Information-seeking process and clinical scenario solving: introduction of a new tool in nursing education.
Nursing education has recently undergone changes to improve care. These changes require innovative and transformative strategies in nursing education. Search as learning is one of the educational methods this study was conducted to determine the effect of the information searching process on scenario-based learning in nursing students. This study is a single group semi-experimental study that was conducted on 38 nursing students in 2021. Students first drew a concept map according to their existing knowledge about two scenarios (diabetes and trauma). The students then searched the medical databases and drew another concept map after the search. Data were analyzed using descriptive statistics, paired mean tests and Pearson correlation coefficients. The results showed that the mean scores of the participants in the diabetes scenario before and after the search were 18.32 ± 5.50 and 19.13 ± 7.54, respectively, and those in the trauma scenario were 18.58 ± 7.69 and 29.61 ± 7, respectively (P < 0.01). The mean scores of the details of the conceptual map before and after the search in terms of themes, number of levels and relationships were statistically significant. In both scenarios, there was a positive correlation (p < 0.01) between learning and the number of correct webpages (r = 0.74 for trauma and r = 0.64 for diabetes), as well as between search time and the amount of learning (r = 0.77 for trauma and 0.64 for diabetes). The results showed that search as learning in nursing education scenarios led to student learning. It is recommended that nurse educators use this method as a tool in nursing education to increase students' awareness and develop their thinking skills. Further research is recommended to determine the effectiveness of this method with other educational methods.


Completion and subject loss within an intensive hepatitis vaccination intervention among homeless adults: the role of risk factors, demographics, and psychosocial variables.
Unprotected sexual behavior, needle sharing, and a prison history are major correlates of hepatitis B Virus (HBV). These risk factors are common among homeless people who also have elevated rates of HBV. We examine whether these behaviors were associated with completion or loss to follow-up of the most intensive and successful condition of a 3-arm HBV vaccination intervention. Significant results would imply that those most in need are the least compliant. Contributions of baseline demographics, physical health, psychosocial variables, and health beliefs were also assessed. Three-hundred thirty-one adults from Los Angeles' Skid Row were assigned to nurse-case-managed sessions with hepatitis education, incentives, and tracking. Successive predictive structural equation models assessed the amount of variance accounted for by the risk variables, demographics, and the health-related variables. (1) Completion of 3 injections by 6 months; and (2) loss to a 6-month follow-up questionnaire. The 3 risk factors explained 2% of the variance in completion and 1% of the variance in loss. Adding the other variables increased the variance explained to 14% for completion and 13% for loss. African American ethnicity, positive coping, social support, poorer health, no prison history, and greater efficacy significantly predicted completion. White ethnicity, less social support, better health, and less intention to complete predicted participant loss. The program was not strongly rejected differentially as a function of preexisting hepatitis B risk behaviors. Programs designed for homeless people should include malleable psychosocial and health belief model variables. These aspects of the lives of homeless people provide leverage points for future interventions.


Glaucoma-related adverse events in the Infant Aphakia Treatment Study: 1-year results.
To report the incidence of glaucoma and glaucoma suspects in the IATS, and to evaluate risk factors for the development of a glaucoma-related adverse event in patients in the IATS in the first year of follow-up. A total of 114 infants between 1 and 6 months of age with a unilateral congenital cataract were assigned to undergo cataract surgery either with or without an intraocular lens implant. Standardized definitions of glaucoma and glaucoma suspect were created and used in the IATS. Of these 114 patients, 10 (9%) developed glaucoma and 4 (4%) had glaucoma suspect, for a total of 14 patients (12%) with a glaucoma-related adverse event in the treated eye through the first year of follow-up. Of the 57 patients who underwent lensectomy and anterior vitrectomy, 5 (9%) developed a glaucoma-related adverse event; of the 57 patients who underwent an intraocular lens implant, 9 (16%) developed a glaucoma-related adverse event. The odds of developing a glaucoma-related adverse event were 3.1 times higher for a child with persistent fetal vasculature and 1.6 times higher for each month of age younger at cataract surgery. Modern surgical techniques do not eliminate the early development of glaucoma following congenital cataract surgery with or without an intraocular lens implant. Younger patients with or without persistent fetal vasculature seem more likely to develop a glaucoma-related adverse event in the first year of follow-up. Vigilance for the early development of glaucoma is needed following congenital cataract surgery, especially when surgery is performed during early infancy or for a child with persistent fetal vasculature. Five-year follow-up data for the IATS will likely reveal more glaucoma-related adverse events. clinicaltrials.gov Identifier: NCT00212134.


Rapid discovery of inhibitors of Toxoplasma gondii using hybrid structure-based computational approach.
Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects individuals worldwide, and is a leading cause of severe congenital neurologic and ocular disease in humans. No vaccine to protect humans is available, and hypersensitivity and toxicity limit the use of the few available medicines. Therefore, safer and more effective medicines to treat toxoplasmosis are urgently needed. Using the Hybrid Structure Based (HSB) method, we have previously identified small molecule inhibitors of P. falciparum that seem to target a novel protein-protein interaction between the Myosin tail interacting protein and myosin light chain. This pathway has been hypothesized to be involved in invasion of host erythrocytes by the parasite and is broadly conserved among the apicomplexans. Guided by similar computational drug design approaches, we investigated this series of small molecules as potential inhibitors of T. gondii. Compound C3-21, identified as the most active inhibitor in this series, exhibited an IC(50) value ~500 nM against T. gondii. Among the 16 structural analogs of C3-21 tested thus far, nine additional compounds were identified with IC(50) values <10.0 μM. In vitro assays have revealed that C3-21 markedly limits intracellular growth of T. gondii tachyzoites, but has no effect on host cell human foreskin fibroblasts (HFF) at concentrations more than a log greater than the concentration that inhibits the parasites.


Endobronchial ultrasound skills and tasks assessment tool: assessing the validity evidence for a test of endobronchial ultrasound-guided transbronchial needle aspiration operator skill.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is becoming standard of care for the sampling of mediastinal adenopathy. The need for a safe, effective, accurate procedure makes EBUS-TBNA ideal for mastery training and testing. The Endobronchial Ultrasound Skills and Tasks Assessment Tool (EBUS-STAT) was created as an objective competency-oriented assessment tool of EBUS-TBNA skills and knowledge. This study demonstrates the reliability and validity evidence of this tool. The EBUS-STAT objectively scores the EBUS-TBNA operator's skills, including atraumatic airway introduction and navigation, ultrasound image acquisition and optimization, identification of mediastinal nodal and vascular structures, EBUS-TBNA sampling, and recognition of EBUS/computed tomography images of mediastinal structures. It can be administered at the bedside or using combination of low- and high-fidelity simulation platforms. Two independent testers administered the EBUS-STAT to 24 operators at three levels of EBUS-TBNA experience (8 beginners, 8 intermediates, and 8 experienced) at three institutions; operators were also asked to self-assess their skills. Scores were analyzed for intertester reliability, correlation with prior EBUS-TBNA experience, and association with self-assessments. Intertester reliability between testers was very high (r = 0.9991, P < 0.00005). Mean EBUS-STAT scores for beginner, intermediate, and experienced groups, respectively, were 31.1, 74.9, and 93.6 out of 100 (F(2,21) = 118.6, P < 0.0001). Groups were nonoverlapping: post hoc tests showed each group differed significantly from the others (P < 0.001). Self-assessments corresponded closely to actual EBUS-STAT scores (r(2) = 0.81, P < 0.001). The EBUS-STAT can be used to reliably and objectively score and classify EBUS-TBNA operators from novice to expert. Its use to assess and document the acquisition of knowledge and skill is a step toward the goal of mastery training in EBUS-TBNA.


Understanding hard-to-reach communities: local perspectives and experiences of trachoma control among the pastoralist Maasai in northern Tanzania.
As progress to eliminate trachoma is made, addressing hard-to-reach communities becomes of greater significance. Areas in Tanzania, inhabited by the Maasai, remain endemic for trachoma. This study assessed the effectiveness of Mass Drug Administration (MDA) through an ethnographic study of trachoma amongst a Maasai community. The MDA experience in the context of the livelihoods of the Maasai in a changing political economy was explored using participant observation and household interviews. Factors influencing MDA effectiveness within five domains were analysed. 1) Terrain of intervention: Human movement hindered MDA, including seasonal migration, domestic chores, grazing and school. Encounters with wildlife were significant. 2) Socio-cultural factors and community agency: Norms around pregnancy led women to accept the drug but hide refusal to swallow the drug. Timing of Community Drug Distributor (CDD) visits conflicted with livestock grazing. Refusals occurred among the ilmurrani age group and older women. Mistrust significantly hindered uptake of drugs. 3) Strategies and motivation of drug distributors: Maa-speaking CDDs were critical to effective drug delivery. Maasai CDDs, whilst motivated, faced challenges of distances, encounters with wildlife and compensation. 4) Socio-materiality of technology: Decreases in side-effects over years have improved trust in the drug. Restrictions to swallowing drugs and/or water were relevant to post-partum women and the ilmurrani. 5) History and health governance: Whilst perceptions of the programme were positive, communities questioned government priorities for resources for hospitals, medicines, clean water and roads. They complained of a lack of information and involvement of community members in health care services. With elimination in sight, hard-to-reach communities are paramount as these are probably the last foci of infection. Effective delivery of MDA programmes in such communities requires a critical understanding of community experiences and responses that can inform tailored approaches to trachoma control. Application of a critical social science perspective should be embedded in planning and evaluation of all NTD programmes.


The relationship of carbon disulfide metabolism to development of toxicity.
The metabolism of CS2 proceeds by two distinct metabolic pathways, direct reaction with amine or thiol functions of cellular constituents, and microsomal oxidation to reactive intermediates that covalently bind to cell macromolecules. Reaction with amines or thiols may alter protein function by two primary mechanisms: formation of dithiocarbamate metabolites capable of inactivating metalloenzymes by chelation of metal ions such as copper and zinc, and direct reaction with such functional groups on proteins. Both of these mechanisms may contribute to CS2-induced neurotoxicity. Formation of reactive intermediates catalyzed by microsomal metabolism is clearly important in mediating CS2-induced hepatotoxicity. Its role in catalyzing neurotoxicity is less certain, however, since the mixed function oxidase activity of the central and peripheral systems has not been well characterized.


Diversity of human immune system multigene families and its implication in the genetic background of rheumatic diseases.
A large number of molecules in the immune system are encoded by multigene families. These genes are rich in pairs of activating and inhibitory receptors that share the same ligands, thereby playing a crucial role in immunoregulation. Furthermore, multigene families tend to be highly polymorphic. Thus, multigene families are strong candidates for containing genes that enhance susceptibility to immune system-related diseases. Here, we review studies from our group, as well as other investigators, on three multigene families that belong to the immunoglobulin (Ig) - like receptor superfamily: Fcgamma receptor (FCGR), killer cell Ig-like receptor (KIR) and leukocyte Ig-like receptor (LILR) families. FCGR genes have been implicated in susceptibility to systemic lupus erythematosus (SLE). In FCGR2B encoding an inhibitory receptor expressed in B cells, monocytes and dendritic cells, a polymorphism within the transmembrane region, Ile232Thr, was identified and found to be associated with susceptibility to SLE in three Asian populations. Functional analyses revealed that SLE-associated FcgammaRIIb-232Thr was less efficient in entering the membrane lipid raft, and exhibited reduced inhibitory potential against B cell receptor signaling. Although the frequency of this polymorphism was low in Caucasians, another polymorphism within the promoter region was reported to be associated with SLE. KIR/HLA combinations have been shown to be associated with various autoimmune and infectious diseases. Recently, LILR families have also been found to be highly polymorphic, and association with several diseases has been identified. These results emphasize the role of multigene families in the diversity of human immune response and susceptibility to diseases.


Surface modification of Ni-rich LiNi0.8Co0.1Mn0.1O2 with perovskite LaFeO3 for high voltage cathode materials.
Ni-rich LiNi0.8Co0.1Mn0.1O2 (NCM811) is regarded as a potential cathode material due to its higher capacity. However, the severe capacity fading which occurs above 4.2 V vs. Li/Li+ needs to be addressed to enhance the electrochemical performance. Herein, we report the surface modification of NCM811 cathodes with a perovskite material, i.e., lanthanum iron oxide (LaFeO3), which has drawn attention for various research areas due to its non-toxicity, electric conductivity, chemical stability, and low cost and systematically investigate the influence of the LaFeO3 coating on NCM811. The LaFeO3 coating layer significantly protects the cathode material from corrosion due to the HF formation and restrains the dissolution of other ions into liquid electrolyte during high voltage charge-discharge processes. Even after 80 cycles, 0.5 wt% LaFeO3-coated NCM811 cathode material shows about 13% higher cycling stability when compared to the bare NCM811 and other ratios of coated materials. Furthermore, the 0.5 wt% LaFeO3-coated NCM811 delivers excellent rate capability and demonstrates improved structural stability at 4.6 V vs. Li/Li+ under high voltage conditions with Ni-rich cathode active materials.


A further comparison of radioassay results for serum and plasma.
We evaluated results for serum vs. plasma for 12 selected radioassay procedures. Blood samples were collected with heparin, oxalate-fluoride, or ethylenediaminetetraacetate as anticoagulant and compared with the corresponding serum samples. In combination with a previous report [Kubasik, N.P., and Sine, H.E., Clin. Chem. 24 137 (1978)] we have now tested a total of 25 different analytes, using 31 manufacturers' kits. Differences were again demonstrated between serum and plasma that may be of sufficient magnitude to alter clinical interpretation of the results. Assays also demonstrated differences based on the procedure used.


Effectively leading for quality.
Although significant advances have occurred in medical and related sciences, the quality improvement and patient safety movements have been slow to gain traction. There are many "pockets" of progress around the globe; however, the scale and spread has been slow. Stimulating culture and system change in healthcare requires a definitive change in leadership style and approach. Health leaders of today must commit to the critical success factors and demonstrate the attributes necessary to create change and raise the bar for quality improvement and safety.


Dimensional assessment of DSM-5 social anxiety symptoms among university students and its relationship with functional impairment.
Social anxiety disorder is a common condition often associated with severe impairment in educational career. The aim of this paper was to evaluate prevalence rates and correlates of mild, moderate, and severe forms of social anxiety spectrum in a large sample of university students. Overall, 717 university students were assessed with the Social Anxiety Spectrum Self-Report questionnaire. Using two cut-off scores, 61.4% of subjects were classified as low scorers, 10% as medium scorers, and 28.6% as high scorers. Both high and medium scorers reported fears related to social situations. Interpersonal sensitivity and specific phobias were more common among women with low scores. Childhood/adolescence social anxiety features were more common among males with medium scores. Behavioral inhibition was more common among males with high scores. Functional impairment was severe among high scorers and, to a lesser extent, among medium scorers. Social anxiety spectrum is largely represented among university students. Future studies should investigate whether sufferers of social phobia underachieve or end their professional objectives prematurely.


Stress and fitness in parthenogens: is dormancy a key feature for bdelloid rotifers?
Bdelloid rotifers are the most common and abundant group of animals that reproduce by ameiotic parthenogenesis, only. They are common in temporally ephemeral habitats, and it is unclear if they dwell in unstable habitats because are excluded from better conditions by stronger competitors, or because they need unstable conditions for their success. We tested the hypothesis that bdelloids 'require' stressful conditions for their persistence by comparing fitness-related traits of stressed (desiccated, D) and unstressed (hydrated, H) lines of two species, Adineta ricciae and Macrotrachela quadricornifera. For both bdelloid species, fecundity was significantly lower in H than in parallel D line. Fitness components decreased with time progressively in the H line but not in the D line. Recovery rates of D lines were recorded after every desiccation and did not reveal any trend in time, suggesting that no selection was operating. Stress in the form of reiterated desiccations seemed to help both bdelloid species to keep fitness stable; in contrast under stable conditions, like permanent hydration, these bdelloid species had poorer performances. Bdelloids, although aquatic animals, are not only efficient in tolerating desiccation, but seem somehow dependent on anhydrobiosis, a circumstance that might represent a key event in their life cycle. If this is true, life in unpredictable habitats should not be seen as the result of competitive exclusion from 'easier' habitats, but a requirement for long-term survival of these parthenogenetic animals.


Associations between genetic variation in one-carbon metabolism and LINE-1 DNA methylation in histologically normal breast tissues.
Genome-wide DNA hypomethylation is an early event in the carcinogenic process. Percent methylation of long interspersed nucleotide element-1 (LINE-1) is a biomarker of genome-wide methylation and is a potential biomarker for breast cancer. Understanding factors associated with percent LINE-1 DNA methylation in histologically normal tissues could provide insight into early stages of carcinogenesis. In a cross-sectional study of 121 healthy women with no prior history of cancer who underwent reduction mammoplasty, we examined associations between plasma and breast folate, genetic variation in one-carbon metabolism, and percent LINE-1 methylation using multivariable regression models (adjusting for race, oral contraceptive use, and alcohol use). Results are expressed as the ratio of LINE-1 methylation relative to that of the referent group, with the corresponding 95% confidence intervals (CI). We found no significant associations between plasma or breast folate and percent LINE-1 methylation. Variation in MTHFR, MTR, and MTRR were significantly associated with percent LINE-1 methylation. Variant allele carriers of MTHFR A1289C had 4% lower LINE-1 methylation (Ratio 0.96, 95% CI 0.93-0.98), while variant allele carriers of MTR A2756G (Ratio 1.03, 95% CI 1.01-1.06) and MTRR A66G (Ratio 1.03, 95% CI 1.01-1.06) had 3% higher LINE-1 methylation, compared to those carrying the more common genotypes of these SNPs. DNA methylation of LINE-1 elements in histologically normal breast tissues is influenced by polymorphisms in genes in the one-carbon metabolism pathway. Future studies are needed to investigate the sociodemographic, environmental and additional genetic determinants of DNA methylation in breast tissues and the impact on breast cancer susceptibility.


Concerns and potential improvements in end-of-life care from the perspectives of older patients and informal caregivers: a scoping review.
Overtreatment in advanced age i.e. aggressive interventions that do not improve survival and are potentially harmful, can impair quality of care near the end of life (EOL). As healthcare provider perspectives on care quality may differ from that of service users, the aim of this study was to explore the views of older patients near EOL or their caregivers about the quality of health care at the EOL based on their lived experience, and to identify healthcare service improvements. Medline and backward citation searches were conducted for qualitative or quantitative studies reported on the views of patients and/or informal caregivers about EOL care quality. Thematic analysis was used to summarise qualitative data (primary analysis); narrative and tabulations were used to summarise quantitative data (secondary analysis). Thirty articles met the inclusion criteria. Five main qualitative themes regarding quality care emerged: (1) Effective communication between clinicians and patients/caregivers; (2) Healthcare that values patient preferences and shared decision making; (3) Models of care that support quality of life and death with dignity; (4) Healthcare services that meet patient expectations; and (5) Support for informal caregivers in dealing with EOL challenges. The quantitative articles supported various aspects of the thematic framework. The findings of this study show that many of the issues highlighted by patients or bereaved relatives have persisted over the past two decades. There is an urgent need for comprehensive evaluation of care across the healthcare system and targeted redesign of existing EOL care pathways to ensure that care aligns with what patients and informal caregivers consider high-quality patient-centred care at the EOL.


Immunological and clinical efficacy of COVID-19 vaccines in immunocompromised populations: a systematic review.
Available data show that COVID-19 vaccines may be less effective in immunocompromised populations, who are at increased risk of severe COVID-19. We conducted a systematic review of literature to assess immunogenicity, efficacy and effectiveness of COVID-19 vaccines in immunocompromised populations. We searched Medline and Embase databases. We included studies of COVID-19 vaccines after complete vaccination in immunocompromised patients until 31 August 2021. Studies with <10 patients, safety data only and case series of breakthrough infections were excluded. Risk of bias was assessed via the tool developed by the National Institutes of Health on interventional and observational studies. Immunogenicity was assessed through non-response rate defined as no anti-SARS-CoV-2 spike protein antibodies, efficacy and effectiveness by the relative reduction in risk of SARS-CoV-2 infection or COVID-19. We collected factors associated with the risk of non-response. We presented collected data by immunosuppression type. We screened 5917 results, included 162 studies. There were 157 on immunogenicity in 25 209 participants, including 7835 cancer or haematological malignancy patients (31.1%), 6302 patients on dialysis (25.0%), 5974 solid organ transplant recipients (23.7%) and 4680 immune-mediated disease patients (18.6%). Proportion of non-responders seemed higher among solid organ transplant recipients (range 18-100%) and patients with haematological malignancy (range 14-61%), and lower in patients with cancer (range 2-36%) and patients on dialysis (range 2-30%). Risk factors for non-response included older age, use of corticosteroids, immunosuppressive or anti-CD20 agent. Ten studies evaluated immunogenicity of an additional dose. Five studies evaluated vaccine efficacy or effectiveness: three on SARS-CoV-2 infection (range 71-81%), one on COVID-19-related hospitalization (62.9%), one had a too small sample size. This systematic review highlights the risk of low immunogenicity of COVID-19 vaccines in immunocompromised populations, especially solid organ transplant recipients and patients with haematological malignancy. Despite lack of vaccine effectiveness data, enhanced vaccine regimens may be necessary.


Perinatal brain injury.
Perinatal brain damage in the mature fetus is usually brought about by severe intrauterine asphyxia following an acute reduction of the uterine or umbilical circulation. The areas most heavily affected are the parasagittal region of the cerebral cortex and the basal ganglia. The fetus reacts to a severe lack of oxygen with activation of the sympathetic-adrenergic nervous system and a redistribution of cardiac output in favor of the central organs (brain, heart and adrenals). If the asphyxic insult persists, the fetus is unable to maintain circulatory centralization, and the cardiac output and extent of cerebral perfusion fall. Owing to the acute reduction in oxygen supply, oxidative phosphorylation in the brain comes to a standstill. The Na+/K+ pump at the cell membrane has no more energy to maintain the ionic gradients. In the absence of a membrane potential, large amounts of calcium ions flow through the voltage-dependent ion channels, down an extreme extra-/intracellular concentration gradient, into the cell. Current research suggests that the excessive increase in levels of intracellular calcium, so-called calcium overload, leads to cell damage through the activation of proteases, lipases and endonucleases. During ischemia, besides the influx of calcium ions into the cells via voltage-dependent calcium channels, more calcium enters the cells through glutamate-regulated ion channels. Glutamate, an excitatory neurotransmitter, is released from presynaptic vesicles during ischemia following anoxic cell depolarization. The acute lack of cellular energy arising during ischemia induces almost complete inhibition of cerebral protein biosynthesis. Once the ischemic period is over, protein biosynthesis returns to preischemic levels in non-vulnerable regions of the brain, while in more vulnerable areas it remains inhibited. The inhibition of protein synthesis, therefore, appears to be an early indicator of subsequent neuronal cell death. A second wave of neuronal cell damage occurs during the reperfusion phase. This cell damage is thought to be caused by the postischemic release of oxygen radicals, synthesis of nitric oxide (NO), inflammatory reactions and an imbalance between the excitatory and inhibitory neurotransmitter systems. Part of the secondary neuronal cell damage may be caused by induction of a kind of cellular suicide programme known as apoptosis. Interestingly, there is increasing evidence from recent clinical studies that perinatal brain damage is closely associated with ascending intrauterine infection before or during birth. However, a major part of this damage is likely to be of hypoxic-ischemic nature due to LPS-induced effects on fetal cerebral circulation. Knowledge of these pathophysiological mechanisms has enabled scientists to develop new therapeutic strategies with successful results in animal experiments. The potential of such therapies is discussed here, particularly the promising effects of intravenous administration of magnesium or postischemic induction of cerebral hypothermia.


Lymphocyte subpopulation reference ranges for monitoring human immunodeficiency virus-infected Chinese adults.
Two hundred eight healthy human immunodeficiency virus (HIV) type 1- and HIV type 2-seronegative Chinese adults (78 males and 130 females; mean age, 32 years; age range, 18 to 71 years) were analyzed for lymphocyte subsets by a standardized and quality-controlled flow cytometric immunophenotyping technique. While the leukocyte differential values were comparable to those found in studies of Caucasians, the means, medians, and 95% reference ranges of lymphocyte subsets were very different. The 95% reference ranges in absolute counts per microliter of whole blood (percentage of lymphocytes) for CD3+, CD3+ CD4+, CD3+ CD8+, CD3- CD19+ (B), and CD3- with CD16+ and/or CD56+ (NK) cells were 672 to 2,368 (54.8 to 83.0%), 292 to 1,366 (23.1 to 51.0%), 240 to 1,028 (17.9 to 47.5%), 82 to 560 (5.1 to 20.8%), and 130 to 938 (7.1 to 38.0%), respectively. CD3+ CD4+ cells showed significant sex difference (for males, mean of 702 [34.8%] and standard deviation of 258 [7.5%]; for females, mean of 728 [37.3%] and standard deviation of 254 [7.4%]) as well as an increase with age of 42 (1.6%) per decade. Investigations of the NK cell population did not show similar findings. Classification of HIV disease, treatment, and prophylactic regimens based on studies which relied heavily on estimations of lymphocyte subsets alone should be used with special caution for Chinese patients. Provided that adequate quality control measures are taken to ensure comparability of data, we recommend that these ranges be used on a day-to-day basis in laboratories that have not yet established their own reference ranges.


Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia.
Tyrosine kinase inhibitors (TKI) against Bcr-Abl are the first-line therapeutics for chronic myelogenous leukemia (CML). However, the resistance to Bcr-Abl TKIs is induced in leukemic cells not only by loss of sensitivity to TKIs through Bcr-Abl-related molecular mechanisms but also by loss of addiction to Bcr-Abl TK activity by acquiring Bcr-Abl-unrelated additional oncogenic mutations. Therefore, the identification of an additional therapeutic target has been anticipated for achievement of a complete cure and to overcome resistance to treatment. We here showed that modified human Galectin-9 (hGal9), a lectin that show specific affinity for beta-galactosides, inhibits the proliferation of five CML-derived cell lines by inducing apoptosis at their IC(50)s from 17.5 to 164.9 nmol/L. Our study revealed that activating transcription factor 3 (ATF3), a member of the ATF/cAMP-responsive element binding protein family transcription factors, is the critical mediator for cell killing by hGal9, and that Noxa is one of the downstream effector molecules of ATF3. Bim, on the other hand, the BH3-only protein essential for apoptosis by Bcr-Abl TKIs, was not associated with hGal9-induced cell death. ATF3-mediated cell death by hGal9 was not hampered by the absence of p53, the presence of mutant Abl(T315I), or by P-glycoprotein overexpression. In addition, hGal9 showed the additive growth-inhibitory effect with imatinib on CML cell lines. Collectively, hGal9 is a candidate agent that may overcome various kinds of resistance to treatment for CML and may suggest that ATF3 may be a new target molecule for the development of new treatment modalities that can overcome resistance to currently available chemotherapeutics.


An immunohistochemical study of EGFR expression in colorectal cancer and its correlation with lymph nodes status and tumor grade.
Colorectal cancer (CRC) is a common human malignancy. Epidermal growth factor receptor (EGFR) is expressed in wide variety of human malignancies and is of some therapeutic and prognostic utility. The relationship between EGFR expression and regional lymph nodes involvement, and tumor grade in CRC has not been cleared, thus we decided to show it in a case-control study. We chose paraffin-embedded tissue blocks of 46 CRCs with regional lymph nodes involvement as case group, and 46 CRCs without lymph nodes involvement as control group and then performed immunohistochemical staining for both groups. Moderate to strong, and complete staining of more than 10% of tumor cells was regarded as EGFR-positive. In analysis, P-value less than 0.05 was considered as significant. EGFR expression was positive in 80.4% and 56.5% of patients in the case and the control groups, respectively, which the difference between them was statistically significant. EGFR was positive in 48% of grade I, 60% of grade II and 100% of grade III tumors. EGFR expression had relationship with lymph node involvement and tumor grade in CRC. Also, lymph node-involved CRCs showed higher scores of EGFR staining than control group. Thus, EGFR may be an additional factor to develop more aggressive CRCs and may predict the probability of lymph node involvement in these tumors.


Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes.
Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.


A role for the Rcs phosphorelay in regulating expression of plant cell wall degrading enzymes in Pectobacterium carotovorum subsp. carotovorum.
The Rcs phosphorelay is a signal transduction system that influences the virulence phenotype of several pathogenic bacteria. In the plant pathogen Pectobacterium carotovorum subsp. carotovorum (Pcc) the response regulator of the Rcs phosphorelay, RcsB, represses expression of plant cell wall degrading enzymes (PCWDE) and motility. The focus of this study was to identify genes directly regulated by the binding of RcsB that also regulate expression of PCWDE genes in Pcc. RcsB-binding sites within the regulatory regions of the flhDC operon and the rprA and rsmB genes were identified using DNase I protection assays, while in vivo studies using flhDC : : gusA, rsmB : : gusA and rprA : : gusA gene fusions revealed gene regulation. These experiments demonstrated that the operon flhDC, a flagellar master regulator, was repressed by RcsB, and transcription of rprA was activated by RcsB. Regulation of the rsmB promoter by RcsB is more complicated. Our results show that RcsB represses rsmB expression mainly through modulating flhDC transcription. Neverthless, direct binding of RcsB on the rsmB promoter region is possible in certain conditions. Using an rprA-negative mutant, it was further demonstrated that RprA RNA is not essential for regulating expression of PCWDE under the conditions tested, whereas overexpression of rprA increased protease expression in wild-type cells. Stationary-phase sigma factor, RpoS, is the only known target gene for RprA RNA in Escherichia coli; however, in Pcc the effect of RprA RNA was found to be rpoS-independent. Overall, our results show that the Rcs phosphorelay negatively affects expression of PCWDE by inhibiting expression of flhDC and rsmB.


p63 and p73, the ancestors of p53.
p73 and p63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, p73 and p63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides overlapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for p63 and p73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and p73 knockout mouse phenotypes. Here, we describe the contribution of p63 and p73 to human pathology with emphasis on their roles in tumorigenesis and development.


Sea urchin coelomocytes specifically express a homologue of the complement component C3.
A homologue of complement component C3 (SpC3) has been cloned and sequenced from the purple sea urchin, Strongylocentrotus purpuratus. The preprocessed, deduced protein size is estimated to be 186 kDa with a short leader and two chains, alpha and beta. There are cysteines in conserved positions for interchain disulfide bonding, and there is a conserved thioester site in the alpha-chain with an associated histidine. There are five consensus N-linked glycosylation sites, and putative cleavage sites for factor I and C3 convertase. Partially purified SpC3 on protein gels shows a nonreduced size of 210 kDa and, under reducing conditions, reveals an alpha-chain of 130 kDa and a beta-chain of 80 kDa. These sizes are larger than the deduced sizes, suggesting that the protein has carbohydrates added to most of the consensus N-linked glycosylation sites. Phylogenetic analysis of SpC3 compared with other members of the thioester protein family, which includes C3, C4, C5, and alpha2-macroglobulin, shows that SpC3 is the first divergent complement protein, falling at the base of the complement protein clade. Transcripts from the SpC3 gene (Sp064) are 9 kb, and the gene is expressed specifically in coelomocytes, which are the immunocytes in the sea urchin. Genome blots suggest that SpC3 is encoded by a single copy gene per haploid genome. This is the first identification of a complement component in an invertebrate, and suggests homology of the innate immune system within the deuterostome lineage of animals.


Non-Invasive Assessment of Liver Fibrosis and Steatosis in End-Stage Renal Disease Patients Undergoing Renal Transplant Evaluation.
Non-alcoholic fatty liver disease (NAFLD) has an increased prevalence in end-stage renal disease (ESRD) due to similar risk factors. The aim of this study was to assess non-invasive testing including transient elastography (TE) for liver stiffness (LS), controlled attenuated parameter (CAP) for steatosis, Fibrosis-4 (FIB-4) score, aspartate aminotransferase (AST) to platelet ratio index (APRI) and NAFLD fibrosis score (NFS), for evaluation of NAFLD along with advanced fibrosis (AF) in patients with ESRD undergoing renal transplant evaluation. Data were retrospectively collected within 12 weeks of TE. Primary outcomes were AF, defined by LS ≥ 9 kPa compared to APRI > 1.5, FIB-4 > 2.67, and NFS of 0.675, and ≥ 5% steatosis by CAP ≥ 263 dB/m compared to liver histology when available. A total of 171 patients were evaluated: mean age 56, 65% male, 36% obese, 47% had diabetes, 96% hypertension, and 56% dyslipidemia. Mean LS was 6.5 kPa with 21% having AF. Mean CAP was 232 dB/m, with 25% having steatosis. Those with AF were older with higher NFS. Those with steatosis were obese and had diabetes without higher LS or fibrosis scores. Only NFS was associated with LS ≥ 9 kPa. In those with liver histology, AF was associated with LS ≥ 9 kPa but not with APRI, FIB-4, or NFS. Despite normal liver enzymes, non-invasive assessment via TE in ESRD patients exhibited high prevalence of AF and steatosis not detected by APRI or FIB-4 scores. This high prevalence was secondary to the common risk factors such as obesity and diabetes, among patients with NAFLD and ESRD.


The Age Factor in Adaptability of a Sarcoma Virus to Other Animal Species.
The age of the chicken in which the Rous sarcoma is grown has an influence on the variation and subsequent adaptation of the causative virus to ducks. Adaptation is relatively easy to accomplish when the tumor has been grown in adult chickens several months of age. It has never been accomplished when the tumor has been grown in chicks and only occasionally when it has been grown in old chickens.


Prediction models for mortality in adult patients visiting the Emergency Department: a systematic review.
We provide a systematic overview of literature on prediction models for mortality in the Emergency Department (ED). We searched various databases for observational studies in the ED or similar setting describing prediction models for short-term mortality (up to 30 days or in-hospital mortality) in a non-trauma population. We used the CHARMS-checklist for quality assessment. We found a total of 14.768 articles and included 17 articles, describing 22 models. Model performance ranged from AUC 0.63-0.93. Most articles had a moderate risk of bias in one or more domains. The full model and PARIS model performed best, but are not yet ready for implementation. There is a need for validation studies to compare multiple prediction models and to evaluate their accuracy.


Health status: types of validity and the index of well-being.
The concept of validity as it applies to measures of health and health status is examined in the context of a set of standard, widely accepted definitions of validity. Criterion validity is shown to be irrelevant to health status measures because of the lack of a single specific, directly observable measure of health for use as a criterion. To overcome this problem, the Index of Well-being has been constructed to fulfill the definition of content validity by including all levels of function and symptom/problem complexes, a clearly defined relation to the death state, and consumer ratings of the relative desirability of the function levels. Data from a two-wave household interview survey provide convergent evidence of construct validity by demonstrating an expected positive correlation of the Index of Well-being with self-rated well-being and expected negative correlations with age, number of chronic medical conditions, number of reported symptoms or problems, number of physician contacts, and dysfunctional status. Discriminant evidence of construct validity is demonstrated by predicted differences in correlation between concurrent Index of Well-being scores and self-assessed overall health status, and between the Index of Well-being scores and self-rated well-being on different days. A simple method of estimating a currently usable comprehensive population index of health status, the Weighted Life Expectancy, is described.


The QTc effect of low-dose methadone for chronic pain: a prospective pilot study.
Methadone is associated with QT prolongation and serious cardiac complications, but this has been primarily demonstrated in opioid dependent patients receiving moderate to high doses. This study investigates the effect of low-dose methadone on the QTc interval in a chronic pain population. We conducted a prospective cohort study in a chronic pain clinic including 82 patients receiving methadone and 102 patients receiving non-methadone opioid therapy. We analyzed automated QTc calculations from 12-lead electrocardiograms at baseline and during the subsequent 6 months. The primary outcome of interest was the incidence of QTc greater than 470 milliseconds or an increase from baseline of greater than 60 milliseconds. The methadone group did not manifest an overall higher frequency of QTc > 470 milliseconds (6% for the methadone group vs 5% for controls, P = 0.722) or an increase in the QTc of > 60 milliseconds (4% for the methadone group vs 4% for controls, P = 0.94). In the first month after initiating methadone, patients demonstrated an increase in QTc compared to controls (5% for the methadone group vs 0% for the controls, P = 0.073) but the difference disappeared in the third and sixth months. Data from our chronic pain clinic support a potential association of QTc prolongation during the initiation of methadone, but this effect is small and short lived. We believe larger scale studies to further characterize the safety profile of low-dose methadone are warranted.


Literature review: using pictographs in discharge instructions for older adults with low-literacy skills.
To evaluate current visual aids used in health education; to explore evidence regarding the use of pictographs (simple line drawings showing explicit health care actions); and to provide suggestions for uses of pictographs in discharge instructions for older adults with low-literacy skills. Discharge instructions consist of recommended homecare actions. However, these healthcare actions are provided in text-based discharge instructions, which are often difficult for patients with low-literacy skills to follow precisely at home. Various forms of visual aids are currently used to improve health education; however, the appropriateness of these visual aids for educating discharge instructions for older adults with low-literacy skills is unknown. A narrative literature review. Eligible articles were identified via electronic searches of databases. In total, 44 articles were reviewed and analysed. Among various visual aids, pictographs using simple line drawings combined with simplified text are the most efficient and effective tool to improve discharge education. Indeed, pictographs are well suited to show a step-by-step procedure of complex and lengthy discharge instructions consisting of multiple actions, thus making an entire action sequence easier to learn. By using pictographs with simplified text, healthcare educators can improve discharge instructions for low-literate older adults. Further research is needed to develop pictographs representing explicit healthcare actions themselves rather than concepts associated with healthcare actions; and to examine the effects of pictographs on adherence and health outcomes. Healthcare education materials using pictographs provide effective strategies in improving discharge education for low-literate older adults in acute healthcare settings where nurses have primary responsibility as a first line of healthcare providers. It can also serve as an efficient tool to improve health education for immigrants speaking English as a second language.


Influence of temperature and soil water content on bacterial, archaeal and denitrifying microbial communities in drained fen grassland soil microcosms.
In this study, microcosms were used to investigate the influence of temperature (4 and 28 degrees C) and water content (45% and 90% WHC) on microbial communities and activities in carbon-rich fen soil. Bacterial, archaeal and denitrifier community composition was assessed during incubation of microcosms for 12 weeks using terminal restriction fragment length polymorphism (T-RFLP) profiling of 16S rRNA and nitrous oxide reductase (nosZ) genes. In addition, microbial and denitrifier abundance, potential denitrification activity and production of greenhouse gases were measured. No detectable changes were observed in prokaryote or denitrifier abundance. In general, cumulatively after 12 weeks more carbon was respired at the higher temperature (3.7 mg CO(2) g(-1) soil), irrespective of the water content, whereas nitrous oxide production was greater under wet conditions (98-336 microg N(2)O g(-1) soil). After an initial lag phase, methane emissions (963 microg CH(4) g(-1) soil) were observed only under warm and wet conditions. T-RFLP analyses of bacterial 16S rRNA and nosZ genes revealed small or undetectable community changes in response to temperature and water content, suggesting that bacterial and denitrifying microbial communities are stable and do not respond significantly to seasonal changes in soil conditions. In contrast, archaeal microbial community structure was more dynamic and was strongly influenced by temperature.


A comparative study of the binding and inhibition of four copper-containing amine oxidases by azide: implications for the role of copper during the oxidative half-reaction.
Copper amine oxidases (CuAOs) catalyze the oxidative deamination of primary amines operating through a ping-pong bi-bi mechanism. In this work, azide (an exogenous monodentate ligand) was used to probe the role of copper during the oxidative half-reaction of CuAO catalysis. The effects of azide on both the reductive and oxidative half-reactions of pea seedling amine oxidase (PSAO), the recombinant human kidney diamine oxidase (rhDAO), Arthrobacter globiformis amine oxidase (AGAO), and Pichia pastoris amine oxidase (PPLO) have been examined. For the reductive half-reaction, defined as the oxidation of amine substrate to an aldehyde, azide was discovered to exhibit either noncompetitive or competitive inhibition with respect to the amine, depending on the enzyme source. With regard to the oxidative half-reaction, defined as the reoxidation of the enzyme via reduction of O(2) to H(2)O(2), azide has been determined to exhibit competitive inhibition with respect to O(2) in PSAO with a calculated K(i) value that is in excellent agreement with the experimentally determined K(d) value for the Cu(II)-N(3)(-) complex. Azide was found to exhibit mixed-type/partially competitive inhibition with respect to substrate O(2) in rhDAO, with an apparent K(i) that is similar to the K(d) value for the Cu(II)-N(3)(-) complex. The competitive inhibition for PSAO and the partially competitive inhibition for rhDAO are consistent with O(2) interacting directly with copper during enzymatic reoxidation. For the enzymes AGAO and PPLO, pure noncompetitive and mixed-type/partially competitive inhibition is observed. K(i) values for reductive and oxidative half-reactions are equivalent and are lower than measured K(d) values for the Cu(II)-N(3)(-) complexes in oxidized and substrate-reduced forms of these enzymes. Given these observations, it appears that substantial inhibition of the reductive half-reaction occurs at the concentrations of azide used for the oxidative half-reaction experiments, thereby complicating kinetic interpretation. At this time, the data do not permit us to distinguish between two possibilities: (1) inhibition by azide with respect to O(2) is intrinsically competitive in CuAOs, but this effect cannot always be deconvolved experimentally from the effects of azide on the reductive half-reaction; or (2) CuAOs differ in some steps of their reoxidation mechanisms.


Ecological boundaries in the context of hierarchy theory.
Ecological boundaries have been described as being multiscalar or hierarchical entities. However, the concept of the ecological boundary has not been explicitly examined in the context of hierarchy theory. We explore how ecological boundaries might be envisioned as constituents of scalar hierarchical systems. Boundaries may be represented by the surfaces of constituents or as constituents themselves. Where surfaces would correspond to abrupt transition zones, boundary systems might be quite varied depending on hierarchical context. We conclude that hierarchy theory is compatible with a functional vision of ecological boundaries where functions can be largely represented as the processing or filtering of ecological signals. Furthermore, we postulate that emergent ecological boundaries that arise on a new hierarchical level may contribute to the overconnectedness of mature ecosystems. Nevertheless, a thermodynamic approach to the emergence and development of boundary systems does indicate that in many situations, ecological boundaries would persist in time by contributing to the energy production of higher hierarchical levels.


Correlates between autoantibodies to nucleolar antigens and clinical features in patients with systemic sclerosis (scleroderma).
Immunofluorescence on rat liver sections was used to select high-titer antinucleolar antibodies (ANoA) in the sera of patients with systemic sclerosis (scleroderma). In 646 patients, 53 ANoA sera (8%) were identified, and of these, 46 were available in sufficient quantities for further analysis. The complex of RNA polymerase I was immunoprecipitated by 7 sera (15%), which uniformly produced punctate nucleolar staining. The PM-Scl antigen, a particle consisting of 11 polypeptides, was immunoprecipitated by 8 sera (17%), all of which displayed homogeneous nucleolar staining. A 34-kd nucleolar protein (fibrillarin) of the U3 RNP complex was positive in immunoblotting of 22 sera (48%), which characteristically produced clumpy nucleolar staining. Antibodies against RNA polymerase I were associated with diffuse scleroderma of short duration, which was characterized by a high prevalence of internal organ involvement, including renal crisis. Anti-U3 RNP antibodies had a high prevalence in men with significantly less joint involvement, compared with ANoA-negative patients. Anti-PM-Scl antibodies identified a group of scleroderma patients with a high prevalence of concomitant myositis and renal involvement.


Thy-1+ Cancer-associated Fibroblasts Adversely Impact Lung Cancer Prognosis.
Cancer-associated fibroblasts (CAFs) regulate diverse intratumoral biological programs and can promote or inhibit tumorigenesis, but those CAF populations that negatively impact the clinical outcome of lung cancer patients have not been fully elucidated. Because Thy-1 (CD90) marks CAFs that promote tumor cell invasion in a murine model of KrasG12D-driven lung adenocarcinoma (KrasLA1), here we postulated that human lung adenocarcinomas containing Thy-1+ CAFs have a worse prognosis. We first examined the location of Thy-1+ CAFs within human lung adenocarcinomas. Cells that co-express Thy-1 and α-smooth muscle actin (αSMA), a CAF marker, were located on the tumor periphery surrounding collectively invading tumor cells and in perivascular regions. To interrogate a human lung cancer database for the presence of Thy-1+ CAFs, we isolated Thy-1+ CAFs and normal lung fibroblasts (LFs) from the lungs of KrasLA1 mice and wild-type littermates, respectively, and performed global proteomic analysis on the murine CAFs and LFs, which identified 425 proteins that were differentially expressed. Used as a probe to identify Thy-1+ CAF-enriched tumors in a compendium of 1,586 lung adenocarcinomas, the presence of the 425-gene signature predicted a significantly shorter survival. Thus, Thy-1 marks a CAF population that adversely impacts clinical outcome in human lung cancer.


Recovery of Homogeneous Platinoid Catalysts from Pharmaceutical Media: Review on the Existing Treatments and the Perspectives of Membrane Processes.
Catalyst recovery is a major challenge for reaching the objectives of green chemistry for industry. Indeed, catalysts enable quick and selective syntheses with high reaction yields. This is especially the case for homogeneous platinoid catalysts which are almost indispensable for cross-coupling reactions often used by the pharmaceutical industry. However, they are based on scarce, expensive, and toxic resources. In addition, they are quite sensitive and degrade over time at the end of the reaction. Once degraded, their regeneration is complex and hazardous to implement. Working on their recovery could lead to highly effective catalytic chemistries while limiting the environmental and economic impacts of their one-time uses. This review aims to describe and compare conventional processes for metal removal while discussing their advantages and drawbacks considering the objective of homogeneous catalyst recovery. Most of them lead to difficulty recycling active catalysts due to their ability to only treat metal ions or to chelate catalysts without the possibility to reverse the mechanism. However, membrane processes seem to offer some perspectives with limiting degradations. While membranes are not systematically the best option for recycling homogeneous catalysts, current development might help improve the separation between pharmaceutical active ingredients and catalysts and enable their recycling.


New prospectives on treatment opportunities in RASopathies.
The RASopathies are a group of clinically defined developmental syndromes caused by germline variants of the RAS/mitogen-activated protein (MAPK) cascade. The prototypic RASopathy is Noonan syndrome, which has phenotypic overlap with related disorders such as cardiofaciocutaneous syndrome, Costello syndrome, Noonan syndrome with multiple lentigines, and others. In this state-of-the-art review, we summarize current knowledge on unmet therapeutic needs in these diseases and novel treatment approaches informed by insights from RAS/MAPK-associated cancer therapies, in particular through inhibition of MEK1/2 and mTOR in patients with severe disease manifestations. We explore the possibilities of integrating a larger arsenal of molecules currently under development into future care plans. Lastly, we describe both medical and ethical challenges and opportunities for future clinical trials in the field.


Induction of the heat shock response of E. coli through stabilization of sigma 32 by the phage lambda cIII protein.
The cIII protein of phage lambda favors the lysogenic response to infection by inhibiting the degradation of the lambda cII protein, which exerts the primary control on the developmental decision for lysis or lysogeny. To study the mechanism and scope of cIII-mediated regulation, we have used plasmid systems to examine the specific effect of cIII overproduction on the growth of Escherichia coli and the synthesis of bacterial proteins. We have found that maximal production of cIII prolongs the heat-induced synthesis of E. coli heat shock proteins and provokes elevated production of heat shock proteins even at low temperature. The overproduction of heat shock proteins is correlated with a rapid inhibition of cell growth, as judged by measurements of optical density. We suggest that an overactive heat shock response inhibits bacterial growth, either because excessive production of one or more of the proteins is highly deleterious or because only heat shock promoters are transcribed efficiently. To examine the effect of cIII on sigma 32, the specificity factor for the heat shock response, we have studied the stability of sigma 32 in cells carrying both cIII- and sigma 32-producing plasmids; the half-life of sigma 32 is increased fourfold in the presence of cIII. We conclude that overproduction of cIII provokes the heat shock response by increasing the steady-state level of active sigma 32. These studies also support the concept that the rate of expression of heat shock proteins is directly correlated with the amount of active sigma 32 and that regulation of the stability of sigma 32 may be an important factor for control of the heat shock response.


Lactoferrin-deficient neutrophil polymorphonuclear leucocytes in leukaemias: a semiquantitative and ultrastructural cytochemical study.
Semiquantitative analysis of lactoferrin deficiency in neutrophil polymorphonuclear leucocytes in various haematological and non-haematological disease was carried out by scoring polymorphonuclear leucocytes stained for lactoferrin by the immunoperoxidase method. The staining patterns for lactoferrin were classified into four types (0-III) based on the intensity of reaction, and the sum of the ratings of 100 polymorphonuclear leucocytes was considered as "lactoferrin score" with a possible range of 0-300. As a result, significantly low lactoferrin-scores were frequently observed in acute leukaemias and the acute phase of chronic leukaemias. Of 35 cases with leukaemias, lactoferrin-negative polymorphonuclear leucocytes (type 0) were observed in the following cases: eight cases of acute myelogenous leukaemia (8/14), a case of chronic myelogenous leukaemia (1/10) in blast crisis, one of acute promyelocytic leukaemia (1/1), one of acute monocytic leukaemia (1/2), and a case of chronic myelomonocytic leukaemia (1/2) in a transitional phase to an acute myelomonocytic leukaemia. In two cases of acute myelogenous leukaemia, in which the majority of polymorphonuclear leucocytes were negative for lactoferrin, ultrastructural cytochemical study revealed total lack of specific granules in these polymorphonuclear leucocytes. This suggests that lactoferrin is localised in the specific granules of neutrophils as has been postulated previously by others.


Frailty and Transplantation.
Consequences of aging are gaining clinical relevance. In transplantation, aging and immunosenescence impact treatment and outcomes. The impact of aging, however, will critically depend on distinguishing healthy, chronological aging from biological aging that may result into frailty. Approximately 15% of individuals older than 65 years are frail, and it is expected that this condition will gain more clinical relevance with an expected increase to greater than 20% over the next 5 years. Clearly, frailty impacts various general aspects of health care and organ transplantation in particular including patient selection, waitlist management and treatment after transplantation. In general, frailty has been characterized by a compromised physiological reserve and an augmented vulnerability. In comparison to healthy aging, inflammatory markers and cytokines are increased in frail older adults. Thus, modifications of the immune response, in addition to physical limitations and changes of metabolism, are likely to impact outcomes after transplantation. Here, we provide a risk assessment of frailty at the time of transplant evaluation and review effects on outcomes and recovery after transplantation. Moreover, we summarize our current understanding of the pathophysiology of frailty and consequences on immune responses and metabolism.


Avidity within the N-terminal anchor drives α-synuclein membrane interaction and insertion.
In the brain, α-synuclein (aSN) partitions between free unbound cytosolic and membrane bound forms modulating both its physiological and pathological role and complicating its study due to structural heterogeneity. Here, we use an interdisciplinary, synergistic approach to characterize the properties of aSN:lipid mixtures, isolated aSN:lipid co-structures, and aSN in mammalian cells. Enabled by the isolation of the membrane-bound state, we show that within the previously described N-terminal membrane anchor, membrane interaction relies both on an N-terminal tail (NTT) head group layer insertion of 14 residues and a folded-upon-binding helix at the membrane surface. Both binding events must be present; if, for example, the NTT insertion is lost, the membrane affinity of aSN is severely compromised and formation of aSN:lipid co-structures hampered. In mammalian cells, compromised cooperativity results in lowered membrane association. Thus, avidity within the N-terminal anchor couples N-terminal insertion and helical surface binding, which is crucial for aSN membrane interaction and cellular localization, and may affect membrane fusion.


Structural changes that occur in scallop myosin filaments upon activation.
Myosin filaments isolated from scallop striated muscle have been activated by calcium-containing solutions, and their structure has been examined by electron microscopy after negative staining. The orderly helical arrangement of myosin projections characteristic of the relaxed state is largely lost upon activation. The oblique striping that arises from alignment of elongated projections along the long-pitched helical tracks is greatly weakened, although a 145 A axial periodicity is sometimes partially retained. The edges of the filaments become rough, and the myosin heads move outwards as their helical arrangement becomes disordered. Crossbridges at various angles appear to link thick and thin filaments after activation. The transition from order to disorder is reversible and occurs over a narrow range of free calcium concentration near pCa 5.7. Removal of nucleotide, as well as dissociation of regulatory light chains, also disrupts the ordered helical arrangement of projections. We suggest that the relaxed arrangement of the projections is probably maintained by intermolecular interactions between myosin molecules, which depend on the regulatory light chains. Calcium binding changes the interactions between light chains and the rest of the head, activating the myosin molecule. Intermolecular contacts between molecules may thus be altered and may propagate activation cooperatively throughout the thick filament.


Niche Breadth and Dominance of Parasitic Insects Sharing the Same Host Species.
A guild of six parasitic insects (Hymenoptera) which attack cocoons of the same sawfly populations was composed of four indigenous and two introduced species. The indigenous parasitoids included the ichneumonids, Pleolophus indistinctus (Prov.), Mastrus aciculatus (Prov.), Gelis urbanus (Brues) and Endasys subclavatus (Say), and the introduced species were the ichneumonid, Pleolophus basizonus (Grav.), and the eulophid, Dahlbominus fuscipennis (Zett.). Their distributions were sampled on five variable requirements, or resource sets. Litter moisture content and seasonal activity varied within plots, and host density, host species, and plant community varied between lots. Although the distributions of the indigenous species overlapped, in relative terms each species occupied one position in the niche space that was poorly exploited by all other guild members. Such an enclave permitted each of the first three species to develop a zone of dominance over the other parasitoids. The introduced species had no recognizable enclave. The most abundant guild member, P. basizononus, was dominant in the sites most favorable to litter-searching parasitoids. It had the broadest niche over the range of litter moisture content and length of seasonal activity, and it interacted more with all other species than any other guild member. It was a better competitor than the next most broadly adapted species, P. indistinctus. Competitive superiority is proposed as the driving force behind abundance, leading to dominance in favorable sites. The density-dependent interaction between individuals, which results in dispersal, appears to be responsible for the occupation of a broader niche.


Involvement of cyclic AMP systems in morphine physical dependence in mice: prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor.
In this study, we examined whether morphine dependence was inhibited by rolipram, a cyclic AMP selective phosphodiesterase inhibitor in mice, since a role for the cyclic AMP systems in the development of morphine dependence has been reported. Mice, which received morphine (10 mg kg(-1) s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing and forepaw tremor following naloxone challenge (5 mg kg(-1) i.p.) on the 6th day. Such mice exhibited a significant elevation of cyclic AMP levels in the thalamus compared to control mice. However, co-administration of rolipram (1 mg kg(-1) i.p.) with morphine for 5 days significantly attenuated the severity of the withdrawal syndrome and the increase in the cyclic AMP levels after the administration of naloxone. In naïve mice, acute morphine treatment (10 mg kg(-1) s.c.) decreased cyclic AMP levels in the thalamus and cerebral cortex 10 min later. The decrease of cyclic AMP levels induced by acute morphine treatment was blocked by co-administration of rolipram (1 mg kg(-1) i.p.). However, acute rolipram did not affect the naloxone-precipitated morphine withdrawal syndrome. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence.


Insights into Hildebrand Solubility Parameters - Contributions from Cohesive Energies or Electrophilicity Densities?
We introduce certain concepts and expressions from conceptual density functional theory (DFT) to study the properties of the Hildebrand solubility parameter. The original form of the Hildebrand solubility parameter is used to qualitatively estimate solubilities for various apolar and aprotic substances and solvents and is based on the square root of the cohesive energy density. Our results show that a revised expression allows the replacement of cohesive energy densities by electrophilicity densities, which are numerically accessible by simple DFT calculations. As an extension, the reformulated expression provides a deeper interpretation of the main contributions and, in particular, emphasizes the importance of charge transfer mechanisms. All calculated values of the Hildebrand parameters for a large number of common solvents are compared with experimental values and show good agreement for non- or moderately polar aprotic solvents in agreement with the original formulation of the Hildebrand solubility parameters. The observed deviations for more polar and protic solvents define robust limits from the original formulation which remain valid. Likewise, we show that the use of machine learning methods leads to only slightly better predictability.


The role of dwelling type on food expenditure: a cross-sectional analysis of the 2015-2016 Australian Household Expenditure Survey.
To explore differences in proportion of food budget and total food expenditure by dwelling type. A cross-sectional study using data from the Australian Bureau of Statistics 2015-2016 Household Expenditure Survey. Food expenditure was examined on multiple categories: fresh fruits, fresh vegetables, pre-prepared meals, meals in restaurants, hotels and clubs, and fast food and takeaway meals, using two-part models and zero-one inflated beta regression models. Dwelling types were categorised as separate house, semi-detached house, low-rise apartment and high-rise apartment. Australia, 2015-2016. Seven thousand three hundred and fifty-eight households from greater capital city areas. Households living in high-rise apartments were estimated to allocate a greater proportion of their food budget to meals in restaurants, hotels and clubs, and to spend more (actual dollars) on that category, compared with other dwelling types. No substantial differences were estimated in the proportion of food budget allocated to the other food categories across dwelling types. The dwelling type households live in may play a role in their food budget. Households living in a high-rise apartment may potentially spend more on meals in restaurants, hotels and clubs than those living in other dwelling types. Given the growth in urban population and the changes in living arrangements, findings point to the critical need for a better understanding of the influence of dwelling types on food expenditure and call for research investigating the relationship between the two.


Genetic counseling and testing for FMR1 gene mutations: practice guidelines of the national society of genetic counselors.
Fragile X syndrome (FXS) is one of several clinical disorders associated with mutations in the X-linked Fragile X Mental Retardation-1 (FMR1) gene. With evolving knowledge about the phenotypic consequences of FMR1 transcription and translation, sharp clinical distinctions between pre- and full mutations have become more fluid. The complexity of the issues surrounding genetic testing and management of FMR1-associated disorders has increased; and several aspects of genetic counseling for FMR1 mutations remain challenging, including risk assessment for intermediate alleles and the widely variable clinical prognosis for females with full mutations. FMR1 mutation testing is increasingly being offered to women without known risk factors, and newborn screening for FXS is underway in research-based pilot studies. Each diagnosis of an FMR1 mutation has far-reaching clinical and reproductive implications for the extended family. The interest in large-scale population screening is likely to increase due to patient demand and awareness, and as targeted pharmaceutical treatments for FXS become available over the next decade. Given these developments and the likelihood of more widespread screening, genetic counselors across a variety of healthcare settings will increasingly be called upon to address complex diagnostic, psychosocial, and management issues related to FMR1 gene mutations. The following guidelines are intended to assist genetic counselors in providing accurate risk assessment and appropriate educational and supportive counseling for individuals with positive test results and families affected by FMR1-associated disorders.


New threshold temperatures for the development of a North American diamondback moth (Lepidoptera: Plutellidae) population and its larval parasitoid, Diadegma insulare (Hymenoptera: Ichneumonidae).
The currently accepted lower threshold temperature for the development of diamondback moth, Plutella xylostella (Lepidoptera: Plutellidae), the world's most destructive insect pest of cruciferous crops, is around 6.0°C, and there is no known upper threshold temperature. Neither are there established threshold temperatures for diamondback moth's major natural enemy, Diadegma insulare (Hymenoptera: Ichneumonidae). Laboratory studies were undertaken to determine the survival and development of a North American diamondback moth population and its parasitoid D. insulare at 20 constant temperatures ranging from 2.0 to 38.0°C. Diamondback moth completed development from second instar to adult within a temperature range of 4.0-37°C, and D. insulare completed its life cycle from egg to adult within a temperature range of 4.0-33°C. The developmental data were fitted into one linear and four nonlinear models. Using goodness-of-fit and the ability to estimate parameters of biological significance as selection criteria, the Wang model was the most acceptable among the nonlinear models to describe the relationship between temperature and development of both species. According to this model, the lower and upper threshold temperatures for diamondback moth were 2.1 and 38.0°C, respectively, and for D. insulare they were 2.1 and 34.0°C, respectively. Based on the Degree Day model, diamondback moth required 143 d above the lower threshold of 4.23°C to complete the life cycle, while D. insulare required 286 d above the lower threshold of 2.57°C. This study suggests that temperatures during the crop-growing seasons in North America are not limiting factors for development of either diamondback moth or D. insulare.


Academic nursing education guidelines: tool for bridging the gap between theory, research and practice.
The aim of the present study was to develop educational guidelines to be used as a tool for the integration of theory, research and practice to ensure that nursing knowledge and practical skills form the basis of academic nursing education. An additional aim was to describe the nursing competence expected of the students at four academic levels: introductory, intermediate and advanced levels I and II. Clinical nursing education plays a crucial role in assisting nursing students to integrate the theory and practice of nursing at the baccalaureate level, as well as in further specialization and in-depth nursing studies at the advanced level. A research group consisting of lecturers from the Institute of Nursing, Göteborg University, Sweden, was given the objective to formulate educational guidelines for clinical practice within nursing education. The study took the form of a literature search. In addition, the Delphi method, aimed at reaching a consensus of opinion among colleagues, was used. Based on the literature review and the collegial discussions, four core concepts emerged: professional stance, reflective processes, problem-solving processes, and practical skills, from which the educational guidelines were developed. Guidelines were formulated both in general and abstract form. They were not connected to a specific care context, specific patient group or specific nursing problems. The most important objective of academic education is that the student develops abilities and techniques necessary for life-long learning. Students will, in their professional life as nurses, continuously meet situations where they are challenged to take appropriate decisions and actions. This demands training in problem-solving, reflection, decision-making and the ability to use both deductive and inductive learning strategies. The guidelines describe what is expected of the students in terms of nursing competence and personal qualifications to ensure that they will be ready to meet the demands of their future profession.


The interrelationship between promoter strength, gene expression, and growth rate.
In exponentially growing bacteria, expression of heterologous protein impedes cellular growth rates. Quantitative understanding of the relationship between expression and growth rate will advance our ability to forward engineer bacteria, important for metabolic engineering and synthetic biology applications. Recently, a work described a scaling model based on optimal allocation of ribosomes for protein translation. This model quantitatively predicts a linear relationship between microbial growth rate and heterologous protein expression with no free parameters. With the aim of validating this model, we have rigorously quantified the fitness cost of gene expression by using a library of synthetic constitutive promoters to drive expression of two separate proteins (eGFP and amiE) in E. coli in different strains and growth media. In all cases, we demonstrate that the fitness cost is consistent with the previous findings. We expand upon the previous theory by introducing a simple promoter activity model to quantitatively predict how basal promoter strength relates to growth rate and protein expression. We then estimate the amount of protein expression needed to support high flux through a heterologous metabolic pathway and predict the sizable fitness cost associated with enzyme production. This work has broad implications across applied biological sciences because it allows for prediction of the interplay between promoter strength, protein expression, and the resulting cost to microbial growth rates.


Measurements of methane emissions from natural gas gathering facilities and processing plants: measurement results.
Facility-level methane emissions were measured at 114 gathering facilities and 16 processing plants in the United States natural gas system. At gathering facilities, the measured methane emission rates ranged from 0.7 to 700 kg per hour (kg/h) (0.6 to 600 standard cubic feet per minute (scfm)). Normalized emissions (as a % of total methane throughput) were less than 1% for 85 gathering facilities and 19 had normalized emissions less than 0.1%. The range of methane emissions rates for processing plants was 3 to 600 kg/h (3 to 524 scfm), corresponding to normalized methane emissions rates <1% in all cases. The distributions of methane emissions, particularly for gathering facilities, are skewed. For example, 30% of gathering facilities contribute 80% of the total emissions. Normalized emissions rates are negatively correlated with facility throughput. The variation in methane emissions also appears driven by differences between inlet and outlet pressure, as well as venting and leaking equipment. Substantial venting from liquids storage tanks was observed at 20% of gathering facilities. Emissions rates at these facilities were, on average, around four times the rates observed at similar facilities without substantial venting.


Plasma norepinephrine level in affective disorders. Relationship to melancholia.
The plasma norepinephrine (NE) level was measured in 45 depressed patients and in 41 normal control subjects. Patients who met DSM-III criteria for a major depressive episode with melancholia (MDE-MEL; N = 16), and those with MDE but with melancholia in a previous episode (MDE-PMEL; N = 8), had significantly higher levels of plasma NE than normal control subjects while lying and standing and a greater change in the levels; whereas, patients with MDE alone (N = 10) and patients with dysthymic disorder (N = 11) had levels of NE comparable with control levels. Bipolar patients (N = 7), all with current melancholia or a history of it, had significantly lower levels of NE while lying down or standing than depressed unipolar patients with similar histories of melancholia. Among unipolar patients with melancholia, nonsuppressors on the dexamethasone suppression test had significantly higher lying-down NE values than did suppressors, suggesting that dysregulation of both the hypothalamic-pituitary-adrenal axis and the peripheral sympathetic nervous system occur together in this subgroup of depressed patients.


An analysis of failed Harrington rods.
Eight mechanically failed Harrington rods have been retrieved and examined clinically, metallurgically, and biomechanically to characterize the mode of instrument failure and to determine how future failure rates might be minimized. The results of the study indicated fatigue to be the mode of mechanical failure in all cases, however, in only one case was any significant metallurgical defect observed. Failure occurred at the ratchet-shaft junction in seven of eight cases with the remaining failure occurring at the midshaft region. This occurred in the rod with the metallurgical defect. The possibility of fatigue failure can be lowered by implementing both clinical and design considerations. Clinically, stress on the rod can be lowered by placing the ratchet-shaft junction as close to the hook as possible and by using the shortest rod possible. Both of these will minimize the moment arm at the vulnerable ratchet-shaft junction. Design modifications, including increased rod diameter, polishing the ratchet-shaft interface and material changes, can also be used to lower the stress on the rods and thus reduce the risk of mechanical failure.


The Equity Tool for Valuing Global Health Partnerships.
Global health partnerships (GHPs) involve complex relationships between individuals and organizations, often joining partners from high-income and low- or middle-income countries around work that is carried out in the latter. Therefore, GHPs are situated in the context of global inequities and their underlying sociopolitical and historical causes, such as colonization. Equity is a core principle that should guide GHPs from start to end. How equity is embedded and nurtured throughout a partnership has remained a constant challenge. We have developed a user-friendly tool for valuing a GHP throughout its lifespan using an equity lens. The development of the EQT was informed by 5 distinct elements: a scoping review of scientific published peer-reviewed literature; an online survey and follow-up telephone interviews; workshops in Canada, Burkina Faso, and Vietnam; a critical interpretive synthesis; and a content validation exercise. Findings suggest GHPs generate experiences of equity or inequity yet provide little guidance on how to identify and respond to these experiences. The EQT can guide people involved in partnering to consider the equity implications of all their actions, from inception, through implementation and completion of a partnership. When used to guide reflective dialogue with a clear intention to advance equity in and through partnering, this tool offers a new approach to valuing global health partnerships. Global health practitioners, among others, can apply the EQT in their partnerships to learning together about how to cultivate equity in their unique contexts within what is becoming an increasingly diverse, vibrant, and responsive global health community.


Autoantibodies to Multiple Epitopes on the Non-Collagenous-1 Domain of Type VII Collagen Induce Blisters.
Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by autoantibodies against type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different epitopes is pathogenically relevant. To address this issue, we generated recombinant proteins covering the entire NC1 domain. IgG reactivity with these proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of antibodies specific to different NC1 subdomains, rabbit antibodies were generated. All these antibodies caused dermal-epidermal separation ex vivo. Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal blisters. We here document that autoantibodies to COL7, independent of the targeted epitopes, induce blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of autoantibodies binding to human COL7.


The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment, Metastasis and Drug Resistance in Colorectal Cancer.
Colorectal cancer (CRC) is one of the most common cancers worldwide, with high morbidity and mortality rates. A number of factors including modulation of the tumor microenvironment, high metastatic capability, and resistance to treatment have been associated with CRC disease progression. Recent studies have documented that tumor-derived extracellular vesicles (EVs) play a significant role in intercellular communication in CRC via transfer of cargo lipids, proteins, DNA and RNAs to the recipient tumor cells. This transfer influences a number of immune-related pathways leading to activation/differentiation/expression of immune cells and modulation of the tumor microenvironment that plays a significant role in CRC progression, metastasis, and drug resistance. Furthermore, tumor-derived EVs are secreted in large amounts in biological fluids of CRC patients and as such the expression analysis of EV cargoes have been associated with prognosis or response to therapy and may be a source of therapeutic targets. This review aims to provide a comprehensive insight into the role of EVs in the modulation of the tumor microenvironment and its effects on CRC progression, metastasis, and drug resistance. On the other hand, the potential role of CRC derived EVs as a source of biomarkers of response and therapeutic targets will be discussed in detail to understand the dynamic role of EVs in CRC diagnosis, treatment, and management.


Adhesion Energy of MoS2 Thin Films on Silicon-Based Substrates Determined via the Attributes of a Single MoS2 Wrinkle.
Understanding the energetics of adhesion between two-dimensional nanomaterials and their supporting substrates is crucial for the design and fabrication of corrersponding structures with controlled interfacial effects that influence phononics, charge-carrier distribution, and electronic response. Here, we show a mechanical energy model that equates the adhesion energy of MoS2 on rigid and flat substrates (SiO2 and Si3N4) to the attributes of a single wrinkle in a MoS2 flake. The amplitude of the observed wrinkles was normalized for thickness (A/t) to select the wrinkles valid for the model. The adhesion energy values of 0.170 ± 0.033 J m-2 for MoS2 on SiO2 and 0.252 ± 0.041 J m-2 for MoS2 on Si3N4 were determined. This mechanical energy model is consistent with the model based on the local equilibrium at the contact point in the Young's equation. We also propose a method to measure the plane-strain in wrinkled MoS2. The geometrical properties (symmetry and normalized dimensions) of wrinkles and substrate effects are also discussed.


Spatial targeting of fibrosis-promoting macrophages with nanoscale metal-organic frameworks for idiopathic pulmonary fibrosis therapy.
Targeted delivery of therapeutic drugs to fibrosis-promoting macrophages (FPMs) holds promise as a challenging yet effective approach for the treatment of idiopathic pulmonary fibrosis (IPF). Here, nanocarriers composed of Mn-curcumin metal-organic frameworks (MOFs) were utilized to deliver the immune inhibitor BLZ-945 to the lungs, with the goal of depleting fibrosis-promoting macrophages (FPMs) from fibrotic lung tissues. FPM targeting was achieved by functionalizing the nanocarrier surface with an M2-like FPM binding peptide (M2pep). As a result, significant therapeutic benefits were observed through the successful depletion of approximately 80% of the M2-like macrophages (FPMs) in a bleomycin-induced fibrosis mouse model treated with the designed M2-like FPM-targeting nanoparticle (referred to as M2NP-BLZ@Mn-Cur). Importantly, the released Mn2+ and curcumin after the degradation of M2NP-BLZ@Mn-Cur accumulated in the fibrotic lung tissue, which can alleviate inflammation and oxidative stress reactions, thereby further improving IPF therapy. This study presents a novel strategy with promising prospects for molecular-targeted fibrosis therapy. STATEMENT OF SIGNIFICANCE: Metal-organic frameworks (MOFs)- based nanocarriers equipped with both fibrosis-promoting macrophage (FPM)-specific targeting ability and therapeutic drugs are appealing for pulmonary fibrosis treatment. Here, we prepared M2pep (an M2-like FPM binding peptide)-modified and BLZ945 (a small molecule inhibitor of CSF1/CSF-1R axis)-loaded Mn-curcumin MOF nanoparticles (M2NP-BLZ@Mn-Cur) for pulmonary fibrosis therapy. The functionalized M2NP-BLZ@Mn-Cur nanoparticles can be preferentially taken up by FPMs, resulting in their depletion from fibrotic lung tissues. In addition, Mn2+ and curcumin released from the nanocarriers have anti-inflammation and immune regulation effects, which further enhance the antifibrotic effect of the nanoparticles.


Associations of Class-Time Sitting, Stepping and Sit-to-Stand Transitions with Cognitive Functions and Brain Activity in Children.
Previous research showed that children's physical activity is positively related to executive functions, whilst screen time shows negative associations. However, it is unclear how school-based sitting time and transitions from sitting to standing relate to cognition. We investigated the relationship between class time sitting/stepping/sit-to-stand transitions and cognitive functions in Grade 1-2 children. Overall, 149 children (7.7 ± 0.6 years old, 54% boys) participated. Measures included class time sitting/stepping/sit-to-stand transitions and: (i) response inhibition (i.e., response time and accuracy); (ii) lapses of attention; (iii) working memory; and (iv) brain activity (cortical haemodynamic response). Linear mixed-models, adjusting for age, sex, and clustering at the classroom level, found that more sitting time was associated with higher lapses of attention (β = 0.12, p < 0.05). Children who stepped more had quicker inhibition response time (β = -0.95, p < 0.01); however, they were less accurate in their responses (β = -0.30, p < 0.05) and this was also observed with sit-to-stand transitions (β = -0.26, p < 0.05). No associations were found with brain activity. In conclusion, reducing and breaking up sitting may help keep children focused, but the evidence regarding response inhibition is unclear.


Combined Prenatal Pesticide Exposure and Folic Acid Intake in Relation to Autism Spectrum Disorder.
Maternal folic acid (FA) protects against developmental toxicity from certain environmental chemicals. We examined combined exposures to maternal FA and pesticides in relation to autism spectrum disorder (ASD). Participants were California children born from 2000-2007 who were enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) case-control study at age 2-5 y, were clinically confirmed to have ASD (n=296) or typical development (n=220), and had information on maternal supplemental FA and pesticide exposures. Maternal supplemental FA and household pesticide product use were retrospectively collected in telephone interviews from 2003-2011. High vs. low daily FA intake was dichotomized at 800μg (median). Mothers' addresses were linked to a statewide database of commercial applications to estimate agricultural pesticide exposure. High FA intake (≥800μg) during the first pregnancy month and no known pesticide exposure was the reference group for all analyses. Compared with this group, ASD was increased in association with <800μg FA and any indoor pesticide exposure {adjusted odds ratio [OR]=2.5 [95% confidence interval (CI): 1.3, 4.7]} compared with low FA [OR=1.2 (95% CI: 0.7, 2.2)] or indoor pesticides [OR=1.7 (95% CI: 1.1, 2.8)] alone. ORs for the combination of low FA and regular pregnancy exposure (≥6 mo) to pet pesticides or to outdoor sprays and foggers were 3.9 (95% CI: 1.4, 11.5) and 4.1 (95% CI: 1.7, 10.1), respectively. ORs for low maternal FA and agricultural pesticide exposure 3 mo before or after conception were 2.2 (95% CI: 0.7, 6.5) for chlorpyrifos, 2.3 (95% CI: 0.98, 5.3) for organophosphates, 2.1 (95% CI: 0.9, 4.8) for pyrethroids, and 1.5 (95% CI: 0.5, 4.8) for carbamates. Except for carbamates, these ORs were approximately two times greater than those for either exposure alone or for the expected ORs for combined exposures under multiplicative or additive models. In this study population, associations between pesticide exposures and ASD were attenuated among those with high versus low FA intake during the first month of pregnancy. Confirmatory and mechanistic studies are needed. https://doi.org/10.1289/EHP604.


The Last Day Narratives: An Exploration of the End of Life for Patients with Cancer from a Caregivers' Perspective.
Background: Surviving family caregivers describe the end-of-life experience as "very distressing" and half of those surveyed indicate inadequate emotional support; however, little is known about the causes of distress on the last day of life. Objective: The purpose of this study was to explore the experience of the last day of life from the perspective of the surviving caregiver. Design: The study used a narrative inquiry approach. Setting/Subject: Surviving caregivers of deceased adult cancer patients at a single institution were invited to participate. Measurements: After reviewing, coding, and categorizing the narratives individually, they were collectively considered and thematically analyzed across all cases to provide a summative analysis. Results: Six themes captured the overall experiences: (1) relationships and communication with health care providers impact overall experience, (2) being able to prepare for death was a source of comfort, (3) being a caregiver impacts quality of life and identity, (4) spiritual visitations as a welcome experience, (5) navigating the dying days and early grief period wrought with guilt and closure, and (6) loss of community contributes to distress and distracts from healing. Conclusions: In this study, distress was most often linked to communication failures. Caregivers also experienced distress and guilt related to the loss of their caregiver role. Findings also support a need for increased preparation for caregivers. Finally, the study showed the frequency of visitations/spiritual experiences during grieving.


[The actual aspects of evaluation of proliferation and apoptosis in clinical laboratory diagnostic: a review].
The article deals with the issues of studying cell proliferation and apoptosis, relationship and conditionality of these two important physiologic processes. The main cytological markers of proliferation and apoptosis are analyzed, including the techniques of intravital non-invasive visualization of apoptosis. The value of these markers in clinical laboratory diagnostic and investigation is considered. The mechanisms of action of antineoplastic pharmaceuticals and issues of choosing the optimal scheme of treatment are analyzed.