Mapping the cause-specific premature mortality reveals large between-districts disparity in Belgium, 2003-2009.
Reducing premature mortality is a crucial public health objective. The goal of this paper, beside updating previous mortality atlases with recent data, is to explore the relative between-districts disparity using a relative-scale map design. Causes of deaths and population data were provided by Statistics Belgium. All deaths occurring in the periods 1993-1999 and 2003-2009, in people aged 1-74 residing in Belgium were included. Age-adjusted rates by cause of death were computed for both periods; the 2003-2009 rates were classified using a relative scale with a 10% change between each level and represented on chloropleths maps with a green-to-red divergent colour scheme centred on the national mean. This particular design allows the comparability across all the maps since a same meaning is given to a specific colour. The variation coefficient and the decile ratio were calculated and compared between the 2 periods. A clear-cut regional divide at the disadvantage of Wallonia, and to some extent, of Brussels, was seen for all-cause, cardiovascular, cerebrovascular, diabetes, alcohol-related, mental and neurological diseases and non-transport accidents premature mortality. A NE-SW pattern parallel to the French border was observed for Lip, Oral Cavity, Pharynx, Larynx and oesophageal cancers, while various patterns are observed for the other cancers. The highest rates of road accident mortality are observed in the Southern districts. Many of those patterns are in continuity with earlier observations. However, the pattern of diabetes and mental and neurological diseases are new features. The variation coefficient and the decile ratios increased by 10% between the 1993-1997 and 2003-2009 periods. The use of a relative scale in the maps highlights the importance of the between-districts disparity in premature mortality, with for most causes, a clear-cut regional divide at the disadvantage of Wallonia; this health gap results of complex interactions between various factors, including the socioeconomic context, cultural habits and environmental influences, as well as public health policies. It should be considered as a warning signal, warranting the attention of the policy makers. Meanwhile, these results also highlight the potential for improvement in the more disadvantaged regions.


'Locus of control', health-related quality of life, emotional distress and disability in Parkinson's disease.
This cross-sectional study evaluated locus of control and its subscales in Parkinson's disease. A total of 50 consecutive Parkinson's disease participants and 50 healthy volunteers (control group) were enrolled. External locus of control was significantly higher in Parkinson's disease participants, whereas internal locus of control had no significant differences. External locus of control and internal locus of control were correlated in control group, but not in Parkinson's disease. In Parkinson's disease participants, external locus of control was negatively associated with health-related quality of life as well as positively associated with emotional distress and disease severity (but not with disability). After adjusting to confound variables, the associations remained. On the other hand, internal locus of control was negatively associated with depression.


Comment on "Effect of short-term fluctuations in outdoor air pollution on the number of hospital admissions due to acute myocardial infarction among inhabitants of Kraków, Poland".


Therapeutic disasters that hastened safety testing of new drugs.
New drugs were not required to undergo premarket safety testing in the United States until 1938, when a therapeutic disaster-the Elixir Sulfanilamide tragedy-prompted Congress to pass a bill mandating this now-routine process. History repeated itself nearly 25 years later, when another therapeutic disaster-the thalidomide tragedy-led to passage of new amendments in 1962 to ensure drug efficacy and greater drug safety. As is typical with historical events, critical information was gained that led to novel approaches for understanding, predicting, diagnosing, and managing drug-induced toxicities. Continued refinement of current, along with development of new, approaches will mitigate future drug-related catastrophes, with the goal of avoiding them entirely.


Intrauterine growth retardation associated with hypoxia due to bronchiectasis.
Two pregnancies in a young patient who had undergone lobectomy for bronchiectasis are described. Both were complicated by intrauterine growth retardation. The only abnormality detected was maternal hypoxaemia, and this was assumed to be causal.


Refinement of the Citrus tristeza virus resistance gene (Ctv) positional map in Poncirus trifoliata and generation of transgenic grapefruit (Citrus paradisi) plant lines with candidate resistance genes in this region.
Citrus tristeza virus (CTV) is a major pathogen of Citrus. A single dominant gene Ctv present in the trifoliate relative of Citrus, Poncirus trifoliata confers broad spectrum resistance against CTV. Refinement of genetic maps has delimited this gene to a 121 kb region, comprising of ten candidate Ctv resistance genes. The ten candidate genes were individually cloned in Agrobacterium based binary vector and transformed into three CTV susceptible grapefruit varieties. Two of the candidate R-genes, R-2 and R-3 are exclusively expressed in transgenic plants and in Poncirus trifoliata, while five other genes are also expressed in non-transformed Citrus controls. Northern blotting with a CTV derived probe for assessment of infection in virus inoculated plants over a span of three growth periods, each comprising of six to eight weeks, indicates either an absence of initiation of infection or it's slow spread in R-2 plant lines or an initial appearance of infection and it's subsequent obliteration in some R-1 and R-4 plant lines. Limited genome walk up- and downstream form R-1 gene, based on it's 100% sequence identity between Poncirus and Citrus, indicates promoter identity of 92% between the two varieties. Further upstream and downstream sequencing indicates the presence of an O-methyl transferase and a Copia like gene respectively in Citrus instead of the amino acid transporter like gene upstream and a sugar transporter like gene downstream in Poncirus. The possibility of recombinations in the resistance locus of Citrus and the need for consistent monitoring for virus infection and gene expression in the transgenic Citrus trees is discussed.


COVID-19 mortality among selective serotonin reuptake inhibitor users-results from a nationwide cohort.
To examine differences in mortality and/or severe acute respiratory syndrome between selective serotonin reuptake inhibitor- (SSRI) users and non-SSRI users up to 60 days after a positive SARS-CoV-2 real-time reverse transcription PCR test. Retrospective cohort study including all Danish residents above the age of eighteen with a positive SARS-CoV-2 PCR test from 26 February, 2020 to 5 October, 2021. The follow-up period was 60 days. The primary outcome was all-cause mortality, and the secondary outcome was severe acute respiratory syndrome. Exposure of interest was SSRI use. Differences between SSRI users and non-users were examined with Cox regression. Altogether, 286,447 SARS-CoV-2 positive individuals were identified, and 7113 met the criteria for SSRI use. SSRI users had a mean age of 50.4 years, and 34% were males. Non-SSRI users had a mean age of 41.4 years, and 50% were males. Similar vaccination frequency was observed among the two groups. Sertraline was the most commonly used SSRI, followed by citalopram and escitalopram. We found 255 deaths among SSRI users (3.6%) and 2872 deaths among non-SSRI users (1.0%). SSRI use was significantly associated with increased mortality, with a hazard ratio of 1.32 (95% confidence interval, 1.16 -1.50; p 0.015), even when adjusting for age, sex, vaccination status, and comorbidities. We found significantly higher mortality when comparing SSRI users to non-SSRI users within 60 days after a positive SARS-CoV-2 PCR test. Even when considering possible residual confounding, a positive effect of SSRI intake seems highly unlikely. Our study therefore speaks against the hypothesis of repurposing SSRI drugs for COVID-19 treatment.


Biliopleural fistula after penetrating thoracoabdominal injury: A case report.
Biliopleural fistula is a rare complication of thoraco-abdominal injury. Due to its rarity, the experience of any one surgeon is minimal, there is a paucity of literature regarding optimal treatment. This case report can be an addition to the existing reports to guide surgeons in better understanding and management of such cases. A 30 yrs old male patient presented 2 weeks after he sustained gunshot injury over the right posterior chest. He was referred to our hospital because there was bilious chest tube output. Thoracotomy was done and finding was 10 cm right diaphragmatic defect with lacerated liver oozing bile and subcapsular hematoma that herniated into chest. Clotted blood had trapped the lung with pleural peel. Clot evacuation, decortication, biliary leak and liver laceration repair was done. The diaphragmatic defect was then closed. Patient had smooth postoperative course. Patients with BPF after thoracoabdominal injury can present with shortness of breath, bile output through chest tube and pleural effusion. Since bile has corrosive effect on lung with subsequent complications like empyema and bronchobiliary fistula, early diagnosis and treatment are imperative. BPF after thoracoabdominal injury can be effectively managed with thoracotomy, decortication and closure of diaphragmatic defect. Biliopleural fistula is uncommon after penetrating thoraco-abdominal injury and high index of suspicion and early diagnosis are of paramount importance to prevent complication. Surgery is best treatment option to stop biliary leak, close the diaphragmatic defect, manage further injuries in the chest and release trapped lung.


Methods for the detection of reactive oxygen species employed in the identification of plant photosensitizers.
Over the past ten years, alternative methods for the rapid screening of PSs have been developed. In the present work, a study was undertaken to correlate the phototoxicity of plant extracts on either prokaryotic or eukaryotic cells, with the total oxidation status (TOS) as well as with their ability to produce 1O2. Results demonstrated that the extracts containing PSs that were active either on eukaryotic cells or bacteria increased their TOS after illumination, and that there was a certain degree of positive correlation between the extract phototoxic efficacy and TOS levels. The production of 1O2 by the illuminated extracts was indirectly measured by the use of the fluorescence of "singlet oxygen sensor green", which is a method that has proved highly sensitive for such measurement. 1O2 was detectable only upon illumination of the most active extracts. In addition, the oxidation of tryptophan and was employed as a method capable of measuring ROS generated by both type I and II ROS reactions. However, it turned out to be not sensitive enough to detect the species generated by plant extracts. Results demonstrated that the TOS method, initially developed to measure the oxidant status in plasma, can be readily applied to plant extracts. Unlike the method used to detect 1O2, the method employed for the detection of TOS proved to be accurate, since all the extracts that displayed a high phototoxic activity on either prokaryotic or eukaryotic cells, presented high TOS levels after illumination.


The Impact of Patient Self-Monitoring Via Electronic Medication Monitor and Mobile App Plus Remote Clinician Feedback on Adherence to Inhaled Corticosteroids: A Randomized Controlled Trial.
Poor adherence to inhaled corticosteroids (ICSs) and overuse of short-acting beta2-agonists (SABAs) are associated with increased asthma morbidity. To assess whether patient self-monitoring via electronic medication monitoring and smartphone application plus remote clinician feedback influences ICS and SABA use. Adults with uncontrolled asthma and prescribed ICS and SABA were enrolled in this 14-week study. Inhalers were fitted with electronic medication monitoring to track real-time usage. After a 14-day baseline, participants were randomly assigned to the treatment group where they received reminders and feedback on ICS and SABA use via a smartphone application and clinician phone calls, or control group without feedback. Linear mixed models compared the baseline percentage of SABA-free days and ICS adherence to the last 14 study days. Participants (n = 100) had a mean age of 48.5 years, 80% were female, 68% white, and 80% privately insured. The percentage of SABA-free days increased significantly in the treatment group (19%; 95% CI, 12 to 26; P < .01) and nonsignificantly in the control group (6%, 95% CI, -3 to 16; P = .18), representing a 13% (95% CI, 1-26; P = .04) difference. ICS adherence changed minimally in the treatment group (-2%; 95% CI, -7 to 3; P = .40), but decreased significantly (-17%; 95% CI, -26 to -8; P < .01) in the control group, representing a 15% (95% CI, 4 to 25; P < .01) difference. Patient self-monitoring via a digital platform plus remote clinician feedback maintained high baseline ICS adherence and decreased SABA use.


Validity of linear measurements of the jaws using ultralow-dose MDCT and the iterative techniques of ASIR and MBIR.
To assess the comparability of linear measurements of dental implant sites recorded from multidetector computed tomography (MDCT) images obtained using standard-dose filtered backprojection (FBP) technique with those from various ultralow doses combined with FBP, adaptive statistical iterative reconstruction (ASIR), and model-based iterative reconstruction (MBIR) techniques. The results of the study may contribute to MDCT dose optimization for dental implant site imaging. MDCT scans of two cadavers were acquired using a standard reference protocol and four ultralow-dose test protocols (TP). The volume CT dose index of the different dose protocols ranged from a maximum of 30.48-36.71 mGy to a minimum of 0.44-0.53 mGy. All scans were reconstructed using FBP, ASIR-50, ASIR-100, and MBIR, and either a bone or standard reconstruction kernel. Linear measurements were recorded from standardized images of the jaws by two examiners. Intra- and inter-examiner reliability of the measurements were analyzed using Cronbach's alpha and inter-item correlation. Agreement between the measurements obtained with the reference-dose/FBP protocol and each of the test protocols was determined with Bland-Altman plots and linear regression. Statistical significance was set at a P-value of 0.05. No systematic variation was found between the linear measurements obtained with the reference protocol and the other imaging protocols. The only exceptions were TP3/ASIR-50 (bone kernel) and TP4/ASIR-100 (bone and standard kernels). The mean measurement differences between these three protocols and the reference protocol were within ±0.1 mm, with the 95 % confidence interval limits being within the range of ±1.15 mm. A nearly 97.5 % reduction in dose did not significantly affect the height and width measurements of edentulous jaws regardless of the reconstruction algorithm used.


Diagnosis of vocal cord dysfunction/inducible laryngeal obstruction: An International Delphi Consensus Study.
Vocal cord dysfunction/inducible laryngeal obstruction (VCD/ILO) is characterized by breathing difficulties in association with excessive supraglottic or glottic laryngeal narrowing. The condition is common and can occur independently; however, it may also be comorbid with other disorders or mimic them. Presentations span multiple specialties and misdiagnosis or delayed diagnosis is commonplace. Group-consensus methods can efficiently generate internationally accepted diagnostic criteria and descriptions to increase clinical recognition, enhance clinical service availability, and catalyze research. We sought to establish consensus-based diagnostic criteria and methods for VCD/ILO. We performed a modified 2-round Delphi study between December 7, 2021, and March 14, 2022. The study was registered at ANZCTR (Australian New Zealand Clinical Trials Registry; ACTRN12621001520820p). In round 1, experts provided open-ended statements that were categorized, deduplicated, and amended for clarity. These were presented to experts for agreement ranking in round 2, with consensus defined as ≥70% agreement. Both rounds were completed by 47 international experts. In round 1, 1102 qualitative responses were received. Of the 200 statements presented to experts across 2 rounds, 130 (65%) reached consensus. Results were discussed at 2 international subject-specific conferences in June 2022. Experts agreed on a diagnostic definition for VCD/ILO and endorsed the concept of VCD/ILO phenotypes and clinical descriptions. The panel agreed that laryngoscopy with provocation is the gold standard for diagnosis and that ≥50% laryngeal closure on inspiration or Maat grade ≥2 define abnormal laryngeal closure indicative of VCD/ILO. This Delphi study reached consensus on multiple aspects of VCD/ILO diagnosis and can inform clinical practice and facilitate research.


A new vision on the averaging technique for the estimation of non-stationary Brainstem Auditory-Evoked Potentials: application of a metaheuristic method.
The aim of this paper consists in highlighting the use of the averaging technique in some biomedical applications, such as evoked potentials (EP) extraction. We show that this technique, which is generally considered as classical, can be very efficient if the dynamic model of the signal to be estimated is a priori known. Therefore, using an appropriate model and under some specific conditions, one can show that the estimation can be performed efficiently even in case of a very low signal to noise ratio (SNR), which occurs when handling Brainstem Auditory-Evoked Potentials.


Stimulation of Peroxisome Proliferator-Activated Receptor-Gamma (PPARγ) using Pioglitazone Decreases the Survival of Acute Promyelocytic Leukemia Cells through Up-Regulation of PTEN Expression.
The intertwining between cancer pathogenesis and aberrant expression of either oncogenes or tumor suppressor proteins ushered the cancer therapeutic approaches into a limitless road of modern therapies. For the nonce and among the plethora of promising anticancer agents, intense interest has focused on pioglitazone, a first in-class of Thiazolidinedione (TZD) drugs that is currently used to treat patients with diabetes. Intrigued by the overexpression of PPARγ in Acute Promylocytic Leukemia (APL), this study was designed to investigate the effects of pioglitazone in APL-derived NB4 cells. To assess the anti-leukemic effect of pioglitazone on myeloid leukemia cell lines, we used MTT and trypan blue assays. Given the higher expression level of PPARγ in NB4 cells, we then expanded our experiments on this cell line. To ascertain the molecular mechanism action of pioglitazone in APL-derived NB4 cells, we evaluated the expression levels of a large cohort of target genes responsible for the regulation of apoptosis, autophagy and cell proliferation. Afterward, to examine whether there is a correlation between PPARγ and the PI3K signaling pathway, the amount of Akt phosphorylation was evaluated using western blot analysis. Our results showed that pioglitazone exerted its cytotoxic effect in wild-type PTEN-expressing NB4 cells, but not in leukemic K562 cells harboring mutant PTEN; suggesting that probably this member of TZD drugs induced its anti-leukemic effects through a PTEN-mediated manner. Moreover, we found that not only pioglitazone reduced the survival rate of NB4 through the induction of p21-mediated G1 arrest, also elevated the intracellular level of Reactive Oxygen Species (ROS) which was coupled with upregulated FOXO3a. Notably, this study proposed for the first time that the stimulation of autophagy as a result of the compensatory activation of PI3K pathway may act as a plausible mechanism through which the anti-leukemic effect of pioglitazone may be attenuated; suggestive of the application of either PI3K or autophagy inhibitors along with pioglitazone in APL. By suggesting a mechanistic pathway, the results of the present study shed more light on the favorable anti-leukemic effect of pioglitazone and suggest it as a promising drug that should be clinically investigated in APL patients.


A high-efficiency model indicating the role of inhibition in the resilience of neuronal networks to damage resulting from traumatic injury.
Recent investigations of traumatic brain injuries have shown that these injuries can result in conformational changes at the level of individual neurons in the cerebral cortex. Focal axonal swelling is one consequence of such injuries and leads to a variable width along the cell axon. Simulations of the electrical properties of axons impacted in such a way show that this damage may have a nonlinear deleterious effect on spike-encoded signal transmission. The computational cost of these simulations complicates the investigation of the effects of such damage at a network level. We have developed an efficient algorithm that faithfully reproduces the spike train filtering properties seen in physical simulations. We use this algorithm to explore the impact of focal axonal swelling on small networks of integrate and fire neurons. We explore also the effects of architecture modifications to networks impacted in this manner. In all tested networks, our results indicate that the addition of presynaptic inhibitory neurons either increases or leaves unchanged the fidelity, in terms of bandwidth, of the network's processing properties with respect to this damage.


Asymmetric competition between distant taxa: poecilid fishes and water striders.
Competition for water surface prey between fish (Priapichtus annectens: Poeciliidae) and water striders (Potamobates unidentatus: Gerridae) was studied in the laboratory and in pools in a small tropical stream. Laboratory experiments showed that fish depressed activity and foraging success of water striders. Large fish (4-5 cm) had a greater effect than small fish (2-3 cm). The field experiment showed that competition was highly asymmetric. Presence of fish decreased water strider foraging success while the reverse interaction was insignificant. It is suggested that the higher individual foraging success of the fish, harassment of water striders by fish and the use of an exclusive resource, benthic invertebrates, by the fish, contribute to this pattern. Habitat use differed between the two species. Fish used the deeper parts of stream pools and water striders used the shallower parts of the pools. Asymmetric interference and exploitation competition may force water striders to use shallow edge habitats.


P2Y1 purinoreceptors are fundamental to inhibitory motor control of murine colonic excitability and transit.
Activation of enteric inhibitory motor neurons causes inhibitory junctional potentials (IJPs) and muscle relaxation in mammalian gastrointestinal (GI) muscles, including humans. IJPs in many GI muscles are bi-phasic with a fast initial hyperpolarization (fIJP) due to release of a purine neurotransmitter and a slower hyperpolarization component (sIJP) due to release of nitric oxide. We sought to characterize the nature of the post-junctional receptor(s) involved in transducing purinergic neural inputs in the murine colon using mice with genetically deactivated P2ry1. Wild-type mice had characteristic biphasic IJPs and pharmacological dissection confirmed that the fIJP was purinergic and the sIJP was nitrergic. The fIJP was completely absent in P2ry1(−/−) mice and the P2Y1 receptor antagonist MRS2500 had no effect on electrical activity or responses to electrical field stimulation of intrinsic nerves in these mice. Contractile experiments confirmed that purinergic responses were abolished in P2ry1(−/−) mice. Picospritzing of neurotransmitter candidates (ATP and its primary metabolite, ADP) and β-NAD (and its primary metabolite, ADP-ribose, ADPR) caused transient hyperpolarization responses in wild-type colons, but responses to β-NAD and ADPR were completely abolished in P2ry1(−/−) mice. Hyperpolarization and relaxation responses to ATP and ADP were retained in colons of P2ry1(−/−) mice. Video imaging revealed that transit of fecal pellets was significantly delayed in colons from P2ry1(−/−) mice. These data demonstrate the importance of purinergic neurotransmission in regulating colonic motility and confirm pharmacological experiments suggesting that purinergic neurotransmission is mediated via P2Y1 receptors.


Immunohistochemically demonstrated altered expression of cytochrome P-450 molecular forms and epoxide hydrolase in N-ethyl-N-hydroxyethylnitrosamine-induced rat kidney and liver lesions.
A comparison of N-ethyl-N-hydroxyethylnistrosamine (EHEN)-induced preneoplastic and neoplastic lesions in the rat liver and kidney was made with respect to the expression of different drug metabolizing enzymes. Four cytochrome P-450 species (cyt. P-450 UT50, PB3a, MC1 and MC2) and microsomal epoxide hydrolase (mEHb) were investigated along with two glutathione S-transferase species (GST-P and A forms) earlier shown to be elevated in putative preneoplastic lesions in the liver and kidney, respectively. In contrast to the liver lesions, which showed clear decrease in all forms of cyt. P-450s and increase of mEHb, elevated levels of cyt. P-450 PB3a and, to a lesser extent, the other P-450 forms and early elevation to late decrease in mEHb characterized the renal tubular lesions. Thus opposite shift in enzyme phenotype was observed in carcinogen-induced focal lesions of the two organs. Variation in binding levels in the different nephron segments and zones of the liver acinus indicated physiological specialization with regard to the enzymes investigated and suggested that the altered phenotype of preneoplastic populations might be of adaptive significance.


Broadband Photoresponses from Ultraviolet to Near-Infrared (II) Region through Light-induced Pyroelectric Effects in a Hybrid Perovskite.
Broadband photodetection has shown a great promise for diverse applications, while the realization of plateau photoresponse from ultraviolet (UV) to near-infrared (NIR) spectral region is very challenging. Herein, we exploit photoexcited pyroelectric effect in a chiral hybrid perovskite, (N, N-dimethylcyclohexylammonium)PbBr3 (1), serving as a new pathway to drive broadband photoactivities. It is a room-temperature pyroelectric with large polarization of ≈6.4 μC cm-2 and high pyroelectric figure-of-merits (FV =1.0×10-2 cm2 μC-1 and FD =7.1×10-5 Pa-1/2 ). Strikingly, light-induced pyroelectric effect arising from spontaneous polarization is observed in 1, which cover UV (266 nm) to NIR-II (1950 nm) full spectral region. The broadband photoresponses actualized by pyroelectricity break the limit of optical band gap. As the first demonstration of photo-pyroelectricity covering UV-to-NIR spectral region in hybrid perovskites, this work paves a pathway to assemble high-performance smart devices.


A systematic review of frailty assessment tools used in vascular surgery research.
Frailty is common in vascular patients and is recognized for its prognostic value. In the absence of consensus, a multitude of frailty assessment tools exist. This systematic review aimed to quantify the variety in these tools and describe their content and application to inform future research and clinical practice. Multiple cross-disciplinary electronic literature databases were searched from inception to August 2022. Studies describing frailty assessment in a vascular surgical population were eligible. Data extraction to a validated template included patient demographics, tool content, and analysis methods. A secondary systematic search for papers describing the psychometric properties of commonly used frailty tools was then performed. Screening 5358 records identified 111 eligible studies, with an aggregate population of 5,418,236 patients. Forty-three differing frailty assessment tools were identified. One-third of these failed to assess frailty as a multidomain deficit and there was a reliance on assessing function and presence of comorbidity. Substantial methodological variability in data analysis and lack of methodological description was also identified. Published psychometric assessment was available for only 4 of the 10 most commonly used frailty tools. The Clinical Frailty Scale was the most studied and demonstrates good psychometric properties within a surgical population. Substantial heterogeneity in frailty assessment is demonstrated, precluding meaningful comparisons of services and data pooling. A uniform approach to assessment is required to guide future frailty research. Based on the literature, we make the following recommendations: frailty should be considered a continuous construct and the reporting of frailty tools' application needs standardized. In the absence of consensus, the Clinical Frailty Scale is a validated tool with good psychometric properties that demonstrates usefulness in vascular surgery.


Insect defoliation enhances nitrate export from forest ecosystems.
Chronic defoliation by the fall cankerworm, Alsophila pometaria (Harris), accompanied substantial increases in the stream export of nitrate nitrogen (NO3-N) from three mixed hardwood forests in the southern Appalachians. These integrated results clearly demonstrate a measurable effect of insect consumers on ecosystem processes, and provide support for the regulatory importance of insects on a landscape scale.


Direct exfoliation and dispersion of two-dimensional materials in pure water via temperature control.
The high-volume synthesis of two-dimensional (2D) materials in the form of platelets is desirable for various applications. While water is considered an ideal dispersion medium, due to its abundance and low cost, the hydrophobicity of platelet surfaces has prohibited its widespread use. Here we exfoliate 2D materials directly in pure water without using any chemicals or surfactants. In order to exfoliate and disperse the materials in water, we elevate the temperature of the sonication bath, and introduce energy via the dissipation of sonic waves. Storage stability greater than one month is achieved through the maintenance of high temperatures, and through atomic and molecular level simulations, we further discover that good solubility in water is maintained due to the presence of platelet surface charges as a result of edge functionalization or intrinsic polarity. Finally, we demonstrate inkjet printing on hard and flexible substrates as a potential application of water-dispersed 2D materials.


Measurement uncertainty from validation and duplicate analysis results in HPLC analysis of multivitamin preparations and nutrients with different galenic forms.
An approach to calculate the measurement uncertainty in the HPLC analysis of several hydro- and liposoluble vitamins in multivitamin preparations with different galenic composition and properties is described. In the first instance it is examined if duplicate analysis results, obtained with a fully validated analysis method on different lots of an effervescent tablet preparation spread over several points of time, might contribute to calculate the measurement uncertainty of the HPLC method used and if the established uncertainty is acceptable in the assessment of compliance with the legal content limits. Analysis of variance (ANOVA) and precision calculations, based on the ISO 5725-2 norm are applied on the analysis results obtained to estimate precision components, necessary to derive the measurement uncertainty. In the second instance it is demonstrated to which extent the fully validated method of analysis for effervescent tablets is applicable to other galenic forms as e.g. capsules with oily emulsions, tablets, coated tablets, oral solutions, em leader and which specific modifications in the analysis steps are involved. By means of duplicate analysis results, acquired from a large series of real samples over a considerable period of time and classified according to their similarity in content, galenic forms and matrices, estimations of measurement uncertainty calculations are shown.


Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus.
Abnormal angiogenesis plays an important role in pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a newly identified angiogenic factor. To study whether plasma LRG1 may independently predict progression of DKD in individuals with type 2 diabetes mellitus (T2DM). Prospective cohort study in a regional hospital. In total, 1226 T2DM participants were followed for a mean ± standard deviation (SD) of 3.1 ± 0.4 years. Albuminuria progression was defined as elevation in albuminuria level to a higher category. Chronic kidney disease (CKD) progression [rapid estimated glomerular filtration rate (eGFR) decline] was defined as a 40% or greater deterioration in eGFR in 3 years. Both participants with albuminuria progression and those with CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted albuminuria progression above traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio. A 1-SD increment in LRG1 was associated with a 1.26-fold [95% confidence interval (CI), 1.04 to 1.53, P = 0.018] higher adjusted risk for albuminuria progression. The association of LRG1 with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria progression [odds ratio (OR), 1.51; 95% CI, 1.04 to 2.18, P = 0.029 vs OR, 1.09; 95% CI, 0.86 to 1.37, P = 0.486, per 1-SD LRG1 increment]. Also, LRG1 independently predicted CKD progression above traditional risk factors. A 1-SD increment in LRG1 was associated with a 1.48-fold (95% CI, 1.04 to 2.11, P = 0.032) higher adjusted risk for CKD progression. Plasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM.


Super Profile analysis of socioeconomic variations in coronary investigation and revascularisation rates.
To investigate socioeconomic variations in the utilisation of tertiary cardiology services. Cross sectional ecological study, using the Super Profile classification of enumeration districts, and ischaemic heart disease standardised mortality ratios as a proxy for needs. The former Yorkshire Regional Health Authority area in England and its seven constituent district health authority areas. Patients with a primary diagnosis of ischaemic heart disease aged > or = 25 years who underwent investigation by angiography, or treatment by coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), as a primary procedure between April 1992 and March 1994 in an NHS hospital. There is an overall increasing trend in investigation and revascularisation rates from the affluent to the deprived in the region suggesting equity. However, the gradient is slight compared with the corresponding mortality gradient. Age specific analysis shows a more appropriate trend in rates for the under 65s, but a downward trend from affluence to deprivation for the elderly. Much of the regional trend is caused by very high rates in one geographically small but densely populated district that has two tertiary cardiology centres. In other districts, with higher heart disease mortality but much lower procedure rates, there is a decreasing trend from the affluent to the deprived suggesting considerable inequity. This study confirms wide socioeconomic variations in coronary investigation and revascularisation within the former Yorkshire Region, suggesting that in some districts need is not being met and that service utilisation is inequitable. Such inequities are over and above those that result from proximity to tertiary cardiology centres.


Physiological integration among ramets of Lathyrus sylvestris L. : Translocation of assimilates.
Lathyrus sylvestris is a pioneer legume often found in disturbed habitats. Mainly reproduced through vegetative propagation, this clonal species presents a system of ramets that remain connected for several years. The existence of carbon transfer among ramets within a clone has been studied using 14C in situ. Assimilate translocation from primary to secondary ramets was observed in all clones when the primary ramet was exposed to 14CO2. The amount of transfer ranged from trace up to 90% of the total 14C incorporated. However, in only half of the clones there was consistent enrichment of the secondary ramet (5 to 89%) suggesting that interramets transfer of carbon may be facultative. Furthermore, when significant export occurred from the primary ramet, it was always principally towards only one ramet even when the clone included more than one. The transfer of 14C from secondary to primary ramets was shown to be significant only when photosynthesis of the latter was decreased by shading. In this case import of carbon was never more than 60% of the incorporated 14C.No correlation was found between age or size of the ramets and the intensity of transfer. The shading effect let suppose that transfers are mainly driven by carbon limitation due to changing environmental conditions and not to the state of ramet maturity. The adaptative advantage of such facultative physiological integration between ramets of a clone is discussed.


Patient reported quality of life in limb girdle muscular dystrophy.
This study determined the frequency and impact of symptoms on quality of life in patients diagnosed with limb girdle muscular dystrophy (LGMD). Participants with a diagnosis of LGMD in registries based at the Coalition to Cure Calpain-3, the Jain foundation, and the Global FKRP Registry competed a survey to report the frequency and relative impact of themes and symptoms of LGMD. Frequency, mean impact, and population impact scores were calculated, and responses were categorized by age, symptom duration, gender, employment status, use of assistive devices, and LGMD subtypes. 134 participants completed the survey. The most prevalent themes included an inability to do activities (100%), limitation with mobility (99.3%), and lower extremity weakness (97.0%). Themes with the greatest impact were: limitations with mobility, lower extremity weakness, and an inability to do activities. Symptom duration and the use of assistive devices were associated with the presence of multiple themes. Employment was associated with the impact of several themes with no differences in frequency. The prevalence and impact of these themes vary in the LMGD population. The most prevalent and impactful themes were related to weakness, but additional concerns related to emotional challenges should also be considered in clinical and research settings.


Bromodeoxyuridine-induced reversion of transformed characteristics in BHK21 cells: changes at the plasma membrane level.
When BHK21 cells transformed by hamster sarcoma virus are grown in the presence of 5-Bromedeoxyuridine (BUdr), several in vitro properties of the transformed cells such as morphology, adhesiveness, and alignment, revert towards a state close to that of untransformed cells. We have studied plasma membrane changes associated with this phenotypic reversion by several different biochemical methods. Reversion is accompanied by a reappearance of Fibronectin, an increase in a membrane-associated protein of M.W. 100,000 which is increased in transformed cells and a decrease in Con A-agglutinability. On the other hand, several membrane changes associated with malignant transformation namely, the increase in an integral membrane protein M.W. 177,000, the higher rate of hexose uptake, the increase in high molecular weight surface glycopeptides and, to some extent, the increase in the density of intramembranous particles, did not revert under BUdr treatment. Thus, membrane properties of transformed cells may be dissociated into two main groups by BUdr treatment. In addition, the exposure and glycosylation of a growth-regulated membrane protein M.W. 160,000 was highly sensitive to BUdr.


Development of a highly sensitive method for detection of FLT3D835Y.
Acute myeloid leukemia (AML) is a malignant hematological neoplasm of myeloid progenitor cells. Mutations of FLT3 in its tyrosine kinase domain (FLT3-TKD) are found in ~ 8% of patients with AML, with D835Y as the most common substitution. This mutation activates survival signals that drives the disease and is resistant to the first generation FLT3 inhibitors. Development of a highly sensitive method to detect FLT3D835Y is important to direct therapeutic options, predict prognosis, and monitor minimal residual disease in patients with AML. In the present study, we developed a highly sensitive FLT3D835Y detection method by using the restriction fragment nested allele-specific PCR technique. The method consists of three steps: 1) initial amplification of DNA samples with PCR primers surrounding the FLT3D835Y mutation site, 2) digestion of the PCR products with restriction enzyme EcoRV that only cleaves the wild type allele, and 3) detection of FLT3D835Y by allele-specific PCR with nested primers. We were able to detect FLT3D835Y with a sensitivity of 0.001% by using purified plasmid DNAs and blood cell DNAs containing known proportions of FLT3D835Y. We analyzed blood cell DNA samples from 64 patients with AML and found six FLT3D835Y-positive cases, two of which could not be detected by conventional DNA sequencing methods. Importantly, the method was able to detect FLT3D835Y in a sample collected from a relapsed patient while the patient was in complete remission with negative MRD determined by flow cytometry. Therefore, our RFN-AS-PCR detected MRD after treatment that was missed by flow cytometry and Sanger DNA sequencing, by conventional methods. We have developed a simple and highly sensitive method that will allow for detection of FLT3D835Y at a very low level. This method may have major clinical implications for treatment of AML.


Is palatability of a root-hemiparasitic plant influenced by its host species?
Palatability of parasitic plants may be influenced by their host species, because the parasites take up nutrients and secondary compounds from the hosts. If parasitic plants acquired the full spectrum of secondary compounds from their host, one would expect a correlation between host and parasite palatability. We examined the palatability of leaves of the root-hemiparasite Melampyrum arvense grown with different host plants and the palatability of these host plants for two generalist herbivores, the caterpillar of Spodoptera littoralis and the slug Arion lusitanicus. We used 19 species of host plants from 11 families that are known to contain a wide spectrum of anti-herbivore compounds. Growth of M. arvense was strongly influenced by the host species. The palatability of the individual host species for the two herbivores differed strongly. Both A. lusitanicus and S. littoralis discriminated also between hemiparasites grown with different host plants. There was no correlation between the palatability of a host species and that of the parasites grown on that host, i.e., hemiparasites grown on palatable host species were not more palatable than those grown on unpalatable hosts. We suggest an interacting pattern of specific effects of chemical anti-herbivore defences and indirect effects of the hosts on herbivores through effects on growth and tissue quality of the parasites.


Antimicrobial Stewardship in the Emergency Department.
The literature contains robust evidence on the positive impact of antimicrobial stewardship programs (ASP) in the inpatient setting. With national policies shifting toward provisions of quality health care, the impetus to expand ASP services becomes an important strategy for institutions. However data on stewardship initiatives in other settings are less characterized. For organizations with an established ASP team, it is rational to consider expanding these services to the emergency department (ED). The ED serves as an interface between the inpatient and community settings. It is often the first place where patients present for medical care, including for common infections. Challenges inherent to the fast-paced nature of the environment must be recognized for successful ASP implementation in the ED. Based on the current literature, a combination of strategies for initiating ASP services in the ED will be described. Furthermore, common scenarios and management approaches are proposed for respiratory tract, skin and soft tissue, and urinary tract infections. Expansion of ASP services across the health care continuum may improve patient outcomes with a potential associated decrease in health care costs while preventing adverse effects including the development of antibiotic resistance.


Pulmonary infection due to fluoroquinolone-resistant Mycolicibacterium fortuitum: a case report.
Mycolicibacterium fortuitum is a species of the rapidly growing mycobacteria that can cause pulmonary infection. It is susceptible to multiple antibiotics both in vitro and in clinical practice, so that any combination of susceptible drugs is effective. However, we encountered a case of infection due to fluoroquinolone-resistant M. fortuitum. In this study, we report the case and describe the mechanism of resistance. A 65-year-old man with a history of total gastrectomy and immunosuppressant treatment for rheumatoid arthritis developed a recurrence of pulmonary infection caused by M. fortuitum. He was treated with clarithromycin and levofloxacin as a first-line treatment, based on the favorable susceptibility at that time. After recurrence, a high minimum inhibitory concentration to fluoroquinolones was detected. DNA sequencing of the pathogen showed the substitution of serine for tryptophan at residue 83 in the gyrA gene. He was successfully treated with a combination of other antibiotics. This is the first report on the treatment of fluoroquinolone-resistant M. fortuitum and investigation of the mechanism of resistance. We suggest that the susceptibility test remains effective for determining the next line of treatment after a pathogen has acquired resistance, and resistance to fluoroquinolones in M. fortuitum can be attributed to a single change of amino acid.


[Proposal for threshold limit values for organic solvent concentrations in alveolar air].
The n-hexane concentration was determined in upper factory environmental air and in worker alveolar air. The relationship between the hexane alveolar concentration, and the hexane environmental concentration (Ca/Ci) was found to be steady during the 4,5 hours exposure and independent of the alveolar ventilation and hexane environmental concentration. These results suggest the hypothesis that alveolar TLV's can be fixed for hexane and other solvents.


Coronary imaging of cardiac allograft vasculopathy predicts current and future deterioration of left ventricular function in patients with orthotopic heart transplantation.
Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) improve sensitivity of cardiac allograft vasculopathy (CAV) detection compared to invasive coronary angiography (ICA), but their ability to predict clinical events is unknown. We determined whether severe CAV detected with ICA, IVUS, or OCT correlates with graft function. Comparison of specific vessel parameters between IVUS and OCT on 20 patients attending for angiography 12-24 months post-orthotopic heart transplant. Serial left ventricular ejection fraction (EF) was recorded prospectively. Analyzing 55 coronary arteries, OCT and IVUS correlated well for vessel CAV characteristics. A mean intimal thickness (MIT)OCT > .25 mm had a sensitivity of 86.7% and specificity of 74.3% at detecting Stanford grade 4 CAV. Those with angiographically evident CAV had significant reduction in graft EF over 7.3 years follow-up (median ΔEF -2% vs +1.5%, P = .03). Patients with MITOCT > .25 mm in at least one vessel had a lower median EF at time of surveillance (57% vs 62%, P = .014). Two MACEs were noted. Imaging with OCT correlates well with IVUS for CAV detection. Combined angiography and OCT to screen for CAV within 12-24 months of transplant predicts concurrent and future deterioration in graft function.


Estradiol enhances object recognition memory in Swiss female mice by activating hippocampal estrogen receptor α.
In rodents, 17β-estradiol (E2) enhances hippocampal function and improves performance in several memory tasks. Regarding the object recognition paradigm, E2 commonly act as a cognitive enhancer. However, the types of estrogen receptor (ER) involved, as well as the underlying molecular mechanisms are still under investigation. In the present study, we asked whether E2 enhances object recognition memory by activating ERα and/or ERβ in the hippocampus of Swiss female mice. First, we showed that immediately post-training intraperitoneal (i.p.) injection of E2 (0.2 mg/kg) allowed object recognition memory to persist 48 h in ovariectomized (OVX) Swiss female mice. This result indicates that Swiss female mice are sensitive to the promnesic effects of E2 and is in accordance with other studies, which used C57/BL6 female mice. To verify if the activation of hippocampal ERα or ERβ would be sufficient to improve object memory, we used PPT and DPN, which are selective ERα and ERβ agonists, respectively. We found that PPT, but not DPN, improved object memory in Swiss female mice. However, DPN was able to improve memory in C57/BL6 female mice, which is in accordance with other studies. Next, we tested if the E2 effect on improving object memory depends on ER activation in the hippocampus. Thus, we tested if the infusion of intra-hippocampal TPBM and PHTPP, selective antagonists of ERα and ERβ, respectively, would block the memory enhancement effect of E2. Our results showed that TPBM, but not PHTPP, blunted the promnesic effect of E2, strongly suggesting that in Swiss female mice, the ERα and not the ERβ is the receptor involved in the promnesic effect of E2. It was already demonstrated that E2, as well as PPT and DPN, increase the phospho-ERK2 level in the dorsal hippocampus of C57/BL6 mice. Here we observed that PPT increased phospho-ERK1, while DPN decreased phospho-ERK2 in the dorsal hippocampus of Swiss female mice subjected to the object recognition sample phase. Taken together, our results suggest that the type of receptor as well as the molecular mechanism used by E2 to improve object memory may differ in Swiss female mice.


Evaluation of test kits for the determination of aflatoxins in meat products.
A study was conducted to evaluate the performance of 4 different assays for rapidly screening samples of artificially contaminated hams and salami for the presence of aflatoxins (B1+B2+G1+G2) at concentrations ≥5 μg/kg. Test samples were contaminated in the range of 0 - 100μg/kg.At 0 μg/kg level no false positive (all <5 μg/kg) were found for all commodities by the kits tested; all test samples spiked at level >20 μg/kg were found positive by each kit, while most of the errors associated in the assays occurred on samples containing <10μg/kg. For samples either negative or contaminated above 20μg/kg all the methods were suited for use as rapid screening tests.


Peripheral nervous system pathology in relapsing experimental allergic encephalomyelitis.
A recurrent type of primary demyelination was found in the anterior roots and dorsal root ganglia of strain 13 guinea-pigs with relapsing experimental allergic encephalomyelitis. Single nerve fibre studies revealed a predominant nodal--paranodal distribution of the destruction of myelin in these nerves. Damage of the Schwann cell--axolemmal junction was found in the majority of the abnormal nodes of Ranvier. This was accompanied by the formation of supernumerary adaxonal Schwann cell processes which further altered the normal myelinating cell--axon relationship. It is concluded that variations in antigenic composition may play a role in the selective involvement of the anterior roots. The pathogenesis of the observed nodal changes is discussed.


USP26 promotes anaplastic thyroid cancer progression by stabilizing TAZ.
Anaplastic thyroid cancer (ATC) is one of the most lethal and aggressive human malignancies, with no effective treatment currently available. The Hippo tumor suppressor pathway is highly conserved in mammals and plays an important role in carcinogenesis. TAZ is one of major key effectors of the Hippo pathway. However, the mechanism supporting abnormal TAZ expression in ATC remains to be characterized. In the present study, we identified USP26, a DUB enzyme in the ubiquitin-specific proteases family, as a bona fide deubiquitylase of TAZ in ATC. USP26 was shown to interact with, deubiquitylate, and stabilize TAZ in a deubiquitylation activity-dependent manner. USP26 depletion significantly decreased ATC cell proliferation, migration, and invasion. The effects induced by USP26 depletion could be rescued by further TAZ overexpression. Depletion of USP26 decreased the TAZ protein level and the expression of TAZ/TEAD target genes in ATC, including CTGF, ANKRD1, and CYR61. In general, our findings establish a previously undocumented catalytic role for USP26 as a deubiquitinating enzyme of TAZ and provides a possible target for the therapy of ATC.


Cu(I)-catalyzed reductive aldol cyclizations: diastereo- and enantioselective synthesis of beta-hydroxylactones.
[reaction: see text] Copper bisphosphine complexes catalyze the intramolecular reductive aldol reaction of alpha,beta-unsaturated esters with ketones, affording five- and six-membered beta-hydroxylactones in high stereoselectivities. Utilization of chiral nonracemic bisphosphines render the cyclizations enantioselective.


The feasibility of baroreflex sensitivity measurements in heart failure subjects: The role of slow-patterned breathing.
Increased muscle sympathetic nerve activity (MSNA) indicates an adverse outcome in heart failure. Decreased baroreflex modulation of MSNA is a well-known feature of the disease. The determinability of cardiovagal baroreflex sensitivity (BRS) in heart failure is low, however, the determinability of sympathetic BRS is not known. We have assessed the spontaneous, MSNA burst incidence-based baroreflex index (BRSsymp) in 33 stable heart failure patients and in 10 healthy controls using the traditional r ≥ .5 cutoff for acceptable individual diastolic pressure-burst incidence slopes, and also a more stringent r ≥ .7 cutoff. We have also assessed the influence of 6/min breathing. The determinability of BRSsymp in heart failure patients was 64% during spontaneous breathing with r ≥ .5 cutoff, and 39% using the r ≥ .7 cutoff. The determinability of these indices further decreased during 6/min breathing, dropping to 29% with the r ≥ .7 cutoff. In contrast, the determinability of the cardiovagal BRS indices increased significantly with 6/min breathing (from 24% to 66%; p < .001). Patients who still had determinable BRSsymp at the r ≥ .7 cutoff had a significantly lower baseline burst incidence than those with an undeterminable index (70 ± 14 vs. 89 ± 10 burst/100 cycles; p < .002). Neither the 6/min breathing, nor the r ≥ .7 cutoff limit influenced the high availability of BRSsymp in healthy subjects. The determinability of BRSsymp in heart failure patients is limited, especially with the 0.7 limit for correlation. Undeterminable BRSsymp in patients is associated with higher sympathetic activity. 6/min breathing improves the determinability of cardiovagal BRS indices, but not that of BRSsymp.


Auxinic herbicide conjugates with an α-amino acid function: Structural requirements for biological activity on motor cells.
Two Fabaceae exhibiting rapid osmocontractile pulvinar movements were used in this study because this activity is modified by natural auxin and dramatically by 2,4D. A short chain with a carboxylic group being required for auxinic properties, a critical point to analyze is whether the recently synthesized proherbicide ε-(2,4-dichlorophenoxyacetyl)-L-Lys (2-4D-L-Lys) maintains some biological activity despite the increase in length of the chain and the substitution of the carboxyl group by an α-amino acid function. No trace of 2,4D could be detected in the pulvinar tissues treated for 1 h with 2,4D-L-Lys. Complementary approaches (electrophysiology, pH measurements, use of plasma membrane vesicles) suggest that it was less efficient than 2,4D to activate the plasma membrane H+-ATPase (PM-H+-ATPase). However, it modified the various ion-driven reactions of Mimosa pudica and Cassia fasciculata pulvini in a similar way as 2,4D. Additionally, it was much more effective than fusicoccin to inhibit seismonastic movements of M. pudica leaves and, at low concentrations, to promote leaflet opening in dark, indicating that its mode of action is more complex than the only activation of the PM-H+-ATPase. Various substitutions on 2,4D-L-Lys affected its activity in correlation with the molecular descriptor "halogen ratio" of these derivatives. Conjugation with D-Lys also led to a decrease of pulvinar reaction, suggesting that 2,4D-Lys maintains the main signaling properties of 2,4D involved in pulvinar movements providing that the terminal zwitterion is in a suitable orientation. Our data guide future investigations on the effect of 2,4D and 2,4D-L-Lys on the vacuolar pump activity of motor cells.


Pregnancy after corticosteroid administration in premature ovarian failure (polyglandular endocrinopathy syndrome).
A patient with polyglandular failure syndrome first had documented ovarian failure at age 28 years. Fifteen years later after treatment for Addisonian crisis, she resumed menses, conceived, and was delivered of a normal infant. Patients with this syndrome should be identified because they are at risk for other endocrinopathies and because they may have a treatable form of ovarian failure.


SCAR markers and multiplex PCR-based identification of isomorphic species in the Anopheles dirus complex in Southeast Asia.
The Anopheles dirus Peyton & Harrison complex of mosquitoes (Diptera: Culicidae) comprises seven known species, including important malaria vectors in Southeast Asia. Specific identification of each species of the complex, which cannot be distinguished using morphological characters, is crucial for understanding vector ecology and implementing effective control measures. Derived from individual random amplified polymorphic DNA (RAPD) markers, sequence characterized amplified regions (SCAR) were analysed for the design of specific paired-primers. Combination of six SCAR primers resulted in the development of a simple, robust, single multiplex PCR able to identify three important malaria vectors among the four most common species (A, B, C, D) of the complex: species A from several Southeast Asian countries, species B from Perlis, Malaysia, and species C and D from Thailand.


Patterns of protection, infection, and detection: Country-level effectiveness of COVID-19 vaccination in reducing mortality worldwide.
The relationship between COVID-19 vaccination and mortality has been established through clinical trials and other investigations at the individual level. In this study, we aimed to investigate the negative relationship between mortality and COVID-19 vaccination at country level. We conducted an exploratory, correlational, country-level analysis of open data centralized by Our World in Data concerning the cumulative COVID-19 mortality for the winter wave (October 2021-March 2022) of the pandemic as function of the vaccination rate in October 2021. We controlled variables that capture country-level social development and level of testing. We also deployed three segmentation tactics, distinguishing among countries based on their level of COVID-19 testing, age structure, and types of vaccines used. Controlling for confounding factors did not highlight a statistically significant relationship between vaccination and cumulative mortality in the total country sample. Still, a strong, significant, negative relationship between cumulative mortality (log scale) and vaccination was highlighted through segmentation analysis for countries positioned at the higher end of the social development spectrum. The strongest estimate for vaccine effectiveness at ecological level was obtained for the set of countries that used Western-only vaccines. COVID-19 testing (log scale) has a significant and positive relationship with cumulative mortality for all subsamples, consistent with patterns of under- and overreporting of COVID-19 deaths at country level, partly driven by testing. This indicates that testing intensity should be controlled as a potential confounder in future ecological analyses of COVID-19 mortality.


The process of folding proteins into membranes: challenges and progress.
Just 25 years ago the Anfinsen thermodynamic hypothesis was shown to be valid for membrane proteins. Despite the complex biological machinery required for their in vivo assembly and in face of the chemically heterogeneous, anisotropic nature of their biological lipid bilayer "solvent", the evidence continues to suggest that membrane proteins are equilibrium structures. The progress in finding conditions in vitro to investigate the physical origins of their stabilities is the focus of this article. We catalogue in vitro folding studies in detergent micelles and in lipid bilayers. We consider the unique technical obstacles to folding studies of membrane proteins, and we highlight the progress that has been made in quantitative descriptions of membrane protein stability.


The possibility of distinguishing a subset of antigen-presenting cells from macrophages by means of anti S-100 protein sera. Dermal infiltrate of lichen planus as a model.
Macrophages may be distinguished from interdigitating cells and from Langerhans cells in paraffin sections, the latter cells being positive when an antiserum against brain S-100 protein is used. This antiserum was utilized to conduct a retrospective analysis of 10 cases of lichen planus, including both early and late lesions. In addition, staining of macrophages was carried out by means of anti-lysozyme, anti-alpha-1-antitrypsin and anti-alpha-1-antichymotrypsin. The anti-S-100 protein staining by immunoperoxidase methods showed large numbers of positive cells. Few macrophages were noted in the early lesions, but the ratios were reversed in the older lesions, in which macrophages predominated over dermal S-100-positive cells. Both Langerhans cells-interdigitating cells and macrophages could play important roles in various cutaneous disorders. The involvement of Langerhans cells-interdigitating cells or, on the other hand, of macrophages could distinguish among different pathological processes. Even in different evolutionary stages of the same lesion, as lichen planus, a different Langerhans cells-interdigitating cells/macrophages ratio could be important in explaining the pathogenetic development of the disease.


The effect of maternal voice for procedural pain in paediatric intensive care unit: A randomised controlled trial.
The aim of this study was to evaluate the effectiveness of the maternal voice in reducing pain during painful procedures in children between one and three years old receiving treatment in paediatric intensive care unit. This research was designed as a randomised controlled experimental study. Sixty children were randomised into two groups, the maternal-voice group and the controls. The children in the maternal-voice group listened to the maternal voice during the procedure. Although questionnaire forms were used to determine the descriptive characteristics of infants, the Face, Legs, Activity, Cry, Consolability (FLACC) pain assessment scale was used to evaluate pain level. Heart rate and oxygen saturation were also measured. There were significant differences in the pain, heart rate and oxygen saturation levels between the maternal-voice and control groups. Pain levels and heart rates of the children in the experimental group during and after the painful procedures were much lower, and their oxygen saturations were higher than those of the children in the control group. Distraction methods, such as listening to the maternal voice, should be used as a nursing intervention to reduce pain and decrease heart rate and increaseoxygen saturation in children during painful procedures in the paediatric intensive care unit. The maternal voice is recommended as a helpful option in cases when a pain control method is required. Future research needs to explore different interventional practices.


Short-term changes in carbon-isotope discrimination in the C3-CAM intermediate Clusia minor L. growing in Trinidad.
On-line instantaneous carbon isotope discrimination was measured in conjunction with net uptake of CO2 in leaves of exposed and shaded plants of the C3-CAM intermediate Clusia minor growing under natural conditions in Trinidad. At the end of the rainy season (late January-early February, 1992) C3 photosynthesis predominated although exposed leaves recaptured a small proportion of respiratory CO2 at night for the synthesis of malic acid. Citric acid was the major organic acid accumulated by exposed leaves at this time with a citric: malic acid ratio of 11:1. Values of instantaneous discrimination (Δ) in exposed leaves during the wet season rose from 17.1‰ shortly after dawn to 22.7‰ around mid-day just before stomata closed, suggesting that most CO2 was fixed by Rubisco at this time. During the late afternoon, instantaneous Δ declined from 22.2‰ to 17‰, probably reflecting the limited contribution from PEPc activity and an increase in diffusional resistance to CO2 in exposed leaves. Shaded leaves showed no CAM activity and CO2 uptake proceeded throughout the day in the wet season. The decrease in instantaneous Δ from 27‰ in the morning to 19.2‰ in the late afternoon was therefore entirely due to diffusional limitation. Leaves sampled in the dry season (mid-March, 1992) had by now induced full CAM activity with both malic and citric acids accumulated overnight and stomata closed for 4-5 h over the middle of the day. Values of instantaneous Δ measured over the first 3 h after dawn (6.4-9.1‰) indicated that C4 carboxylation dominated CO2 uptake for most of the morning when rates of photosynthesis were maximal, implying that under natural conditions, the down regulation of PEPc in phase II occurs much more slowly than laboratory-based studies have suggested. The contribution from C3 carboxylation to CO2 uptake during phase II was most marked in leaves which accumulated lower quantities of organic acids overnight. In exposed leaves, measurements of instantaneous Δ during the late afternoon illustrated the transition from C3 to C4 carboxylation with stomata remaining open during the transition from dusk into the dark period. Uptake of CO2 by shaded leaves during the late afternoon however appeared to be predominantly limited by decreased stomatal conductance. The short-term measurements of instantaneous Δ were subsequently integrated over 24 h in order to predict the leaf carbon isotope ratios (δp) and to compare this with the δp measured for leaf organic material. Whilst there was close agreement between predicted and measured δp for plants sampled in the wet season, during the dry season the predicted carbon isotope ratios were 5-9‰ higher than the measured isotope ratios. During the annual cycle of leaf growth most carbon was fixed via the C3 pathway although CAM clearly plays an important role in maintaining photochemical integrity in the dry season.


Elaboration and validation of an ICNP® terminology subset for patients with acute myocardial infarction.
To elaborate a terminological subset for the International Classification for Nursing Practice (ICNP®) for patients with acute myocardial infarction using the Activities of Living Model. A methodological study which followed the guidelines of the International Nursing Council and was based on theoretical framework of the Activities of Living Model for its elaboration. Content validation was performed by 22 nursing specialists. Twenty-two (22) diagnoses and 22 nursing outcomes were elaborated. Of these, 17 nursing diagnosis statements and 17 nursing outcome statements presented Content Validity Index (CVI) ≥ 0.80. Of the 113 elaborated nursing interventions, 42 reached a CVI ≥ 0.80, and 51 interventions made up the terminological subset after the expert suggestions. The ICNP® was suitable for use with the Activities of Living Model, having compatible terms with those used in clinical nursing practice, and valid for construction of the terminological subset for patients with acute myocardial infarction and most likely to facilitate clinical nursing judgment.


A comparison of the cerebral uptake and metabolism of labeled glucose and deoxyglucose in vivo in rats.
Experimental evidence indicated that: 1) [14C]deoxyglucose-6-phosphate (14C-DG-6-P) in brain (and other rat tissues) did not increase with time after injection of 14C-DG, 2) 14C-DG-6-P in rat brain (and other tissues) did not correlate with glucose metabolism, 3) 14C-DG-6-P in rat brain (and other tissues) had a significant negative correlation with glucose-6-phosphatase activity. Further, arterio-venous studies in rats, in which the cerebral uptake and metabolism of labeled glucose were compared directly with those of labeled DG (and labeled fluorodeoxyglucose, FDG), employing double labeled techniques, showed that DG (and FDG) cannot be used to measure glucose uptake and/or metabolism.


Computational recognition of LncRNA signatures in tumor-associated neutrophils could have implications for immunotherapy and prognostic outcome of non-small cell lung cancer.
Cancer immune function and tumor microenvironment are governed by long noncoding RNAs (lncRNAs). Nevertheless, it has yet to be established whether lncRNAs play a role in tumor-associated neutrophils (TANs). Here, a computing framework based on machine learning was used to identify neutrophil-specific lncRNA with prognostic significance in squamous cell carcinoma and lung adenocarcinoma using univariate Cox regression to comprehensively analyze immune, lncRNA, and clinical characteristics. The risk score was determined using LASSO Cox regression analysis. Meanwhile, we named this risk score as "TANlncSig." TANlncSig was able to distinguish between better and worse survival outcomes in various patient datasets independently of other clinical variables. Functional assessment of TANlncSig showed it is a marker of myeloid cell infiltration into tumor infiltration and myeloid cells directly or indirectly inhibit the anti-tumor immune response by secreting cytokines, expressing immunosuppressive receptors, and altering metabolic processes. Our findings highlighted the value of TANlncSig in TME as a marker of immune cell infiltration and showed the values of lncRNAs as indicators of immunotherapy.


Role of the spleen and rosette-formation response in experimental Eperythrozoon ovis infection.
The role of the spleen and rosette-formation responses was investigated in sheep experimentally infected with Eperythrozoon ovis. Phagocytic activity was observed in the spleen 19 days after primary infection. Phagocytosis of E. ovis-parasitised and non-parasitised erythrocytes by cordal reticular cells occurred. E. ovis organisms seemed to be detached from the erythrocytes by pseudopodia extending from macrophages and cordal reticular cells without causing damage to the plasmalemma of the erythrocyte. No phagocytic activity was observed in spleens removed 74 and 146 days after infection. Antigen-specific lymphoid cell responsiveness, assessed by rosette formation, indicated that 2.8, 15.4, 8.0 and 6.0% of lymphoid cells in the spleens of the four E. ovis-infected sheep, respectively, formed antigen-specific rosettes. Rosette formation did not occur when splenic lymphocytes from E. ovis-infected sheep were mixed with non-infected erythrocytes or when splenic lymphocytes from an uninfected sheep were used.


[Cytopenia under topical imiquimod in two patients treated with oral hydroxyurea].
Aldara® is a topical immunomodulatory treatment. The risks of systemic passage are minimal. There have been rare reports of systemic adverse effects. Case 1. Five sachets weekly of imiquimod were prescribed for Bowen's disease on the forearm in a patient known to have essential thrombocytosis under Hydrea®. His CBC was normal (6000 leukocytes/mm3, 2200 PMN/mm, 230,000 platelets/mm3). Imiquimod was given in 15 sachets weekly. Fifteen day later, the patient presented bicytopenia (3000 leukocytes/mm3, 1400 PMN/mm3, 119,000 platelets/mm3). Hydroxyurea and imiquimod were suspended until normalization of CBC. Hydroxyurea was resumed without recurrence of the bicytopenia. The patient's history included an identical episode following application of imiquimod. Case 2. Five sachets weekly of imiquimod were prescribed for actinic keratosis on the scalp in a patient known to have primary polycythemia under hydroxyurea. Her CBC was normal except for anemia (Hb 11.5g/L, 160,000 platelets/mm3, 1100 lymphocytes/mm3). Imiquimod was given in 12 sachets weekly. Ten days later, anemia increased (Hb 10g/dL) with lymphopenia (800/mm3) and thrombocytopenia (115,000/mm3). Suspension of imiquimod resulted in normalization of the previous CBC values. . The literature review identified reports of dose-dependent lymphopenia under oral imiquimod but not under Aldara®. The National Pharmacovigilance Database listed 10 cases of hematological disorders most likely caused by Aldara®. Hydroxyurea may induce cytopenia, and while it was not considered the sole causative agent in this case, it is likely to have had a triggering role in these patients with blood dyscrasias. Our findings show that misuse of imiquimod carries a potential risk of hematologic abnormality in patients receiving concomitant hydroxyurea, a commonly combined drug.


Non-hemic autoimmunity in CLL.
Non-hemic autoimmune complications of chronic lymphocytic leukemia are very rare compared to autoimmune haemolytic anemia, which occurs in between 10% and 20% of patients and immune thrombocytopenia, which occurs in between 1% and 2% of patients. A clear relationship has only been established with three non-hemic syndromes: acquired angioedema, glomerulonephritis and paraneoplastic pemphigus. The first is a result of a secreted product of the tumor, but the last two seem to be a product of the disordered immune system, and may be triggered by treatment with purine analogues suggesting a mechanism involving regulatory T cells. Apart from Herpes Zoster infections, neurological syndromes are rare in CLL and most have been attributed to either leukemic infiltration of the CNS or progressive multifocal leukoencephalopathy.


Solid phase synthesis of peptides containing the CH2NH peptide bond isostere.
The CH2NH peptide bond can be directly introduced by the reductive alkylation reaction between a tert-butoxycarbonyl-amino acid aldehyde and an amine on the resin bound peptide employing sodium cyanoborohydride in acidified dimethylformamide solution and this facile method was successfully applied to the synthesis of a psi[CH2NH] pseudopeptide somatostatin octapeptide analogue.


How do I implement a whole blood-based blood preparedness program in a small rural hospital?
Civilian and military guidelines recommend balanced transfusion to patients with life-threatening bleeding. Early start of transfusion has shown improved survival. Thus, a balanced blood inventory must be available in all levels of health care to ensure early stabilization and damage control resuscitation of patients with bleeding. Whole blood has been reintroduced as a blood product for massive bleeding situations because it affords plasma, red blood cells, and platelets in a balanced ratio in a logistically advantageous way. In this article, we describe how to establish a whole blood-based blood preparedness program in a small rural hospital with limited resources. We present an implementation tool kit, which includes discussions on whole blood program strategies and the process of developing detailed procedures on donor selection, collection, storage, and transfusion management of whole blood. The importance of training and audit of the routines is highlighted, and establishment of an emergency walking blood bank is discussed. We conclude that implementation of a whole blood program is achievable in small rural hospitals and recommend that rural health care facilities at all treatment levels enable early balanced transfusion for patients with life-threatening bleeding by establishing protocols for whole blood-based preparedness.


The relationship of wives' treatment to the drinking status of alcoholics.
When an alcoholic's wife is active in Al-Anon, participates in her husband's inpatient treatment or postreatment counseling or receives several types of treatment, her husband is more likely to be abstinent.


Predicting tumor recurrence on baseline MR imaging in patients with early-stage hepatocellular carcinoma using deep machine learning.
Tumor recurrence affects up to 70% of early-stage hepatocellular carcinoma (HCC) patients, depending on treatment option. Deep learning algorithms allow in-depth exploration of imaging data to discover imaging features that may be predictive of recurrence. This study explored the use of convolutional neural networks (CNN) to predict HCC recurrence in patients with early-stage HCC from pre-treatment magnetic resonance (MR) images. This retrospective study included 120 patients with early-stage HCC. Pre-treatment MR images were fed into a machine learning pipeline (VGG16 and XGBoost) to predict recurrence within six different time frames (range 1-6 years). Model performance was evaluated with the area under the receiver operating characteristic curves (AUC-ROC). After prediction, the model's clinical relevance was evaluated using Kaplan-Meier analysis with recurrence-free survival (RFS) as the endpoint. Of 120 patients, 44 had disease recurrence after therapy. Six different models performed with AUC values between 0.71 to 0.85. In Kaplan-Meier analysis, five of six models obtained statistical significance when predicting RFS (log-rank p < 0.05). Our proof-of-concept study indicates that deep learning algorithms can be utilized to predict early-stage HCC recurrence. Successful identification of high-risk recurrence candidates may help optimize follow-up imaging and improve long-term outcomes post-treatment.


Reciprocating free-flow isoelectric focusing with online array ultraviolet detector for process monitoring of protein separation.
Free-flow isoelectric focusing (FFIEF) is a useful tool for separating and purifying proteins, DNA, cells, and organelles, etc. However, the online monitoring of each fraction during an FFIEF run has not been achieved yet, resulting in a lack of process monitoring of FFIEF. Herein, an online array ultraviolet (UV) detection system was developed for the easy assay of FFE fractions. The detector was integrated with an apparatus of FFIEF with 32 fractions to show the online monitoring, and bovine serum albumin (BSA) and lysozyme were chosen as the model proteins for manifesting the UV detector performance. The experiments revealed that (i) all the fluidic cells had good linearity from 0.03 to 10 mg/mL BSA and fair limits of detection (LODs) of 0.01 mg/mL; (ii) all the cells had good uniformity of UV absorbance; and (iii) the deviations of intra-day and inter-day of UV detector were respectively 3.8% and 5.8%, indicating the fair stability of the UV detector. The UV detector could be well used for the process monitoring of two model proteins through the whole FFIEF run, and the online absorbance assay of proteins at the end of FFIEF. The UV detector herein had the evident potential for rapid and convenient assay of protein fraction in FFIEF as well as other FFE modes.


Relations between emotion and conscious recollection of true and false autobiographical memories: an investigation using lorazepam as a pharmacological tool.
Conscious recollection for autobiographical memory is the subjective experience of reliving a personal event mentally. Its frequency is strongly influenced by the emotion experienced at the time of the event. We addressed the issue of whether conscious recollection for autobiographical memories is also influenced by the emotion experienced at the time of retrieval. We used lorazepam, a benzodiazepine, as a pharmacological tool to modulate this emotional experience. Autobiographical memories were recorded in eight healthy volunteers using a diary study methodology. Each day, four entries were made by each subject: two true events, one altered event and one false event. For each event, the subjects were asked to rate emotional variables at encoding and at retrieval. Two months later, there were two sessions of recognition tests during which the subjects received orally an acute administration of either lorazepam (0.038 mg/kg) or placebo using a cross-over design. Subjective states of awareness were assessed using the Remember/Know/Guess procedure. Compared to placebo, lorazepam increased levels of conscious recollection, as assessed by Remember responses, for both true and false memories and induced an overestimation of the personal significance and emotional intensity of past events. Structural equation modelling showed that this overestimation was causal in the increased frequency of conscious recollection. Our results provide experimental evidence that the frequency of conscious recollection for both true and false autobiographical memories is influenced by the emotion experienced at the time of retrieval.


Phase II trial of pyrazine diazohydroxide in androgen-independent prostate cancer.
No effective therapy has been demonstrated for hormone refractory prostate cancer (HRPC). Pyrazine diazohydroxide (PZDH) is a novel antineoplastic agent with a broad range of activity in preclinical studies and a moderate toxicity profile in Phase I trials. We undertook a Phase II study of PZDH in HRPC utilizing decline in PSA as the primary end point. Fifteen patients were enrolled, median age of 70 (55-86), median pretherapy PSA 206 ng/ml (range 42-10,000). Four patients were African American. Sites of disease: bone only 7, soft tissue only 2, both 6. All were evaluable for toxicity and response. PZDH was administered at 250 mg/m2 i.v. every three weeks. The median number of cycles administered was two (range 1-6). Toxicity was mild, with only one patient manifesting serious (grade 3-4) toxicity. Unfortunately, activity was minimal with only a single patient demonstrating a >75% decline in PSA. As this patient's PSA began to rise almost immediately the response was considered transient and not felt to justify pursuing a second stage of the trial. Supporting this conclusion was the disappointing median survival of 220 days. In summary, we conclude that PZDH, while well tolerated at this dose and schedule has only minimal activity in HRPC.


Cross-talk between beta-adrenergic stimulation and estrogen receptors: isoproterenol inhibits 17beta-estradiol-induced gene transcription in A7r5 cells.
The hypothesis that cross-talk between membrane-active beta-adrenergic agonists and estrogens includes beta-adrenergic modulation of estrogen receptor (ER)-regulated gene expression was investigated. Vascular smooth muscle-derived A7r5 cells were transfected with an ERalpha expression plasmid (pCR3.1-hERalpha), the estrogen response element (ERE)-linked reporter pERE-E1b-luciferase (ERE-Luc), and pCMV-beta-galactosidase using a lysine-conjugated adenovirus transfection method. Hormone or agonist treatment and harvest followed 6 hours and 24 hours later, respectively. Treatment with 17beta-estradiol (E(2), 1 nmol/L) significantly stimulated ERE-Luc activity. Isoproterenol (10-9 to 10-6 mol/L) treatment alone did not stimulate ERE-Luc activity. Cotreatment with both E(2) and isoproterenol resulted in complete inhibition of E(2)-stimulated ERE-Luc activity. This isoproterenol effect was prevented by the beta-adrenergic antagonist propanolol (10-6 mol/L). Adrenomedullin treatment in these cells (1-50 nmol/L) did not inhibit ER/ERE-Luc activity, whether in the presence or absence of E(2). Moreover, isoproterenol did not affect vitamin D-stimulated VDRE-Luc expression, indicating that the inhibitory effect of isoproterenol on E(2)-directed ERE-Luc expression is specific among nuclear transcription factor receptors. Moreover, in MCF-7 breast cancer cells, there was no effect of isoproterenol on ER/ERE-directed transcription in the absence or presence of E(2), demonstrating tissue specificity of this isoproterenol effect. These studies demonstrate cross-talk between the beta-adrenergic agonist isoproterenol and ER-directed reporter gene expression in A7r5 cells. Furthermore, this cross-talk is specific with respect to agonist, nuclear receptor species, and cell type. These observations may have important implications both for the use of beta-adrenergic agents to treat hypertension and for possible gender-related differences in cardiovascular regulation.


Tactile stimulation and maternal separation prevent hippocampal damage in rats submitted to neonatal hypoxia-ischemia.
Unilateral neonatal hypoxia-ischemia causes important damage to the hippocampus of the hemisphere ipsilateral to carotid artery occlusion; two forms of neonatal handling, tactile stimulation and maternal separation for a short period, have been shown to produce functional/behavioral protection in distinct models of CNS challenge. In this paper we investigated whether neonatal handling could alter the hippocampal damage caused by neonatal hypoxia-ischemia (HI) in the Wistar rat. Pups at postnatal day 7, P7, received HI (8% O(2)-92% N(2)) for 90 min and were submitted to neonatal handling, tactile stimulation of maternal separation daily, from P8 to P21, for 10 min. On adulthood, hippocampal volume was analyzed by stereological techniques, along with measures of cortical thickness and hemispheric area at the level -3.30 mm from bregma. HI caused a reduction of volume of whole hippocampus, of Amon's horn and of dentate gyrus, with no effect on cortical and hemispheric measures; neonatal handling prevented such effect. This is the first report showing that both tactile stimulation and neonatal handling exert a morphological neuroprotective action for HI-induced damage to the hippocampus.


Use of glue gun in forensic anthropology and pathologic bone reconstruction cases.
Fragmented "wet" bone material can be rapidly reconstructed with a minimum amount of specimen preparation using hot melt adhesives and commercially available electric glue guns. The reconstruction of fragmented bone aids in the analysis and interpretation of extensive trauma cases.


Meaning profiles and the perception of the working alliance at the start of outpatient person-centered, experiential, and existential psychotherapies.
Quantitative research on meaning in life in the context of psychotherapy is relatively limited. The current study aims to investigate the profiles of the meaning of clients and their perception of the working alliance and initial symptomatology at the start of therapy. In a sample of 145 clients (62.1% female; mean age, 34.77) who started person-centered psychotherapy, the relationship between meaning, search for meaning, symptomatology, and the working alliance was analyzed. The assessment took place after the second session. Cluster analysis revealed four profiles: Low Presence High Search, High Presence Low Search, High Presence High Search, and Low Presence Low Search. These meaning profiles are distinguished in terms of symptomatology but not in terms of the working alliance perception. However, the experience of meaning is significantly associated with the working alliance. Results show the relevance of meaning-related questions for certain groups of clients at the start of therapy.


Iron stores in low-income pregnant Mexican women at term.
Iron stores can be depleted during pregnancy. Serum ferritin is the most useful non-invasive test to assess iron stores in women of reproductive age. Iron status of pregnant Mexican women at term from a low-income group was investigated through serum ferritin determinations. Hemoglobin and serum ferritin were measured in 201 low-income urban women with at-term pregnancy receiving attention at a public university hospital. Hemoglobin cut-off value was 110.0 g/L. Depending on their serum ferritin concentration, women were divided into three groups: group I, iron deficiency, serum ferritin <12 microg/L; group II, borderline iron stores, serum ferritin >or=12 microg/L and <30 microg/L, and group III, normal iron stores, serum ferritin >or=30 microg/L. Mean SF value in the entire group was 7.0 +/- 6.4 microg/L, with a mean Hb of 110.1 +/- 15.8 g/L. One hundred seventy-two women (85.6%) had empty iron stores. Ninety-two women (46%) in the entire group had iron deficiency anemia, as did 79 (46%) of the 172 iron-deficient women. During their pregnancy, 165 women (82%) did not ingest any supplemental iron and 131 (65%) did not receive any prenatal care. We documented a high prevalence of iron deficiency and iron deficiency anemia, together with practically no prenatal care utilization and no supplemental iron ingestion in this low-income group. A serum ferritin concentration >or=12 microg/L was always accompanied by a normal hemoglobin concentration. These data suggest that prenatal care and iron supplementation may be considered as major determinants of maternal iron stores to prevent iron deficiency anemia.


Role of sodium tetraborate as a cardioprotective or competitive agent: Modulation of hypertrophic intracellular signals.
Boron is an essential trace element in cellular metabolism; however, the molecular mechanism of boron in the heart is unclear. In this study, we examined the effect of sodium tetraborate (as boron source) as a possible protective agent or competitive inhibitor of cardiac hypertrophy in an in vitro murine model. We evaluated different previously reported sodium tetraborate concentrations and it was found that 13 μM improves viability without affecting the cellular structure. We demonstrated that cardiomyocytes pretreated with sodium tetraborate prevents cellular damage induced by isoproterenol (cardioprotective effect) by increasing proliferation rate and inhibiting apoptosis. In addition, the reduction of the expression of the α1AR and β1AR adrenergic receptors as well as Erk1/2 was notable. Consequently, the expression of the early response genes c-myc, c-fos and c-jun was delayed. Also, the expression of GATA-4, NFAT, NKx2.5 and myogenin transcription factors involved in sarcomere synthesis declined. In contrast, cardiomyocytes, when treated simultaneously with sodium tetraborate and isoproterenol, did not increase their size (cytoplasmic gain), but an increase in apoptosis levels was observed; therefore, the proliferation rate was reduced. Although the mRNA levels of α1AR and β1AR as well as Erk1/2 and Akt1 were low at 24 h, their expression increased to 48 h. Notably, the mRNA of expression levels of c-myc, c-fos and c-jun were lower than those determined in the control, while the transcription factors GATA-4, MEF2c, Nkx2.5, NFAT and CDk9 were determined in most cells. These results suggest that pretreatment with sodium tetraborate in cardiomyocytes inhibits the hypertrophic effect. However, sodium tetraborate attenuates isoproterenol induced hypertrophy damage in cardiomyocytes when these two compounds are added simultaneously.


Cost-utility of real-time continuous glucose monitoring versus self-monitoring of blood glucose and intermittently scanned continuous glucose monitoring in people with type 1 diabetes receiving multiple daily insulin injections in Denmark.
To determine the cost-effectiveness of the Dexcom G6 real-time continuous glucose monitoring (rt-CGM) system compared with both the self-monitoring of blood glucose (SMBG) and the Abbott FreeStyle Libre 1 and 2 intermittently scanned CGM (is-CGM) devices in people with type 1 diabetes receiving multiple daily insulin injections in Denmark. The analysis was performed using the IQVIA Core Diabetes Model, which associates rt-CGM use with glycated haemoglobin reductions of 0.6% and 0.36% based on data from the DIAMOND and ALERTT1 trials, respectively, compared with SMBG and is-CGM use. The analysis was performed from the payer perspective over a 50-year time horizon; future costs and clinical outcomes were discounted at 4% per annum. The use of rt-CGM was associated with an incremental gain of 1.37 quality-adjusted life years (QALYs) versus SMBG. Total mean lifetime costs were Danish Krone (DKK) 894 535 for rt-CGM and DKK 823 474 for SMBG, resulting in an incremental cost-utility ratio of DKK 51 918 per QALY gained versus SMBG. Compared with is-CGM, the use of rt-CGM led to a gain of 0.87 QALYs and higher mean lifetime costs resulting in an incremental cost-utility ratio of DKK 40 879 to DKK 34 367 per QALY gained. In Denmark, the rt-CGM was projected to be highly cost-effective versus both SMBG and is-CGM, based on a willingness-to-pay threshold of 1× per capita gross domestic product per QALY gained. These findings may help inform future policies to address regional disparities in access to rt-CGM.


Brain-wide genome-wide colocalization study for integrating genetics, transcriptomics and brain morphometry in Alzheimer's disease.
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases. However, the AD mechanism has not yet been fully elucidated to date, hindering the development of effective therapies. In our work, we perform a brain imaging genomics study to link genetics, single-cell gene expression data, tissue-specific gene expression data, brain imaging-derived volumetric endophenotypes, and disease diagnosis to discover potential underlying neurobiological pathways for AD. To do so, we perform brain-wide genome-wide colocalization analyses to integrate multidimensional imaging genomic biobank data. Specifically, we use (1) the individual-level imputed genotyping data and magnetic resonance imaging (MRI) data from the UK Biobank, (2) the summary statistics of the genome-wide association study (GWAS) from multiple European ancestry cohorts, and (3) the tissue-specific cis-expression quantitative trait loci (cis-eQTL) summary statistics from the GTEx project. We apply a Bayes factor colocalization framework and mediation analysis to these multi-modal imaging genomic data. As a result, we derive the brain regional level GWAS summary statistics for 145 brain regions with 482,831 single nucleotide polymorphisms (SNPs) followed by posthoc functional annotations. Our analysis yields the discovery of a potential AD causal pathway from a systems biology perspective: the SNP chr10:124165615:G>A (rs6585827) mutation upregulates the expression of BTBD16 gene in oligodendrocytes, a specialized glial cells, in the brain cortex, leading to a reduced risk of volumetric loss in the entorhinal cortex, resulting in the protective effect on AD. We substantiate our findings with multiple evidence from existing imaging, genetic and genomic studies in AD literature. Our study connects genetics, molecular and cellular signatures, regional brain morphologic endophenotypes, and AD diagnosis, providing new insights into the mechanistic understanding of the disease. Our findings can provide valuable guidance for subsequent therapeutic target identification and drug discovery in AD.


Financial Hardship in Childhood Cancer Survivors Treated with Hematopoietic Cell Transplantation: A Report from the Childhood Cancer Survivor Study.
Long-term survivors of childhood cancer are at risk for financial hardship. However, it is not known if HCT leads to an incremental change in financial hardship for survivors who received it versus those who did not. We examined financial outcomes among adult survivors of childhood cancer who had undergone HCT. Using a cross-sectional survey in the Childhood Cancer Survivor Study population between 2017 and 2019, self-reported financial hardship was compared between survivors who received HCT, survivors treated without HCT ("non-HCT"), and siblings and categorized into 3 domains: material hardship/financial sacrifices, behavioral, and psychological hardship. The standardized score of each domain of financial hardship was calculated by adding the item responses and dividing by the standard deviation among siblings. Multivariable linear and logistic regression were used to evaluate associations between sociodemographic characteristics, cancer diagnosis, post-treatment complications, and financial hardship among survivors. The mean adjusted score for each hardship domain was not significantly different between HCT survivors (n = 133) and non-HCT survivors (n = 2711); mean differences were .18 (95% confidence interval [CI], -.05 to .41) for material hardship/financial sacrifices, .07 (95% CI, -.18 to .32) for behavioral hardship, and .19 (95% CI, -.04 to .42) for psychological hardship. Within specific items, a higher proportion of survivors treated with HCT reported greater financial hardship compared to non-HCT survivors. HCT survivors also had significantly higher mean domain scores compared to sibling controls (n = 1027) in all domains. Household income and chronic health conditions, but not HCT, were associated with financial hardship among all survivors. Adult survivors of childhood cancer treated with HCT do not report greater overall financial hardship compared to non-HCT survivors but do report greater overall financial hardship compared to sibling controls. Surveillance and intervention may be necessary for all survivors regardless of HCT status.


Implications for concepts of psychopathology of studies of economic principles in behavior therapy programs.
In several studies of token economies, it has been observed repeatedly that chronic psychiatric patients conform to the same economic principles as explain the activities of presumably normal participants in the national consumer economy. Such observations are consistent with behavior therapy's assumptions that those labeled mentally ill follow the same psychological and social lows as those considered normal and that behavior is responsive to specific situational determinants. Although they disprove nothing, these observations may pose problems for more traditional approaches which view psychopathology as the result of central disorders or deficits with diffuse effects across a wide range of ordinary life situations.