort to perform the task may lead to improved ambulation recovery. The objective of this investigation was to evaluate the efficacy of simultaneous motor & cognitive training (MCT) using virtual reality to improve ambulation; assessed using biomechanical, cognitive, and functional outcomes. Preliminary data is presented for three participants with chronic TBI who received MCT. The results show improved cognition, speed, endurance, step length, gait cycle time, static & reactive balance, dual-task performance, and progression towards healthy ambulation. These preliminary results suggest that integrated cognitive motor training has the potential to induce functional recovery in young adults with TBI.Clinical Relevance - Preliminary data provides initial evidence for MCT as a therapeutic intervention for gait and balance rehabilitation in young adults with TBI.


Role of TGF-beta in the tumor stroma.
Recent findings have demonstrated that the tumor stroma actively contributes to tumorigenesis. The communication of malignant cells and tumor stromal components is orchestrated in part by a network of growth factors. One of these growth factors is transforming growth factor-beta (TGF-beta), a secreted multifunctional protein that acts in a highly cellular contextual manner. TGF-beta can either stimulate or inhibit the tumor-promoting effects of the different components of the tumor stroma. In this review, we discuss our current understanding on how TGF-beta influences different stromal compartments.


Amodiaquine-induced hepatitis. A report of seven cases.
Seven patients developed hepatitis after receiving amodiaquine for malaria prophylaxis for 4 to 15 weeks. Four patients had a minor form of hepatitis: jaundice was mild or absent, serum aminotransferase levels were moderately increased, and recovery was prompt. Three patients had a severe form: jaundice was intense, serum aminotransferase levels were markedly increased, jaundice persisted for 3 to 6 months, and liver tests were still abnormal 7 to 27 months after the onset of hepatitis. In two patients, serum aminotransferase levels increased promptly after readministration of the drug, which is consistent with an immunoallergic mechanism for amodiaquine-induced hepatitis.


Epinephrine hand nebulizer in asthma; technique of use, clinical aspects.
It behooves the physician seeking relief for asthmatic patients not to be casual about the epinephrine hand nebulizer and the manner in which it is used. Patients who claim to get no relief from the nebulizer should be asked to demonstrate their technique. If the nebulizer produces a hardly visible mist, it should be discarded. For many patients, the goal in spraying by hand must be the production of more or less continuous and voluminous aerosol, regardless of the phase of respiration, in order to effect relief. If the respiratory pattern has not deviated too far from normal in rate and depth, inhalations may be carried out in courses or cycles of about a half-minute duration and spaced a few minutes apart. If the respiratory pattern is abnormal during the act of spraying, it must be corrected. Inhaled epinephrine aerosols as constituted today appear to be somewhat irritating to the mouth, throat, and upper portion of the pulmonary tract of some persons, but it has not been convincingly demonstrated that serious and permanent damage to the lower respiratory tract of humans can occur from long-continued use of inhaled epinephrine.


Carbocisteine normalizes the viscous property of mucus through regulation of fucosylated and sialylated sugar chain on airway mucins.
Almost all of fucose and sialic acid in mucus are found on the mucus glycoproteins (mucins), and these sugar components on mucins are known to be associated with the viscous property of mucus. We have reported some aspects of carbocisteine, a mucoregulatory drug, correcting fucose and sialic acid contents in mucus. At present, carbocisteine's expectorant action of airway mucus is postulated to involve - the regulation of fucose and sialic acid contents on mucins. However little information is available about the relationship between the viscosity and sugar contents on mucins when treated with carbocisteine. To investigate further the mechanism behind the action of carbocisteine, the present study prepared MUC5AC fusion protein which has tandem repeat regions associated with MUC5AC, and evaluated the effects of carbocisteine on tumor necrosis factor (TNF)-alpha-induced increases of mucus viscosity and sialyl-Lewis x-epitopes antigen, an antigen which consists of fucosylated and sialylated sugar chains on the MUC5AC fusion proteins. Carbocisteine inhibited the TNF-alpha-induced increases of the viscosity and sialyl-Lewis x-epitopes on MUC5AC fusion protein. These findings suggest that carbocisteine may normalize the viscosity of mucus through "balancing" of fucose and sialic acid contents on airway mucins.


Efficacy and Safety of AFN-1252, the First Staphylococcus-Specific Antibacterial Agent, in the Treatment of Acute Bacterial Skin and Skin Structure Infections, Including Those in Patients with Significant Comorbidities.
This open-label noncontrolled, phase II multicenter trial was designed to evaluate the safety, tolerability, and efficacy of 200 mg of AFN-1252, a selective inhibitor of Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI), given by mouth twice daily in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci. Important aspects of the current study included a comparison of early response efficacy endpoints with end-of-treatment and follow-up endpoints. Many patients in the intent-to-treat population (n = 103) had significant comorbidities. The overall early response rate at day 3 was 97.3% (wound, 100%; abscess, 96.6%; cellulitis, 94.4%) in the microbiologically evaluable (ME) population. Within the ME population, 82.9% of patients had a ≥ 20% decrease in the area of erythema, and 77.9% of patients had a ≥ 20% decrease in the area of induration, on day 3. S. aureus was detected in 97.7% of patients (n = 37 patients with methicillin-resistant S. aureus [MRSA], and n = 39 with methicillin-sensitive S. aureus [MSSA]). No isolates had increased AFN-1252 MICs posttreatment. Microbiologic eradication rates for S. aureus were 93.2% at short-term follow-up (STFU) and 91.9% at long-term follow-up (LTFU) in the ME population. Eradication rates for MRSA and MSSA were 91.9% and 92.3%, respectively, at STFU and 91.9% and 89.7%, respectively, at LTFU. The most frequently reported drug-related adverse events, which were mostly mild or moderate, were headache (26.2%) and nausea (21.4%). These studies demonstrate that AFN-1252 is generally well tolerated and effective in the treatment of ABSSSI due to S. aureus, including MRSA. (This study has been registered at ClinicalTrials.gov under registration no. NCT01519492.).


A parametric study assessing Implicit Solver limits for a generic FEM Simulation of PTA without stent deployment.
This study focuses on the robustness of a generic Finite Element Model (FEM) of Percutaneous Transluminal Angioplasty (PTA) procedure with permanent set. The influence of three different parameters on simulation robustness were investigated: the stenosis percent, the stenosis offset and the arterial caliber. Five arterial calibers are modeled by adapting the ratio between the inner diameter and the wall thickness. Overall, forty configurations were tested with the same simulation settings and boundary conditions. Results shows convergence issues caused by excessive deformations of elements for stenosis above 65% blockage. Moreover, an increasing stenosis offset tends to decrease convergence. Simulation of PTA on small calibers and large calibers are less robust than intermediate e.g., iliac calibers.Clinical Relevance- PTA can benefit from numerical tools to improve the procedure outcomes. A FEM simulation of PTA without stent deployment can predict the permanent strain induced by this surgery for various configurations. However, robustness of the simulation is required to consider its transfer to clinics. This work aims to determine the robustness boundaries of an implicit solver for PTA simulation. It shows that an implicit solver is robust for all artery calibers with a stenosis below 50% blockage. Moreover medium-caliber arteries exhibit better robustness with converging solutions for stenosis reaching 60% blockage.


A new biologic prosthesis for vascular substitute in mongrel dogs.
New glutaraldehyde-treated vascular prosthesis tubes of bovine pericardium were placed in the abdominal aortas of 29 mongrel dogs and observed for 30 to 540 days. Clinical evaluation was performed during follow-up, and histologic and arteriographic studies were done at the end of the study. Patency was shown by arteriography in 27 of 29 tubes (93.1%). Neoendothelialization was found in all grafts, and there was a mixed effect, characterized by both rejection and foreign body reaction in the prostheses from 180 days onward. Both the handling and consistency of the grafts were excellent for implantation. Graft procoagulation and animal anticoagulation were not necessary.


Causal relationship between depression and aging: a bidirectional two-sample Mendelian randomization study.
The causal relationship and the direction of the effect between depression and aging remain controversial. We used a bidirectional two-sample Mendelian randomization analysis to examine the relationship between depression and age proxy indicators. We obtained pooled statistics from genome-wide association studies (GWAS) on depression and the age proxy indicators. We employed five MR analysis methods to address potential biases and ensure robustness of our results, with the inverse variance weighted (IVW) method being the primary outcome. We also conducted outlier exclusion using Radial MR, MRPRESSO, and MR Steiger filters. Additionally, sensitivity analyses were performed to assess heterogeneity and pleiotropy. Our MR analysis revealed that depression causally leads to shortened telomere length (β = - 0.014; P = 0.038), increased frailty index (β = 0.076; P = 0.000), and accelerated GrimAge (β = 0.249; P = 0.024). Furthermore, our findings showed that the frailty index (OR = 1.679; P = 0.001) was causally associated with an increased risk of depression. Additionally, we found that appendicular lean mass (OR = 0.929; P = 0.000) and left-hand grip strength (OR = 0.836; P = 0.014) were causally associated with a reduced risk of depression. Sensitivity analyses demonstrated the robustness of our findings. Our study provides evidence that depression contributes to the accelerated aging process, resulting in decreased telomere length, increased frailty index, and accelerated GrimAge. Additionally, we found that the frailty index increases the risk of depression, while appendicular lean mass and left-handed grip strength reduce the risk of depression.


Visual encoding and fixation target selection in free viewing: presaccadic brain potentials.
In scrutinizing a scene, the eyes alternate between fixations and saccades. During a fixation, two component processes can be distinguished: visual encoding and selection of the next fixation target. We aimed to distinguish the neural correlates of these processes in the electrical brain activity prior to a saccade onset. Participants viewed color photographs of natural scenes, in preparation for a change detection task. Then, for each participant and each scene we computed an image heat map, with temperature representing the duration and density of fixations. The temperature difference between the start and end points of saccades was taken as a measure of the expected task-relevance of the information concentrated in specific regions of a scene. Visual encoding was evaluated according to whether subsequent change was correctly detected. Saccades with larger temperature difference were more likely to be followed by correct detection than ones with smaller temperature differences. The amplitude of presaccadic activity over anterior brain areas was larger for correct detection than for detection failure. This difference was observed for short "scrutinizing" but not for long "explorative" saccades, suggesting that presaccadic activity reflects top-down saccade guidance. Thus, successful encoding requires local scanning of scene regions which are expected to be task-relevant. Next, we evaluated fixation target selection. Saccades "moving up" in temperature were preceded by presaccadic activity of higher amplitude than those "moving down". This finding suggests that presaccadic activity reflects attention deployed to the following fixation location. Our findings illustrate how presaccadic activity can elucidate concurrent brain processes related to the immediate goal of planning the next saccade and the larger-scale goal of constructing a robust representation of the visual scene.


Cannabinoids for neuropathic pain.
Treatment options for neuropathic pain have limited efficacy and use is fraught with dose-limiting adverse effects. The endocannabinoid system has been elucidated over the last several years, demonstrating a significant interface with pain homeostasis. Exogenous cannabinoids have been demonstrated to be effective in a range of experimental neuropathic pain models, and there is mounting evidence for therapeutic use in human neuropathic pain conditions. This article reviews the history, pharmacologic development, clinical trials results, and the future potential of nonsmoked, orally bioavailable, nonpsychoactive cannabinoids in the management of neuropathic pain.


[The neurochemical characteristics of the effect of morphine and pentapeptide FK 33-824 on cerebral cortical excitability].
GABA-stimulating agents (muscimol, depakine, aminohydroxyacetic acid), serotonin stimulants (5-hydroxytryptophan, fluoxetine), catecholaminergic stimulants (L-DOPA, apomorphine) and a cholinergic inhibitor (hemicholinium-3) of the brain were found to enhance the inhibitory effect of morphine and pentapeptide FK 33-824 on the cortical excitability of free-moving cats. GABA-negative agents (thiosemicarbazide, bicuculline, picrotoxin), serotonin-negative agents (p-chlorophenylalanine, methysergide), catecholaminergic inhibitors (6-hydroxydopamine, alpha-methyl-p-tyrosine) and cholinergic stimulant (physostigmine) of the brain appeared to decrease the effects of morphine and pentapeptide FK 33-824 on the excitability of the cortex. beta-adrenoceptor blocker propranolol decreased the effects of morphine and pentapeptide FK 33-824 on the cortical excitability, whereas alpha-adrenoblockers (phentolamine, phenoxybenzamine and yochimbine) exerted no effect on their action.


Impact of Extreme Temperatures on Ambulance Dispatches Due to Cardiovascular Causes in North-West Spain.
Introduction and objectives. The increase in mortality and hospital admissions associated with high and low temperatures is well established. However, less is known about the influence of extreme ambient temperature conditions on cardiovascular ambulance dispatches. This study seeks to evaluate the effects of minimum and maximum daily temperatures on cardiovascular morbidity in the cities of Vigo and A Coruña in North-West Spain, using emergency medical calls during the period 2005-2017. Methods. For the purposes of analysis, we employed a quasi-Poisson time series regression model, within a distributed non-linear lag model by exposure variable and city. The relative risks of cold- and heat-related calls were estimated for each city and temperature model. Results. A total of 70,537 calls were evaluated, most of which were associated with low maximum and minimum temperatures on cold days in both cities. At maximum temperatures, significant cold-related effects were observed at lags of 3-6 days in Vigo and 5-11 days in A Coruña. At minimum temperatures, cold-related effects registered a similar pattern in both cities, with significant relative risks at lags of 4 to 12 days in A Coruña. Heat-related effects did not display a clearly significant pattern. Conclusions. An increase in cardiovascular morbidity is observed with moderately low temperatures without extremes being required to establish an effect. Public health prevention plans and warning systems should consider including moderate temperature range in the prevention of cardiovascular morbidity.


Analysis of 8 X-chromosomal markers in the population of central Croatia.
To analyze 8 X-linked short tandem repeat (STR) markers in the population of central Croatia and to evaluate their forensic efficiency. We carried out a statistical analysis of the data from previously performed genetic analyses, collected during routine forensic work by the Forensic Science Centre ''Ivan Vučetić.'' Mentype® Argus X-8 PCR amplification kit was used for typing the data of 99 unrelated healthy women and 78 men from central Croatia. Haplotype frequencies were calculated only in male samples. Arlequin 3.5 software was used to assess Hardy-Weinberg equilibrium (HWE), linkage disequilibrium (LD), observed and expected heterozygosity. Power of discrimination (PD) for men and women, polymorphism information content (PIC), power of exclusion, and mean exclusion chance for deficiency cases, normal trios, and duos were determined using online database ChrX-STR.org. In female samples, deviations from HWE (P=0.006) for each locus were not found. LD test performed both on female and male samples revealed no significant association between markers (P=0.002). DXS10135 was the most polymorphic locus (PIC=0.931). PD varied from 0.692 to 0.935 in male and from 0.845 to 0.992 in female samples. Combined PD reached 99.999999% in men and 99.9999999999% in women. Performed analyses revealed that the studied marker set contained polymorphic markers with high power of discrimination. We can conclude that Mentype® Argus X-8 PCR is suitable for application in the population of central Croatia. Results of this study, together with collected allele and haplotype frequencies, are the first step in establishing a national reference X-STR database based on 8 X-STR loci.


Economic Evaluation of Occupational Safety and Health Interventions From the Employer Perspective: A Systematic Review.
The aim of this systematic review was to evaluate the cost-effectiveness of occupational safety and health interventions from the employer perspective. A comprehensive literature search (2005 to 2016) in five electronic databases was conducted. Pre-2005 studies were identified from the reference lists of previous studies and systematic reviews, which have similar objective to those of this search. A total of 19 randomized controlled trials and quasi-experimental studies were included, targeting diverse health problems in a number of settings. Few studies included organizational-level interventions. When viewed in relation to the methodological quality and the sufficiency of economic evidence, five of 11 cost-effective occupational safety and health (OSH) interventions appear to be promising. The present systematic review highlights the need for high-quality economic evidence to evaluate the cost-effectiveness of OSH interventions, especially at organizational-level, in all areas of worker health.


Loss of Dnmt3b in Chondrocytes Leads to Delayed Endochondral Ossification and Fracture Repair.
Despite advanced understanding of signaling mediated by local and systemic factors, the role of epigenetic factors in the regulation of bone regeneration remains vague. The DNA methyltransferases (Dnmts) Dnmt3a and Dnmt3b have tissue specific expression patterns and create unique methylation signatures to regulate gene expression. Using a stabilized murine tibia fracture model we find that Dnmt3b is induced early in fracture healing, peaks at 10 days post fracture (dpf), and declines to nearly undetectable levels by 28 dpf. Dnmt3b expression was cell-specific and stage-specific. High levels were observed in chondrogenic lineage cells within the fracture callus. To determine the role of Dnmt3b in fracture healing, Agc1CreERT2 ;Dnmt3bf/f (Dnmt3bAgc1ER ) mice were generated to delete Dnmt3b in chondrogenic cells. Dnmt3bAgc1ER fracture displayed chondrogenesis and chondrocyte maturation defect, and a delay in the later events of angiogenesis, ossification, and bone remodeling. Biomechanical studies demonstrated markedly reduced strength in Dnmt3bAgc1ER fractures and confirmed the delay in repair. The angiogenic response was reduced in both vessel number and volume at 10 and 14 dpf in Dnmt3bAgc1ER mice. Immunohistochemistry showed decreased CD31 expression, consistent with the reduced angiogenesis. Finally, in vitro angiogenesis assays with human umbilical vein endothelial cells (HUVECs) revealed that loss of Dnmt3b in chondrocytes significantly reduced tube formation and endothelial migration. To identify specific angiogenic factors involved in the decreased callus vascularization, a protein array was performed using conditioned media isolated from control and Dnmt3b loss-of-function chondrocytes. Several angiogenic factors, including CXCL12 and osteopontin (OPN) were reduced in chondrocytes following loss of Dnmt3b. DNA methylation analysis further identified hypomethylation in Cxcl12 promoter region. Importantly, the defects in tube formation and cell migration could be rescued by administration of CXCL12 and/or OPN. Altogether, our findings establish that Dnmt3b positively regulates chondrocyte maturation process, and its genetic ablation leads to delayed angiogenesis and fracture repair. © 2017 American Society for Bone and Mineral Research.


Damage of staphylococcal cytoplasmic membrane by Quercus infectoria G. Olivier and its components.
In traditional Thai medicine, nutgall of Quercus infectoria G. Olivier is well-documented as an effective agent for wound and skin infections. The present study was aimed to establish modes of action of the ethanol extract of the plant as well as its main constituents to induce anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. The minimal inhibitory concentration (MIC)/minimal bactericidal concentration (MBC) values of ethyl acetate I, ethyl acetate II, 95% ethanol and 30% ethanol fractions against MRSA were 0.06/0.25, 0.13/0.25, 0.25/0.5 and 0.5/1.00 mg ml(-1), respectively. Ellagic acid, gallic acid, syringic acid and tannic acid as major components of Q. infectoria nutgall extract were included in this study. Among these, gallic acid and tannic acid demonstrated good MIC/MBC values at 0.06/0.06 and 0.13/0.25 mg ml(-1), respectively. A lysis experiment demonstrated that the ethanol extract, ethyl acetate fraction I and all of the main components failed to lyse MRSA cells. In contrast, both MRSA and Staph. aureus ATCC 25923 treated with the ethanol extract, ethyl acetate fraction I, gallic acid and tannic acid displayed significant loss of tolerance to low osmotic pressure and high salt concentration. The results documented the effect of different fractions of Q. infectoria and purified compounds on MRSA and Staph. aureus. In addition, the study demonstrated that treatment with Q. infectoria extract and the purified compounds results in hypersensitivity to low and high osmotic pressure. This study provides scientific information to support the traditional uses of the nutgall extract and suggesting its anti-MRSA mechanisms.


Effectiveness of different irrigation systems in the presence of intracanal-separated file.
The aim of this study was to evaluate conventional syringe irrigation and three different irrigant activation techniques' effectiveness for smear layer removal in the absence and presence of intracanal-separated file (SF) fragment. Mandibular anterior teeth (160 total) with single canal were used and each root canal preparation was finished with the ProTaper Universal F1. The samples were randomly divided into eight equal groups with n = 20 in each group. The Protaper Universal F3 file was used to simulate intracanal file separation in four groups. To remove the smear layer, final irrigation for each group was performed with conventional syringe irrigation (CSI), EndoActivator, Vibringe, and passive ultrasonic irrigation (PUI). The roots were divided into two longitudinal parts and evaluated with scanning electron microscopy, and two observers scored smear layers at 1, 2, and 3 mm away from the minor foramen. The data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests (p < .05). PUI significantly removed the smear layer better at all levels than other nonseparated file groups (p < .05). In the presence of intracanal SF, PUI had the most efficiency loss. Sonic techniques and CSI revealed statistically better smear layer removal efficiency than PUI at 3 mm level in the presence of SF (p < .05). The intragroup score analysis at all levels revealed that there were less smear layers at 3 mm than at 1 mm in all SF groups (p < .001). As a conclusion, sonic/ultrasonic methods did not yield better irrigant by-passing than CSI in the presence of intracanal SF.


Recruitment and screening for a randomized trial investigating Roux-en-Y gastric bypass versus intensive medical management for treatment of type 2 diabetes.
Large-scale randomized clinical trials are needed to assess the role of Roux-en-Y gastric bypass (RYGB) in treating patients with type 2 diabetes mellitus (T2DM). Recruitment challenges must be understood. One hundred twenty participants were needed for a prospective randomized controlled trial investigating treatments for hyperglycemia and cardiovascular disease risk factors in patients with T2DM. The trial had two arms-intensive medical management plus a rigorous lifestyle intervention (LS/IMM) versus LS/IMM with RYGB. Medical inclusion criteria included glycosylated hemoglobin (HbA1c) ≥ 8.0 % while under the care of a physician and body mass index (BMI) 30.0-39.9 kg/m(2). Another inclusion criterion was expressed willingness to accept randomization and participate fully. Varied recruitment strategies were employed at four academic hospitals in the USA and Taiwan, including referrals, mass media, direct mail to patients drawn from a practice-based database, and direct mail to commercial mailing lists. Between February 2008 and December 2011, 2,648 candidates were phone-screened and 240 were screened on site; 120 participants were eventually randomized. Impediments included stringent medical inclusion criteria and a lack of equipoise (i.e., strong beliefs or preferences) among patients and their personal community-based physicians. To meet timeline requirements, the upper limit for BMI was increased from 34.9 to 39.9 kg/m(2) and an additional site was added. We successfully recruited 120 participants with poorly controlled T2DM and mild to moderate obesity. Participants had to be willing to accept randomization to either surgical or nonsurgical treatments. Recruitment took 4 years.


[Change of daily life activity after femoral hip fracture in elderly patients].
Hospital mortality after hip fracture in elderly patients has decreased significantly in previous years. However, patients often show reduction of daily life activity. The aim of the following study was to assess clinical and radiological results nine months after operation of hip fracture. A total of 127 patients (mean age 77.2 years) were stabilized by arthroplasty because of femoral neck fractures or by gamma locking nail because of trochanteric fractures. Modified Harris-Hip-Score as well as social situation at time of follow-up compared to pretrauma situation were evaluated. Hospital mortality was 3.2 percent. Follow-up could be performed in 78 patients clinically and radiologically by examination in the hospital. At time of follow-up 19.7 percent of patients had already died independent of the operative procedure. Only 65 percent of patients were able to live at home. Modified Harris-Hip-Score at follow-up was decreased significantly by 16 points compared to the situation before the trauma. The reduction of the score was caused mainly by deterioration of hip function and less by femoral or hip pain. In future the main scope after hip fracture must be an improvement of rehabilitation of elderly patients.


Infliximab is more effective than cyclosporine as a rescue therapy for acute severe ulcerative colitis: a retrospective single-center study.
Acute severe ulcerative colitis (ASUC) is a potentially life-threatening disease, and the best option in cases of steroid-refractory disease is still debated. We compared the early- and long-term efficacy and safety of the 2 available "rescue therapies", infliximab (IFX) and cyclosporine (CYS), in this setting. We retrospectively evaluated patients admitted for ASUC and treated with "rescue therapy". The primary endpoint was early colectomy-free survival (30 days) and colectomy-free survival until the end of follow up. The secondary endpoints were predictors of colectomy and long-term maintenance of the treatment strategy over time. Of 129 patients admitted, 68 received rescue therapy (47 with IFX), whereas 7 underwent early colectomy (10.3%). At 30 days, fewer patients treated with IFX showed a need for colectomy (8.5% vs. 14.3%) compared to those in the CYS group, though the difference was non-significant (odds ratio [OR] 0.69, 95% confidence interval [CI] 0.10-4.69; P=0.47). No severe side effects due to IFX and CYS were observed. During a mean follow up of 40 months, 23 additional patients (37.7%) underwent colectomy, and the rate was significantly lower in the IFX group (25.6%) than in the CYS group (66.7%) (hazard ratio 0.25, 95%CI 0.10-0.61; P=0.003). Colectomy-free survival was significantly higher in the IFX group than in the CYS group (P=0.018) at 12 months. In our setting, the early outcomes of IFX and CYS for ASUC were comparable. IFX was associated with significantly lower colectomy rates during the observation period and had a similar safety profile to CYS.


Multifaceted Characterization And In Vitro Assessment Of Polyurethane-Based Electrospun Fibrous Composite For Bone Tissue Engineering.
Recently several new approaches were emerging in bone tissue engineering to develop a substitute for remodelling the damaged tissue. In order to resemble the native extracellular matrix (ECM) of the human tissue, the bone scaffolds must possess necessary requirements like large surface area, interconnected pores and sufficient mechanical strength. A novel bone scaffold has been developed using polyurethane (PE) added with wintergreen (WG) and titanium dioxide (TiO2). The developed nanocomposites were characterized through field emission scanning electron microscopy (FESEM), Fourier transform and infrared spectroscopy (FTIR), X-ray diffraction (XRD), contact angle measurement, thermogravimetric analysis (TGA), atomic force microscopy (AFM) and tensile testing. Furthermore, anticoagulant assays, cell viability analysis and calcium deposition were used to investigate the biological properties of the prepared hybrid nanocomposites. FESEM depicted the reduced fibre diameter for the electrospun PE/WG and PE/WG/TiO2 than the pristine PE. The addition of WG and TiO2 resulted in the alteration in peak intensity of PE as revealed in the FTIR. Wettability measurements showed the PE/WG showed decreased wettability and the PE/WG/TiO2 exhibited improved wettability than the pristine PE. TGA measurements showed the improved thermal behaviour for the PE with the addition of WG and TiO2. Surface analysis indicated that the composite has a smoother surface rather than the pristine PE. Further, the incorporation of WG and TiO2 improved the anticoagulant nature of the pristine PE. In vitro cytotoxicity assay has been performed using fibroblast cells which revealed that the electrospun composites showed good cell attachment and proliferation after 5 days. Moreover, the bone apatite formation study revealed the enhanced deposition of calcium content in the fabricated composites than the pristine PE. Fabricated nanocomposites rendered improved physico-chemical properties, biocompatibility and calcium deposition which are conducive for bone tissue engineering.


miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model.
Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on the progression/manifestation of depression and other co-morbid neuropsychiatric disorders. However, non-coding RNAs, another layer of epigenetic regulation is relatively less studied in depression. Here, using the chronic social defeat stress (CSDS)-induced depression model, we hypothesized dysregulation in miRNA-mRNA networks in the neurogenic dentate gyrus (DG) region of male C57BL/6 mice. Among several dysregulated miRNAs identified via miRNA arrays, the most striking finding was the downregulation of miRNAs of the miR-30 family in stressed/defeated mice. To investigate miRNAs in the DG-resident neural stem/progenitor cells (NSCs/NPCs), we used the in vitro neurosphere culture, where proliferating NSCs/NPCs were subjected to differentiation. Among several differentially expressed miRNAs, we observed an upregulation of miR-30 family miRNAs upon differentiation. To search for the gene targets of these miRNAs, we performed gene arrays followed by bioinformatics analysis, miRNA manipulations and luciferase assays. Our results suggest that miR-30 family miRNAs mediate chronic stress-induced depression-like phenotype by altering hippocampal neurogenesis and neuroplasticity via controlling the epigenetic and transcription regulators such as Mll3 and Runx1; and cell signaling regulators like Socs3, Ppp3r1, Gpr125, and Nrp1.


Dendritic cell maturation and survival are differentially regulated by TNFR1 and TNFR2.
The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNFR, TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c(+) DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86, and HLA-DR) as well as enhanced T cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death, indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NF-κB signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65, activation. Accordingly, the p65 NF-κB pathway only played a role in the prosurvival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-xL pathway. Taken together, our data show that TNFR1, but not TNFR2, signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and they demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways.


Identification of superfluid phases of 3He in uniformly isotropic 98.2% aerogel.
Superfluid ^{3}He confined to high porosity silica aerogel is the paradigm system for understanding impurity effects in unconventional superconductors. However, a crucial first step has been elusive: exact identification of the microscopic states of the superfluid in the presence of quenched disorder. Using a new class of highly uniform aerogel materials, we report pulsed nuclear magnetic resonance experiments that demonstrate definitively that the two observed superfluid states in aerogel are impure versions of the isotropic and axial p-wave states. The theoretically predicted destruction of long-range orbital order (Larkin-Imry-Ma effect) in the impure axial state is not observed.


Modeling Multi-View Dependence in Bayesian Networks for Alzheimer's Disease Detection.
Early detection of Alzheimer's disease is important for deploying interventions to prevent or slow disease progression. We propose a multi-view dependence modeling framework that integrates multiple data sources to distinguish patients at different stages of the disease. We design interpretable models that can handle heterogeneous data types including neuro-images, bio- and clinical markers, and historical and genotypical characteristics of the subjects. We learn the dependence structure from data with guidance from domain knowledge in Bayesian Networks, visualizing and quantifying the conditional probabilistic dependence among the variables. Our results indicate that the hybrid dependence models also improve prediction performance.


Maternally derived hormones, neurosteroids and the development of behaviour.
In a wide range of taxa, there is evidence that mothers adaptively shape the development of offspring behaviour by exposing them to steroids. These maternal effects have major implications for fitness because, by shaping early development, they can permanently alter how offspring interact with their environment. However, theory on parent-offspring conflict and recent physiological studies showing that embryos rapidly metabolize maternal steroids have placed doubt on the adaptive significance of these hormone-mediated maternal effects. Reconciling these disparate perspectives requires a mechanistic understanding of the pathways by which maternal steroids can influence neural development. Here, we highlight recent advances in developmental neurobiology and psychiatric pharmacology to show that maternal steroid metabolites can have direct neuro-modulatory effects potentially shaping the development of neural circuitry underlying ecologically relevant behavioural traits. The recognition that maternal steroids can act through a neurosteroid pathway has critical implications for our understanding of the ecology and evolution of steroid-based maternal effects. Overall, compared to the classic view, a neurosteroid mechanism may reduce the evolutionary lability of hormone-mediated maternal effects owing to increased pleiotropic constraints and frequently influence long-term behavioural phenotypes in offspring.


Detection of hyperacute primary intraparenchymal hemorrhage by magnetic resonance imaging.
MRI has become increasingly used in the acute setting to manage patients with stroke. There has been concern that MRI may not be sensitive in the detection of acute intracranial hemorrhage. We assessed whether strongly susceptibility-weighted MRI would be sensitive to intraparenchymal hemorrhage in the first few hours. In the course of our ongoing studies of MRI of acute ischemic stroke in more than 200 patients, 35 patients had MR studies within 6 hours. Six of these patients who presented with acute focal symptoms with definite time of clinical onset (2.5 to 5 hours) were found to have evidence of intraparenchymal hemorrhage. Standard T1- and T2-weighted MR scans were performed. In 5 of the patients, echo-planar imaging and gradient-echo sequences were performed to increase the sensitivity of magnetic susceptibility effects of the pulse sequences. Four of the cases were of putaminal hemorrhage and 2 were lobar hemorrhages. The hemorrhage was most evident as foci of T2* hypointensity (signal loss) and unambiguous on the more susceptibility-weighted sequences, particularly echo-planar gradient-echo images. MRI can detect hemorrhage within 2.5 to 5 hours of onset of clinical symptoms as regions of marked signal loss due to susceptibility effects, whereas conventional MR scans of ischemic stroke may appear normal. These results demonstrate that MR susceptibility sequences may be sensitive to hyperacute hemorrhage and suggest that MR may be an adequate screen for primary intraparenchymal hemorrhage.


Pasa: leveraging population pangenome graph to scaffold prokaryote genome assemblies.
Whole genome sequencing has increasingly become the essential method for studying the genetic mechanisms of antimicrobial resistance and for surveillance of drug-resistant bacterial pathogens. The majority of bacterial genomes sequenced to date have been sequenced with Illumina sequencing technology, owing to its high-throughput, excellent sequence accuracy, and low cost. However, because of the short-read nature of the technology, these assemblies are fragmented into large numbers of contigs, hindering the obtaining of full information of the genome. We develop Pasa, a graph-based algorithm that utilizes the pangenome graph and the assembly graph information to improve scaffolding quality. By leveraging the population information of the bacteria species, Pasa is able to utilize the linkage information of the gene families of the species to resolve the contig graph of the assembly. We show that our method outperforms the current state of the arts in terms of accuracy, and at the same time, is computationally efficient to be applied to a large number of existing draft assemblies.


Molecular detection of eukaryotes in a single human stool sample from Senegal.
Microbial eukaryotes represent an important component of the human gut microbiome, with different beneficial or harmful roles; some species are commensal or mutualistic, whereas others are opportunistic or parasitic. The diversity of eukaryotes inhabiting humans remains relatively unexplored because of either the low abundance of these organisms in human gut or because they have received limited attention from a whole-community perspective. In this study, a single fecal sample from a healthy African male was studied using both culture-dependent methods and extended molecular methods targeting the 18S rRNA and ITS sequences. Our results revealed that very few fungi, including Candida spp., Galactomyces spp., and Trichosporon asahii, could be isolated using culture-based methods. In contrast, a relatively a high number of eukaryotic species could be identified in this fecal sample when culture-independent methods based on various primer sets were used. A total of 27 species from one sample were found among the 977 analyzed clones. The clone libraries were dominated by fungi (716 clones/977, 73.3%), corresponding to 16 different species. In addition, 187 sequences out of 977 (19.2%) corresponded to 9 different species of plants; 59 sequences (6%) belonged to other micro-eukaryotes in the gut, including Entamoeba hartmanni and Blastocystis sp; and only 15 clones/977 (1.5%) were related to human 18S rRNA sequences. Our results revealed a complex eukaryotic community in the volunteer's gut, with fungi being the most abundant species in the stool sample. Larger investigations are needed to assess the generality of these results and to understand their roles in human health and disease.


[Anti-thrombocyte antibodies].
1. There are two possible ways in which platelets may be involved in immune reactions: a) as target cells for antiplatelet antibodies, and b) as receptor cells for circulating antigen-antibody complexes. Since most of the clinical tests used to detect "antiplatelet antibodies" are incapable of discriminating between the two mechanisms, thrombocytopenia in many autoimmune diseases with "antiplatelet antibodies" may well be caused by immune complexes. 2. Immune reactions involving platelets do not always lead to thrombocytopenia. A moderate acceleration of platelet destruction can easily be compensated by increased production: this situation corresponds to a "compensated thrombocytolytic state". Evidence is also presented for immunologically induced functional platelet defects of "immunologic thrombocytopathy.


Psychiatric consultations in a pediatric hospital.
The authors conducted a study of 30 hospitalized children who were referred for psychiatric consultation and 60 hospitalized children who were not. They studied the medical charts of these children and administered a questionnaire including a checklist of behavioral symptoms to their parents. More psychopathology was found in the children referred for consultation, but about 20 percent of the children not referred also showed a high degree of psychopathology. Factors found to be associated with referral for psychiatric consultation were older age, longer hospital stay, many previous hospitalizations, and ambiguous diagnoses.


Depressive state- and disease-related alterations in neural responses to affective and executive challenges in geriatric depression.
Geriatric depression has been associated with a heterogeneous neuropathology. Identifying both depressive state-related and disease-related alterations in brain regions associated with emotion and cognitive function could provide useful diagnostic information in geriatric depression. Twelve late-onset acutely depressed patients, 15 patients fully remitted from major depression, and 20 healthy comparison subjects underwent event-related functional MRI. Brain activation and deactivation associated with executive and emotional processing were investigated using an emotional oddball task in which circles were presented infrequently as attentional targets and sad and neutral pictures as novel distractors. Significant changes in brain activation in patients were found mainly in response to attentional targets rather than to sad distractors. Relative to healthy comparison subjects, the depressed patients had attenuated activation in the regions of the executive system, including the right middle frontal gyrus, the cingulate, and inferior parietal areas. Activity in the middle frontal gyrus revealed depressive state-dependent modulation, whereas attenuated activation in the anterior portion of the posterior cingulate and inferior parietal regions persisted in the remitted subjects, suggesting a disease-related alteration. Enhanced deactivation was observed in the posterior portion of the posterior cingulate, which was also state dependent. The remitted group did not show this deactivation. Our results indicate distinct roles for the right middle frontal gyrus and the anterior and posterior portions of the posterior cingulate cortex in geriatric depression. The deactivation of the posterior portion of the posterior cingulate could be informative for differentiation of cognitive dysfunction related to depression from other conditions, such as mild cognitive impairment.


A comprehensive transcriptomic analysis of alternate interferon signaling pathways in peripheral blood mononuclear cells in rheumatoid arthritis.
Interferon (IFN) signaling pathways play crucial roles in the pathogenesis of rheumatoid arthritis (RA). Prior studies have mainly studied mixed alterations in the IFN signaling pathway in RA, but these studies have not been sufficient to elucidate how imbalanced IFN signaling subtly influences immune cells. Single-cell RNA (scRNA) sequencing makes it possible to better understand the alternations in the interferon signaling pathways in RA. In the present study, we found that IFN signaling pathways were activated in natural killer (NK) cells, monocytes, T cells, B cells, and most immune cell subclasses in RA. We then explored and analyzed the connections between abnormal IFN signaling pathways and cellular functional changes in RA. Single-Cell rEgulatory Network Inference and Clustering (SCENIC) analysis and gene regulatory network (GRN) construction were also performed to identify key transcription factors in RA. Finally, we also investigated altered IFN signaling pathways in multiple RA peripheral blood samples, which indicated that abnormal IFN signaling pathways were universally observed in RA. Our study contributes to a better understanding of the delicate and precise regulation of IFN signaling in the immune system in RA. Furthermore, common alternations in IFN signaling pathway-related transcription factors could help to identify novel therapeutic targets for RA treatment.


ASCL1 regulates the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus.
Tobacco contains a variety of carcinogens as well as the addictive compound nicotine. Nicotine addiction begins with the binding of nicotine to its cognate receptor, the nicotinic acetylcholine receptor (nAChR). Genome-wide association studies have implicated the nAChR gene cluster, CHRNA5/A3/B4, in nicotine addiction and lung cancer susceptibility. To further delineate the role of this gene cluster in lung cancer, we examined the expression levels of these three genes as well as other members of the nAChR gene family in lung cancer cell lines and patient samples using quantitative reverse transcription-PCR. Overexpression of the clustered nAChR genes was observed in small-cell lung carcinoma (SCLC), an aggressive form of lung cancer highly associated with cigarette smoking. The overexpression of the genomically clustered genes in SCLC suggests their coordinate regulation. In silico analysis of the promoter regions of these genes revealed putative binding sites in all three promoters for achaete-scute complex homolog 1 (ASCL1), a transcription factor implicated in the pathogenesis of SCLC, raising the possibility that this factor may regulate the expression of the clustered nAChR genes. Consistent with this idea, knockdown of ASCL1 in SCLC, but not in non-SCLC, led to a significant decrease in expression of the alpha 3 and beta 4 genes without having an effect on any other highly expressed nAChR gene. Our data indicate a specific role for ASCL1 in regulating the expression of the CHRNA5/A3/B4 lung cancer susceptibility locus. This regulation may contribute to the predicted role that ASCL1 plays in SCLC tumorigenesis.


Recommandations francophones pour la pratique clinique concernant la prise en charge des cancers du sein de Saint-Paul-de-Vence 2022-2023.
With more than 60,000 new cases of breast cancer in mainland France in 2023 and 8% of all cancer deaths, breast cancer is the leading cancer in women in terms of incidence and mortality. While the number of new cases has almost doubled in 30 years, the percentage of patients at all stages alive at 5 years (87%) and 10 years (76%) testifies to the major progress made in terms of screening, characterisation and treatment. However, this progress, rapid as it is, needs to be evaluated and integrated into an overall strategy, taking into account the characteristics of the disease (stage and biology), as well as those of the patients being treated. These are the objectives of the St Paul-de-Vence recommendations for clinical practice. We report here the summary of the votes, discussions and conclusions of the Saint-Paul-de-Vence 2022-2023 RPCs.


Design and Experimental Investigation of a Compact Circularly Polarized Integrated Filtering Antenna for Wearable Biotelemetric Devices.
A compact circularly polarized (CP) integrated filtering antenna is reported for wearable biotelemetric devices in the 2.4 GHz ISM band. The design is based on a mutual synthesis of a CP patch antenna connected to a bandpass filter composed of coupled stripline open-loop resonators, which provides an integrated low-profile radiating and filtering module with a compact form factor of 0.44λ(0)×0.44λ(0)×0.04λ(0). The optimized filtering antenna is fabricated and measured, achieving an S11 < -14 dB, an axial ratio of less than 3 dB and gain higher than 3.5 dBi in the targeted ISM band. With the integrated filtering functionality, the antenna exhibits good out-of-band rejection over an ultra-wide frequency range of 1-6 GHz. Further full-wave simulations and experiments were carried out, verifying that the proposed filtering antenna maintains these desirable properties even when mounted in close proximity to the human body at different positions. The stable impedance performance and the simultaneous wide axial ratio and radiated power beam widths make it an ideal candidate as a wearable antenna for off-body communications. The additional integrated filtering functionality further improves utility by greatly reducing interference and crosstalk with other existing wireless systems.


The distribution and possible role of ERK8 in mouse oocyte meiotic maturation and early embryo cleavage.
It is well known that extracellular signal-regulated kinase 8 (ERK8) plays pivotal roles in various mitotic events. But its physiological roles in oocyte meiotic maturation remain unclear. In this study, we found that although no specific ERK8 signal was detected in oocyte at the germinal vesicle stage, ERK8 began to migrate to the periphery of chromosomes shortly after germinal vesicle breakdown. At prometaphase I, metaphase I (MI), anaphase I, telophase I, and metaphase II (MII) stages, ERK8 was stably detected at the spindles. By taxol treatment, we clarified that the ERK8 signal was stained on the spindle fibers as well as microtubule asters in MI and MII oocytes. In fertilized eggs, the ERK8 signal was not observed in the two pronuclei stages. At prometaphase, metaphase, and anaphase of the first mitosis, ERK8 was detected on the mitotic spindle. ERK8 knock down by antibody microinjection and specific siRNA caused abnormal spindles, failed chromosome congression, and decreased first polar body extrusion. Taken together, our results suggest that ERK8 plays an important role in spindle organization during mouse oocyte meiotic maturation and early embryo cleavage.


Does lesion size affect the outcome in avascular necrosis?
The size of the necrotic lesion may be a significant factor in predicting outcome and determining treatment in hips with avascular necrosis. However, to date most reports on the treatment of this condition have not attempted to correlate outcome with lesion size. Seventy-three hips with avascular necrosis were evaluated, 11 in Stage I and 62 in Stage II. All were treated with core decompression and bone grafting. Patients were followed up 2 to 6 years (mean, 39 months). The results were determined by change in Harris hip score, degree of radiographic progression, and the need for total hip replacement. Outcome was correlated with the lesion size, stage, etiology, and other factors. In Stage I, the true three-dimensional size of the lesion was measured with a new technique of quantitative magnetic resonance imaging. In Stage II, measurements were obtained from radiographs using a modular system for quantitative digital analysis. Hips were divided into three groups based on lesion size: Group A, less than 15% of femoral head involvement; Group B, 15% to 30%; and Group C, greater than 30%. There were no significant differences in outcome between Stages I and II and no relationship to etiology or other demographic factors. When correlated with lesion size, radiographs on a 21-point scale showed progression by 1.1, 4.2, and 4.3 points; the Harris hip score showed an improvement of 10.6 and 3.3 points and a loss of 3.6 points; and total hip replacement was required in 7%, 31%, and 33% of Group A, B, and C lesions, respectively. The difference in outcome between small lesions and large or medium lesions was statistically significant, but no significant differences were seen between medium and large lesions. These observations emphasize the importance of lesion size in predicting outcome after core decompression and grafting and possibly after other surgical and nonsurgical methods of managing hips with avascular necrosis. They also encourage the use of methods of evaluation and staging that include a determination of lesion size and stage.


Mental health of healthcare workers during the first year of the COVID-19 pandemic in the Netherlands: a longitudinal study.
In March 2020, the WHO declared COVID-19 a pandemic. Previous virus outbreaks, such as the SARS outbreak in 2003, appeared to have a great impact on the mental health of healthcare workers. The aim of this study is to examine to what extent mental health of healthcare workers differed from non-healthcare workers during the first year of the COVID-19 pandemic. We used data from a large-scale longitudinal online survey conducted by the Corona Behavioral Unit in the Netherlands. Eleven measurement rounds were analyzed, from April 2020 to March 2021 (N = 16,615; number of observations = 64,206). Mental health, as measured by the 5-item Mental Health Inventory, was compared between healthcare workers and non-healthcare workers over time, by performing linear GEE-analyses. Mental health scores were higher among healthcare workers compared to non-healthcare workers during the first year of the pandemic (1.29 on a 0-100 scale, 95%-CI = 0.75-1.84). During peak periods of the pandemic, with over 100 hospital admissions or over 25 ICU admissions per day and subsequently more restrictive measures, mental health scores were observed to be lower in both healthcare workers and non-healthcare workers. During the first year of the COVID-19 pandemic, we observed no relevant difference in mental health between healthcare workers and non-healthcare workers in the Netherlands. To be better prepared for another pandemic, future research should investigate which factors hinder and which factors support healthcare workers to maintain a good mental health.


Fatalities following allergen immunotherapy.
Allergen immunotherapy has been in use for nearly 100 yr and has become an important method of reducing allergic symptoms in select patients with allergic rhinitis, asthma, and insect venom hypersensitivity. Unfortunately, immunotherapy has been associated with anaphylaxis and death. Although the relative risk of severe reactions to immunotherapy is low, the number of such reactions has increased since the introduction of standardized and more potent extracts. There are a number of risk factors associated with such severe anaphylactic reactions. Such risk factors include errors in dosage, failure to reduce the dosage after a longer than scheduled interval, administration of the wrong extract, inadvertent intravenous administration, failure to postpone injection because of infection or asthma exacerbation, failure to observe patients for appropriate length of time, failure to adhere to guidelines for established contraindications, concurrent use of beta-adrenergic blocking agents, uses of mixtures of allergens, immunotherapy during the active allergy season, and types of allergens. In this review, we focus on these and other risk factors in attempts to reduce the risk of anaphylaxis following allergen immunotherapy.


Acute urinary retention and the incarcerated, retroverted, gravid uterus. A case report.
A case of urinary retention was associated with an incarcerated, retroverted, gravid uterus. In a literature review of the English language we encountered 26 similar cases. Although no series of cases has allowed evaluation of a specific protocol for evaluation and management or analysis of outcomes, a review of the literature does outline certain diagnostic tests and treatment modalities that may be useful when one is faced with this uncommon condition.


Egg-laying hormone, serotonin, and cyclic nucleotide modulation of ionic currents in the identified motoneuron B16 of Aplysia.
We have used the 2-electrode voltage-clamp technique to analyze the effects of the neuropeptide, egg-laying hormone (ELH), and the biogenic amine 5-HT on ionic currents in the buccal motoneuron B16 of Aplysia. When B16 is voltage-clamped near resting membrane potential, bath-applied ELH induces a prolonged inward shift in holding current. The ELH-induced inward current is not due to a decrease in the transient, the delayed, or the calcium-activated potassium currents. Current-voltage measurements, along with ion substitution and channel-blocking experiments, indicate that ELH primarily induces or increases a voltage-dependent slow inward current carried by sodium. Serotonin also causes a prolonged inward shift in holding current in B16. Like ELH, 5-HT induces or enhances the voltage-dependent inward current carried by sodium. In addition, 5-HT increases an inwardly rectifying potassium current, and, in some preparations, decreases an outward current that is activated when the cell is depolarized to -40 mV and above. None of the currents modulated by ELH or by 5-HT are affected by 200 microM ouabain or by reducing extracellular chloride concentration. Extracellular application of isobutylmethylxanthine (IBMX), forskolin, 8-bromo-cAMP and 8-bromo-cGMP, and intracellular injection of cAMP elicits the slow inward current carried by sodium. The inward current response to ELH is blocked by prior application of 8-bromo-cAMP, while, under these conditions, 5-HT continues to elicit the increase in inward-rectifier potassium current, but decreases the slow inward sodium current. Serotonin also reduces the slow inward sodium current when applied after ELH. These results suggest that the modulation of B16 by ELH may be mediated entirely by either cAMP or cGMP, while at least a portion of the response to 5-HT may involve an unidentified second messenger in addition to cyclic nucleotides.


Amino acid auxotrophies in human gut bacteria are linked to higher microbiome diversity and long-term stability.
Amino acid auxotrophies are prevalent among bacteria. They can govern ecological dynamics in microbial communities and indicate metabolic cross-feeding interactions among coexisting genotypes. Despite the ecological importance of auxotrophies, their distribution and impact on the diversity and function of the human gut microbiome remain poorly understood. This study performed the first systematic analysis of the distribution of amino acid auxotrophies in the human gut microbiome using a combined metabolomic, metagenomic, and metabolic modeling approach. Results showed that amino acid auxotrophies are ubiquitous in the colon microbiome, with tryptophan auxotrophy being the most common. Auxotrophy frequencies were higher for those amino acids that are also essential to the human host. Moreover, a higher overall abundance of auxotrophies was associated with greater microbiome diversity and stability, and the distribution of auxotrophs was found to be related to the human host's metabolome, including trimethylamine oxide, small aromatic acids, and secondary bile acids. Thus, our results suggest that amino acid auxotrophies are important factors contributing to microbiome ecology and host-microbiome metabolic interactions.


Analysis of progress curves for a highly concentrated Michaelian enzyme in the presence or absence of product inhibition.
Methods are given for analysing the time course of an enzyme-catalysed reaction when the concentration of the enzyme itself is high, a situation which is often found in vivo. (1) The integrated form of the kinetic equation for a concentrated Michaelian enzyme in absence of product inhibition is given. Parameters are shown to be calculated easily using non-linear fitting procedures. (2) A general algorithm to analyse progress-curve data in more complex cases (i.e. when the analytical form of the integrated rate equation is not known or is exceedingly complex) is proposed. This algorithm may be used for any enzyme mechanism for which the differential form of the kinetic equation may be written analytically. We show that the method allows differentiation between the main types of product inhibition which may occur in the case of a highly concentrated Michaelian enzyme.


LocoBox: Modular Hardware and Open-Source Software for Circadian Entrainment and Behavioral Monitoring in Home Cages.
Day-night locomotor activities are the most readily observed outputs of the circadian (~24-h period) clock in many animals. Temporal patterns of the light-dark schedule serve as input to the clock. While circadian activity patterns under various lighting conditions have been observed and documented, the full extent of circadian locomotor activities by genotype and entrainment remains uncharacterized. To facilitate large-scale, parallel cataloging of circadian input-output patterns, we created the LocoBox, an easy-to-construct and easy-to-operate system that can control environmental light with flexible entrainment scenarios combined with the T-cycle and measure locomotor activities in individual home cages. The LocoBox is made using economical, common components, and normal breeding cages can be used for long-term recording. We provide details of the components and blueprints, along with software programs for Arduino and a Python-based graphical user interface (GUI), so that the system can be easily replicated in other laboratories.


[Bacteraemia due to Leuconostoc spp. in a patient without immunological disorders].
Leuconostoc spp are gram-positive coccobacilli, catalase and oxidase negative, vancomycin resistant. Causes of infection have been reported previously but it has not been described confirmed bacteremia due to Leuconostoc spp in patient without other immunological disorders. We describe a case of bacteremia in a 64-years-old man with a prosthetic valve 7 months before to begin fever of unknown origin. We confirmed bacteremia due Leuconostoc spp and the treatment with respective antibiotics permits the cure. Leuconostoc spp should be considered as a potential cause of bacteraemia, but we would be observant to the bacteremias due vancomycin resistant germs, because in most cases the laboratory do not find the sensitivity to this antibiotic.


Diarrheal bacterial pathogens and multi-resistant enterobacteria in the Choqueyapu River in La Paz, Bolivia.
Water borne diarrheal pathogens might accumulate in river water and cause contamination of drinking and irrigation water. The La Paz River basin, including the Choqueyapu River, flows through La Paz city in Bolivia where it is receiving sewage, and residues from inhabitants, hospitals, and industry. Using quantitative real-time PCR (qPCR), we determined the quantity and occurrence of diarrheagenic Escherichia coli (DEC), Salmonella enterica, Klebsiella pneumoniae, Shigella spp. and total enterobacteria in river water, downstream agricultural soil, and irrigated crops, during one year of sampling. The most abundant and frequently detected genes were gapA and eltB, indicating presence of enterobacteria and enterotoxigenic E. coli (ETEC) carrying the heat labile toxin, respectively. Pathogen levels in the samples were significantly positively associated with high water conductivity and low water temperature. In addition, a set of bacterial isolates from water, soil and crops were analyzed by PCR for presence of the genes blaCTX-M, blaKPC, blaNDM, blaVIM and blaOXA-48. Four isolates were found to be positive for blaCTX-M genes and whole genome sequencing identified them as E. coli and one Enterobacter cloacae. The E. coli isolates belonged to the emerging, globally disseminated, multi-resistant E. coli lineages ST648, ST410 and ST162. The results indicate not only a high potential risk of transmission of diarrheal diseases by the consumption of contaminated water and vegetables but also the possibility of antibiotic resistance transfer from the environment to the community.


Adsorption of hydrogen sulphide from aqueous solutions using modified nano/micro fibrillated cellulose.
In the present study, microfibrillated cellulose (MFC) was modified by aminopropyltriethoxysilane (APS), hydroxy-carbonated apatite (HAP), or epoxy in order to produce novel nanostructured adsorbents for the removal of hydrogen sulphide (H2S) from the aqueous solutions. Structural properties of the modified MFC materials were examined using a scanning electron microscope, Fourier transform infrared spectroscopy and acid/base titration. These methods were used to verify the presence of nanostructures on the adsorbents surfaces as well as functionalities suitable for H2S adsorption. Adsorption of H2S by prepared adsorbents was investigated in batch mode under different experimental conditions, i.e., varying pH and H2S concentrations. H2S uptake was found to be 103.95, 13.38 and 12.73 mg/g by APS/MFC, HAP/MFC and epoxy/MFC, respectively from 80 mg/L H2S solution. The equilibrium data were best described by the Langmuir isotherm for HAP/MFC and APS/MFC and the Sips isotherm for epoxy/MFC.


Quality Improvement Feature Series Article 2: Displaying and Analyzing Quality Improvement Data.
In this second article in the quality improvement (QI) methods series, we discuss how data are best displayed and analyzed in QI projects while focusing on some similarities with and differences from traditional clinical research. We demonstrate why displaying data over time on a run or control chart is superior to using pre-post analysis for QI studies. We introduce several types of statistical process control charts for data commonly collected during QI programs and provide guidance on how to use the proper chart. Last, we present solutions to several common data challenges in QI projects.


Incidence of Acute Myocardial Infarction in Patients Presenting With Cerebrovascular Accident in a Tertiary Care Centre in Eastern India.
Acute myocardial infarction in individuals who have had a cerebrovascular accident or transient ischemic attack (CVA-TIA) is a medical emergency, which must be examined and treated as soon as possible. Physicians face a significant problem in managing this scenario because early treatment of one ailment would surely postpone treatment of the other. Early detection and treatment will have an impact on the patient's morbidity and mortality in the future, as well as aid in the patient's rehabilitation. On the basis of ECG alterations and cardiac biomarkers, a prospective observational study was conducted in 103 diagnosed CVA patients to investigate the incidence of myocardial infarction. Infarct and hemorrhagic CVA cases were evenly distributed. According to the age-based distribution, the highest rate of myocardial infarction (8%, 8) was observed in those aged 51-60 years. The male-to-female ratio is 1.86:1. Thirty-two patients had diabetes, among them 75% had only elevated creatine kinase MB (CKMB) with no myocardial infarction (MI), whereas 59 patients had hypertension of which 70% had only elevated CK-MB with no MI. ST-elevation myocardial infarction (STEMI) with high CKMB accounted for 14.78% (15) of the cases, but the majority (71%, 73) of the cases had elevated CKMB with no MI, and the rest presented with normal CKMB. Elevated CKMB with or without STEMI serves as a poor prognosticating factor. Therefore, these patients should be managed on a priority basis for a better outcome.


Gold Half-Shell-Coated Paclitaxel-Loaded PLGA Nanoparticles for the Targeted Chemo-Photothermal Treatment of Cancer.
Conventional cancer therapies suffer from nonspecificity, drug resistance, and a poor bioavailability, which trigger severe side effects. To overcome these disadvantages, in this study, we designed and evaluated the in vitro potential of paclitaxel-loaded, PLGA-gold, half-shell nanoparticles (PTX-PLGA/Au-HS NPs) conjugated with cyclo(Arg-Gly-Asp-Phe-Lys) (cyRGDfk) as a targeted chemo-photothermal therapy system in HeLa and MDA-MB-231 cancer cells. A TEM analysis confirmed the successful gold half-shell structure formation. High-performance liquid chromatography showed an encapsulation efficiency of the paclitaxel inside nanoparticles of more than 90%. In the release study, an initial burst release of about 20% in the first 24 h was observed, followed by a sustained drug release for a period as long as 10 days, reaching values of about 92% and 49% for NPs with and without near infrared laser irradiation. In in vitro cell internalization studies, targeted nanoparticles showed a higher accumulation than nontargeted nanoparticles, possibly through a specific interaction of the cyRGDfk with their homologous receptors, the ανβ3 y ανβ5 integrins on the cell surface. Compared with chemotherapy or photothermal treatment alone, the combined treatment demonstrated a synergistic effect, reducing the cell viability to 23% for the HeLa cells and 31% for the MDA-MB-231 cells. Thus, our results indicate that these multifuncional nanoparticles can be considered to be a promising targeted chemo-photothermal therapy system against cancer.


Extreme particle acceleration in the microquasar Cygnus X-3.
Super-massive black holes in active galaxies can accelerate particles to relativistic energies, producing jets with associated gamma-ray emission. Galactic 'microquasars', which are binary systems consisting of a neutron star or stellar-mass black hole accreting gas from a companion star, also produce relativistic jets, generally together with radio flares. Apart from an isolated event detected in Cygnus X-1, there has hitherto been no systematic evidence for the acceleration of particles to gigaelectronvolt or higher energies in a microquasar, with the consequence that we are as yet unsure about the mechanism of jet energization. Here we report four gamma-ray flares with energies above 100 MeV from the microquasar Cygnus X-3 (an exceptional X-ray binary that sporadically produces radio jets). There is a clear pattern of temporal correlations between the gamma-ray flares and transitional spectral states of the radio-frequency and X-ray emission. Particle acceleration occurred a few days before radio-jet ejections for two of the four flares, meaning that the process of jet formation implies the production of very energetic particles. In Cygnus X-3, particle energies during the flares can be thousands of times higher than during quiescent states.


Genetic dissection of a putative nucleolar localization signal in the coat protein of ourmia melon virus.
Ourmiaviruses became the object of recent attention for their unusual taxonomic placements among plant viruses. The ourmia melon virus (OuMV) RNA3 encodes a 22-kDa coat protein (CP). Besides its role in virion formation, the OuMV CP facilitates systemic virus spread. In Nicotiana benthamiana, an eGFP-CP fusion protein was localized in the nucleus and preferentially in the nucleolus. By bioinformatics analysis, we identified an arginine- and lysine-rich region at the N-terminus of the CP. Here, we demonstrate by deletion and alanine scanning mutagenesis that this region in the CP is responsible for its preferential accumulation in the nucleolus of host cells.


Japan Flavour and Fragrance Materials Association's (JFFMA) safety assessment of food-flavouring substances uniquely used in Japan that belong to the class of aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additional oxygenated functional groups.
We performed a safety evaluation using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) of the following four flavouring substances that belong to the class of 'aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups' and are uniquely used in Japan: butyl butyrylacetate, ethyl 2-hydroxy-4-methylpentanoate, 3-hydroxyhexanoic acid and methyl hydroxyacetate. Although no genotoxicity study data were found in the published literature, none of the four substances had chemical structural alerts predicting genotoxicity. All four substances were categorised as class I by using Cramer's classification. The estimated daily intake of each of the four substances was determined to be 0.007-2.9 μg/person/day by using the maximised survey-derived intake method and based on the annual production data in Japan in 2001, 2005 and 2010, and was determined to be 0.250-600.0 μg/person/day by using the single-portion exposure technique and based on average-use levels in standard portion sizes of flavoured foods. Both of these estimated daily intake ranges were below the threshold of toxicological concern for class I substances, which is 1800 μg/person/day. Although no information from in vitro and in vivo toxicity studies for the four substances was available, these substances were judged to raise no safety concerns at the current levels of intake.


Adenosine and the auditory system.
Adenosine is a signalling molecule that modulates cellular activity in the central nervous system and peripheral organs via four G protein-coupled receptors designated A(1), A(2A), A(2B), and A(3). This review surveys the literature on the role of adenosine in auditory function, particularly cochlear function and its protection from oxidative stress. The specific tissue distribution of adenosine receptors in the mammalian cochlea implicates adenosine signalling in sensory transduction and auditory neurotransmission although functional studies have demonstrated that adenosine stimulates cochlear blood flow, but does not alter the resting and sound-evoked auditory potentials. An interest in a potential otoprotective role for adenosine has recently evolved, fuelled by the capacity of A(1) adenosine receptors to prevent cochlear injury caused by acoustic trauma and ototoxic drugs. The balance between A(1) and A(2A) receptors is conceived as critical for cochlear response to oxidative stress, which is an underlying mechanism of the most common inner ear pathologies (e.g. noise-induced and age-related hearing loss, drug ototoxicity). Enzymes involved in adenosine metabolism, adenosine kinase and adenosine deaminase, are also emerging as attractive targets for controlling oxidative stress in the cochlea. Other possible targets include ectonucleotidases that generate adenosine from extracellular ATP, and nucleoside transporters, which regulate adenosine concentrations on both sides of the plasma membrane. Developments of selective adenosine receptor agonists and antagonists that can cross the blood-cochlea barrier are bolstering efforts to develop therapeutic interventions aimed at ameliorating cochlear injury. Manipulations of the adenosine signalling system thus hold significant promise in the therapeutic management of oxidative stress in the cochlea.


A new approach utilizing real-time qPCR to detect in vitro base excision repair.
DNA lesions in mammalian cells may be induced by reactive oxygen species, alkylation, and ionizing radiation. This damage can then be repaired via the base excision repair (BER) pathway, which includes single strand break repair (SSBR). Thus, the BER (SSBR) pathway plays a critical role in maintaining genomic integrity, and may help us to better understand the mechanisms of aging, tumor formation, and degenerative diseases. AP site (apurinic/apyrimidinic site) or damaged base excision, nucleotide insertion and ligation are included in the BER (SSBR) pathway, which are facilitated by different enzymes at each step. Most previous in vitro BER studies have used modified radiolabeled (32)P oligonucleotide substrates. Which is a very conventional method for in vitro BER assay. However, the use of radioactive isotope material was limited in various laboratories which are unable to handle radioactive hazard. In this study, we developed a novel technique using real-time quantitative PCR (qPCR) to quantify BER activity in in vitro assays. Single strand breaks, DNA ligase activity, and glycosylase activity were detected to establish the feasibility and advantages of this qPCR technique for in vitro BER profiling.


A framework for evaluating and designing citizen science programs for natural resources monitoring.
We present a framework of resource characteristics critical to the design and assessment of citizen science programs that monitor natural resources. To develop the framework we reviewed 52 citizen science programs that monitored a wide range of resources and provided insights into what resource characteristics are most conducive to developing citizen science programs and how resource characteristics may constrain the use or growth of these programs. We focused on 4 types of resource characteristics: biophysical and geographical, management and monitoring, public awareness and knowledge, and social and cultural characteristics. We applied the framework to 2 programs, the Tucson (U.S.A.) Bird Count and the Maui (U.S.A.) Great Whale Count. We found that resource characteristics such as accessibility, diverse institutional involvement in resource management, and social or cultural importance of the resource affected program endurance and success. However, the relative influence of each characteristic was in turn affected by goals of the citizen science programs. Although the goals of public engagement and education sometimes complimented the goal of collecting reliable data, in many cases trade-offs must be made between these 2 goals. Program goals and priorities ultimately dictate the design of citizen science programs, but for a program to endure and successfully meet its goals, program managers must consider the diverse ways that the nature of the resource being monitored influences public participation in monitoring.


Neck pain, concerns of falling and physical performance in community-dwelling Danish citizens over 75 years of age: A cross-sectional study.
The aim of this study was to determine the associations between neck pain, concerns of falling and physical performance in older people. Cross-sectional study of 423 community-dwelling Danes aged 75 years and older. Measures consisted of self-reported neck pain, physical performance (Short Physical Performance Battery), self-reported psychological concerns related to falling (Falls Efficacy Scale International), depression (Major Depression Inventory), cognitive function (Mini Mental State Examination), self-reported low-back pain and self-reported history of falls. Associations between neck pain and fear of falling were determined using multivariable logistic regression modelling. Bothersome neck pain that limits daily activities is significantly associated with concerns of falling (unadjusted odds ratio (OR) 3.29, 95% confidence interval (CI) 1.54-7.03) and impaired physical performance (unadjusted OR 2.26, 95% CI 1.09-4.69). However, these relationships became nonsignificant after adjusting for potential confounders. Bothersome neck pain and concerns of falling is attenuated by depression, and the relationship between bothersome neck pain and decreased physical performance is attenuated by concerns of falling, depression and previous history of falls. Bothersome neck pain in older people is associated with increased concerns of falling and decreased physical performance that are two known risk factors for falls in older people. However, these relationships are complicated by other variables, particularly depression.


Acute type A aortic dissection and left main coronary artery obstruction detected by transesophageal echocardiography.
A 63-year-old man was admitted with severe chest pain. The electrocardiogram demonstrated ST-segment depression in the anterior and lateral leads suggesting acute anterior myocardial ischemia. Contrast-enhanced thoracic computed tomography performed due to severe back pain showed acute dissection of the descending aorta. Coronary angiography showed normal coronary arteries. Transesophageal echocardiography revealed a Stanford type A aortic dissection involving the left main coronary ostium and causing left main coronary occlusion. The dissected flap caused partial obstruction of the coronary ostium and occasional separation of the lumen, resulting in nonsustained ventricular tachycardia. At emergency operation, the entry of the dissection was seen in the ascending aorta and the dissection extended throughout almost the entire sinus of Valsalva and the left main coronary trunk. The aortic flap was seen in the coronary ostium. Both the right and left coronary arteries were prepared widely and sutured directly to a composite graft. The ascending aorta was replaced with a composite graft through a Bentall procedure. Descending aortic repair was planned for a subsequent operation. The patient was hemodynamically stable for three weeks, but then developed respiratory insufficiency due to severe nosocomial pneumonia and died one month after the operation.


EIF2AK2-related Neurodevelopmental Disorder With Leukoencephalopathy, Developmental Delay, and Episodic Neurologic Regression Mimics Pelizaeus-Merzbacher Disease.
To demonstrate that de novo missense single nucleotide variants (SNVs) in EIF2AK2 cause a neurodevelopmental disorder with leukoencephalopathy resembling Pelizaeus-Merzbacher disease (PMD). A retrospective chart review was performed of 2 unrelated males evaluated at a single institution with de novo EIF2AK2 SNVs identified by clinical exome sequencing (ES). Clinical and radiographic data were reviewed and summarized. Both individuals presented in the first year of life with concern for seizures and developmental delay. Common clinical findings included horizontal and/or pendular nystagmus during infancy, axial hypotonia, appendicular hypertonia, spasticity, and episodic neurologic regression with febrile viral illnesses. MRI of the brain demonstrated severely delayed myelination in infancy. A hypomyelinating pattern was confirmed on serial imaging at age 4 years for proband 1. In proband 2, repeat imaging at age 13 months confirmed persistent delayed myelination. These clinical and radiographic features led to a strong suspicion of PMD. However, neither PLP1 copy number variants nor pathogenic SNVs were detected by chromosomal microarray and trio ES, respectively. Reanalysis of trio ES identified heterozygous de novo EIF2AK2 missense variant c.290C>T (p.Ser97Phe) in proband 1 and c.326C>T (p.Ala109Val) in proband 2. The autosomal dominant EIF2AK2-related leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome should be considered in the differential diagnosis for PMD and other hypomyelinating leukodystrophies (HLDs). A characteristic history of developmental regression with febrile illnesses may help distinguish it from other HLDs.


Placebo effects on all-cause mortality of patients with COVID-19 in randomized controlled trials of interleukin 6 antagonists: A systematic review and network meta-analysis.
Many randomized controlled trials (RCTs) have investigated the use of interleukin 6 antagonists for the treatment of coronavirus disease 2019 (COVID-19), yielding inconsistent results. This network meta-analysis (NMA) aimed to identify the source of these inconsistent results by reassessing whether participants treated with standard of care (SoC) plus placebo have different all-cause mortality from those treated with SoC alone and to reevaluate the efficacy of interleukin 6 antagonists in the treatment of COVID-19. We conducted a systematic search for relevant RCTs from the inception of electronic databases through 1 September 2022. The primary outcome was all-cause mortality. The secondary outcomes were the incidences of major medical events, secondary infections, all-cause discontinuation, and serious adverse events. The results of NMA of 33 RCTs showed that patients with COVID-19 treated with SoC plus placebo had lower odds of all-cause mortality than those who received SoC alone (OR, 0.75 [95% confidence interval, 0.58-0.97]). This finding remained consistent after excluding studies with no incident deaths. In addition, when we consider the impact of the widely promoted COVID-19 vaccination and newly developed antiviral treatment strategy, the results from the analysis of the RCT published in 2021 and 2022 remained similar. These findings suggest the potential influence of placebo effects on the treatment outcomes of COVID-19 in RCTs. When evaluating the efficacy of treatment strategies for COVID-19, it is crucial to consider the use of placebo in the design of clinical trials.


Measures of individual differences in taste and creaminess perception.
Previous reports that the sensitivity to the bitter tasting substance 6-n-propylthiouracil (PROP) is related to the sensitivity to other tastes, to chemical irritants, and to fats and oils have led to adoption of PROP as a measure of general oral sensitivity and as a predictor of dietary habits that could impact health. The results, however, have not been consistent. It was recently discovered that the ability to perceive "thermal taste" (i.e., sweetness from thermal stimulation alone) was associated with higher responsiveness to 4 prototypical taste stimuli but not to PROP. This finding implied that individual differences in taste perception are determined in large part by factors other than those related to genetic expression of the PROP receptor. The present study followed up this observation by comparing individual differences in perception of 4 prototypical taste stimuli (sucrose, NaCl, citric acid, and quinine) and PROP under conditions that also enabled assessment of the reliability of individual intensity ratings of taste. Creaminess ratings of 3 milk products that had different fat contents were also collected to investigate further the relationship between taste and oral somatosensory perception. The results showed that intensity ratings across 2 trials were significantly correlated for all 5 taste stimuli and that averaging across replicates led to significant correlations among the 4 prototypical stimuli. In contrast, the bitterness of PROP was correlated only with the bitterness of quinine. None of the taste stimuli, including PROP, was significantly correlated with ratings of creaminess. These results imply 1) that with the exception of PROP, as few as 2 intensity ratings of common taste stimuli can reveal individual differences in overall taste perception and 2) that any relationship between taste and oral sensation is too weak to be detected under the same conditions. Accordingly, the results support other evidence that the genetic factors which determine the ability to perceive PROP do not play a major role in overall taste and oral somatosensory perception.