Overnight Video-Polysomnographic Studies in Children with Intractable Epileptic Encephalopathies.
BACKGROUND The aim of this study was to assess sleep architecture and respiration during sleep in children with intractable epileptic encephalopathies using overnight video-polysomnography (V-PSG). MATERIAL AND METHODS Between 2015 to 2017 overnight V-PSG recordings were made for 31 children (22 boys and 9 girls) with intractable epileptic encephalopathy with a mean age of 6.78±3.61 years and a mean body mass index (BMI) of 15.83±3.16 kg/m3. Thirty-one healthy children were matched for sex, age, and BMI as the control group. The phases of sleep studied included rapid eye movement (REM) sleep, and non-REM (NREM) phases NREM 1, NREM 2, and NREM 3. Respiratory function during sleep was evaluated. RESULTS Children with epileptic encephalopathies receiving antiepileptic treatment had significantly decreased total sleep time (TST) (p=0.038), significantly increased percentage of NREM1 (p=0.033), and a significantly lower percentage of total REM (p<0.0001), compared with the control group. All children 31/31 (100%) with epileptic encephalopathies had interictal epileptiform discharges, and 4/31 (12.9%) had ictal events. The number of respiratory events did not differ significantly between the two groups (p=0.118), but children in the epileptic encephalopathy group had a significantly shorter average duration (p=0.008) and longest duration (p=0.048) of respiratory events. Average (p=0.006) and least (p=0.0004) oxygen saturation (SatO2) were significantly lower in children with epileptic encephalopathies compared with the control group. CONCLUSIONS Children with epileptic encephalopathies had altered sleep architecture and marked oxygen desaturation, which supports the need for referral of children with epileptic encephalopathy for overnight sleep evaluation.


Effects of PCB exposure on neuropsychological function in children.
In the last decade advances in the analytic methods for quantification of polychlorinated biphenyls (PCBs) have resulted in widespread availability of congener-specific analysis procedures, and large amounts of data on PCB congener profiles in soil, air, water, sediments, foodstuffs, and human tissues have become available. These data have revealed that the PCB residues in environmental media and human tissues may not closely resemble any of the commercial PCB mixtures, depending on source of exposure, bioaccumulation through the food chain, and weathering of PCBs in the environment. At the same time, toxicological research has led to a growing awareness that different classes of PCB congeners have different profiles of toxicity. These advances in analytic techniques and toxicological knowledge are beginning to influence the risk assessment process. As the data from ongoing PCB studies assessing the mediators of neurobehavioral outcomes in children are published, the weight of evidence for PCB effects on neurodevelopment is growing. Studies in Taiwan, Michigan (USA), New York (USA), Holland, Germany, and the Faroe Islands have all reported negative associations between prenatal PCB exposure and measures of cognitive functioning in infancy or childhood. The German study also reported a negative association between postnatal PCB exposure and cognitive function in early childhood--a result that had not been found in previous studies. Only one published study in North Carolina (USA) has failed to find an association between PCB exposure and cognitive outcomes. Despite the fact that several more recent studies have used congener-specific analytic techniques, there have been only limited attempts to assess the role of specific PCB congeners or classes of congeners in mediating neurodevelopmental outcomes. From a statistical standpoint, attempts to determine the role of individual congeners in mediating outcomes are hampered by the fact that concentrations of most individual congeners are highly correlated with each other and with total PCBs. From a toxicological standpoint, these efforts are hampered by the fact that many of the PCB congeners present in human tissues have never been studied in the laboratory, and their relative potency to produce nervous system effects is unknown. More complete information on the health effects of various congeners or congener classes would allow more informed scientific and risk assessment decisions.


A multiple instance learning approach for detecting COVID-19 in peripheral blood smears.
A wide variety of diseases are commonly diagnosed via the visual examination of cell morphology within a peripheral blood smear. For certain diseases, such as COVID-19, morphological impact across the multitude of blood cell types is still poorly understood. In this paper, we present a multiple instance learning-based approach to aggregate high-resolution morphological information across many blood cells and cell types to automatically diagnose disease at a per-patient level. We integrated image and diagnostic information from across 236 patients to demonstrate not only that there is a significant link between blood and a patient's COVID-19 infection status, but also that novel machine learning approaches offer a powerful and scalable means to analyze peripheral blood smears. Our results both backup and enhance hematological findings relating blood cell morphology to COVID-19, and offer a high diagnostic efficacy; with a 79% accuracy and a ROC-AUC of 0.90.


Efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes mellitus: a meta-analysis.
Obesity is closely related to type 2 diabetes mellitus, and weight reduction is an important part of the care delivered to obese persons with diabetes. The objective of this review was to assess the efficacy of pharmacotherapy for weight loss in adults with type 2 diabetes. A systematic review of the literature was performed, and studies were included if pharmacotherapy was used as the primary strategy for weight loss among adults with type 2 diabetes. Published and unpublished studies with any design were included. A random effects model was used to combine outcomes from randomized controlled trials. Sufficient data for the meta-analysis were available for fluoxetine, orlistat, and sibutramine. Fourteen randomized, placebo-controlled trials were included in the review, with a total of 2231 patients. Pharmacotherapy produced modest reductions in weight for fluoxetine (3.4 kg [95% confidence interval (CI), 1.7-5.2 kg] at 8-16 weeks of follow-up; 5.1 kg [95% CI, 3.3-6.9 kg] at 24-30 weeks; and 5.8 kg [ 95% CI, 0.8-10.8 kg] at 52 weeks); orlistat (2.6 kg [95% CI, 2.1-3.2 kg] [2.6% loss] at 52 weeks); and sibutramine (4.5 kg [95% CI, 1.8-7.2 kg] [3.3% loss] at up to 26 weeks). Glycated hemoglobin was also modestly reduced: fluoxetine (1.0% [95% CI, 0.4%-1.5%] at 8-16 weeks; 1.0% [95% 0.6%-1.4%] at 24-30 weeks; and 1.8% [95% CI, -0.2%-3.8%] at 52 weeks); orlistat (0.4% [95% CI, 0.3%-0.5%]); and sibutramine (0.7% [95% CI, -0.5%-1.9%]). Gastrointestinal adverse effects were common with orlistat; tremor, somnolence, and sweating with fluoxetine; and palpitations with sibutramine. Fluoxetine, orlistat, and sibutramine can achieve statistically significant weight loss over 26 to 52 weeks. However, the magnitude of weight loss was modest, and the long-term health benefits and safety remain unclear. Interventions that combine pharmacologic therapy with intensive behavioral interventions may be more effective but need additional research.


Peculiar Feeding of Amphiuma under Conditions of Enforced Starvation.
Two Amphiuma means confined in aquaria with flowing artesian water for 3 years, with no known supply of food, increased in size. In the latter part of this period they were observed to shed a sheet of skin by a peculiar process and to devour it. This shed skin contained bacteria of the spirilla type, diatoms, and large amounts of unicellular algae, and possibly other organisms. Similar behavior in unstarved specimens of Cryptobranchus confined in an aquarium at the University of Alabama has been observed by E. L. Bishop.


Development of Network Synchronization Predicts Language Abilities.
Synchronization of oscillations among brain areas is understood to mediate network communication supporting cognition, perception, and language. How task-dependent synchronization during word production develops throughout childhood and adolescence, as well as how such network coherence is related to the development of language abilities, remains poorly understood. To address this, we recorded magnetoencephalography while 73 participants aged 4-18 years performed a verb generation task. Atlas-guided source reconstruction was performed, and phase synchronization among regions was calculated. Task-dependent increases in synchronization were observed in the theta, alpha, and beta frequency ranges, and network synchronization differences were observed between age groups. Task-dependent synchronization was strongest in the theta band, as were differences between age groups. Network topologies were calculated for brain regions associated with verb generation and were significantly associated with both age and language abilities. These findings establish the maturational trajectory of network synchronization underlying expressive language abilities throughout childhood and adolescence and provide the first evidence for an association between large-scale neurophysiological network synchronization and individual differences in the development of language abilities.


Trauma and orthopaedic capacity of 267 hospitals in east central and southern Africa.
Trauma and road traffic accidents are predicted to increase significantly in the next decade in low-income and middle-income countries. The College of Surgeons of East, Central, and Southern Africa (COSECSA) covers Ethiopia, Kenya, Tanzania, Uganda, Rwanda, Burundi, Mozambique, Malawi, Zimbabwe, and Zambia. Ministry of Health websites for these ten countries show that 992 hospitals are covering an estimated 318 million people. The WHO Tool for Situational Analysis to Assess Emergency and Essential Surgical Care was used with added questions relevant to trauma and orthopaedic care. A web-based survey platform was used and hospitals were contacted via COSECSA representatives. Consent to share data was requested, anonymised for country and hospital. 267 (27%) of 992 hospitals completed the survey. 185 were district level hospitals and 82 were referral or tertiary level hospitals. Formal accident and emergency departments were present in only 29% of district hospitals (95% CI 22·5-35·5) and 35% (24·7-45·3) of referral or tertiary level hospitals. The mean number (SD) of surgeons was 1·4 (3·0) in district hospitals and 2·6 (4·6) in referral or tertiary level hospitals. The mean number (SD) of orthopaedic surgeons was 0·3 (0·9) in district hospitals and 0·5 (0·9) in referral or tertiary level hospitals. Medically qualified anaesthetists were available in 16% (95% CI 10·7-21·3) of district hospitals and 20% (11·4-28·6) of referral or tertiary level hospitals. C arm radiography was available in 3% (95% CI 0·5-5·5) of district hospitals and 32% (21·9-42·1) of referral or tertiary level hospitals. CT scanning was available in 6% (95% CI 2·6- 9·4) of district hospitals and 21% (12·2-29·8) of referral or tertiary level hospitals. Closed fracture treatment was offered in 75% (95% CI 68·8- 81·2) of district hospitals and 82% (73·7-90·3) of referral or tertiary level hospitals. 37% (95% CI 30·1-43·9) of district hospitals and 40% (29·4-50·6) of referral or tertiary level hospitals had adequate instruments for the surgical treatment of fractures, but only 7% (3·4-10·6) of district hospitals and 8% (2·1-13·9) of referral or tertiary level hospitals had a sustainable supply of fracture implants. Elective orthopaedic surgery took place in 30% (95% 23·4- 36·6) of district hospitals and 34% (23·8-44·2) of referral or tertiary level hospitals. Ponseti treatment of clubfoot was available at 46% (95% 38·8-53·2) of district hospitals and 44% (33·3-54·7) of referral or tertiary level hospitals. This study has limitations in that only 27% of eligible hospitals completed the survey, and it is certainly possible that there could be bias in that the less well resourced institutions could also be less likely to cooperate with data collection. Thus, it is possible that the figures we present overestimate the resources available in the region as a whole. However, despite the limitations in data quality, it is clear that current capacity to treat trauma and orthopaedic conditions is very limited, with particular areas of concern being manpower, training, facilities, and equipment. COSECSA will use these data as a baseline for further surveys and to develop a strategy to improve trauma and orthopaedic care in the region. UK Department for International Development (DFID).


Patterns of complementary and alternative medical therapy use in children diagnosed with autism spectrum disorders.
Previous studies suggest that complementary and alternative medical (CAM) therapy use in children with chronic illnesses is higher than in children in the general population. In this study, we investigated patterns of CAM therapy use in children diagnosed with autism spectrum disorders (ASD, n = 50) as compared to a control population of children with no ASD (n = 50). Over half of the parents in the ASD group reported using, or had used at least one CAM therapy for their child (52%) as compared to 28% of the control group (P = 0.024). Seventy percent of therapies used in the ASD group were biologically based therapies comprised of special diets or supplements, and parents felt that 75% of the therapies used were beneficial.


Development of PCR assays targeting genes in O-antigen gene clusters for detection and identification of Escherichia coli O45 and O55 serogroups.
The Escherichia coli O45 O-antigen gene cluster of strain O45:H2 96-3285 was sequenced, and conventional (singleplex), multiplex, and real-time PCR assays were designed to amplify regions in the wzx (O-antigen flippase) and wzy (O-antigen polymerase) genes. In addition, PCR assays targeting the E. coli O55 wzx and wzy genes were designed based on previously published sequences. PCR assays targeting E. coli O45 showed 100% specificity for this serogroup, whereas by PCR assays specific for E. coli O55, 97/102 strains serotyped as E. coli O55 were positive for wzx and 98/102 for wzy. Multiplex PCR assays targeting the E. coli O45 and the E. coli O55 wzx and wzy genes were used to detect the organisms in fecal samples spiked at levels of 10(6) and 10(8) CFU/0.2 g feces. Thus, the PCR assays can be used to detect and identify E. coli serogroups O45 and O55.


Wnt/IL-1β/IL-8 autocrine circuitries control chemoresistance in mesothelioma initiating cells by inducing ABCB5.
Malignant pleural mesothelioma (MPM) is a tumor with high chemoresistance and poor prognosis. MPM-initiating cells (ICs) are known to be drug resistant, but it is unknown if and how stemness-related pathways determine chemoresistance. Moreover, there are no predictive markers of IC-associated chemoresistance. Aim of this work is to clarify if and by which mechanisms the chemoresistant phenotype of MPM IC was due to specific stemness-related pathways. We generated MPM IC from primary MPM samples and compared the gene expression and chemo-sensitivity profile of IC and differentiated/adherent cells (AC) of the same patient. Compared to AC, IC had upregulated the drug efflux transporter ABCB5 that determined resistance to cisplatin and pemetrexed. ABCB5-knocked-out (KO) IC clones were resensitized to the drugs in vitro and in patient-derived xenografts. ABCB5 was transcriptionally activated by the Wnt/GSK3β/β-catenin/c-myc axis that also increased IL-8 and IL-1β production. IL-8 and IL-1β-KO IC clones reduced the c-myc-driven transcription of ABCB5 and reacquired chemosensitivity. ABCB5-KO clones had lower IL-8 and IL-1β secretion, and c-myc transcriptional activity, suggesting that either Wnt/GSK3β/β-catenin and IL-8/IL-1β signaling drive c-myc-mediated transcription of ABCB5. ABCB5 correlated with lower time-to-progression and overall survival in MPM patients treated with cisplatin and pemetrexed. Our work identified multiple autocrine loops linking stemness pathways and resistance to cisplatin and pemetrexed in MPM IC. ABCB5 may represent a new target to chemosensitize MPM IC and a potential biomarker to predict the response to the first-line chemotherapy in MPM patients.


Aromatic L-amino acid decarboxylase (AADC) is crucial for brain development and motor functions.
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare pediatric neuro-metabolic disease in children. Due to the lack of an animal model, its pathogenetic mechanism is poorly understood. To study the role of AADC in brain development, a zebrafish model of AADC deficiency was generated. We identified an aadc gene homolog, dopa decarboxylase (ddc), in the zebrafish genome. Whole-mount in situ hybridization analysis showed that the ddc gene is expressed in the epiphysis, locus caeruleus, diencephalic catecholaminergic clusters, and raphe nuclei of 36-h post-fertilization (hpf) zebrafish embryos. Inhibition of Ddc by AADC inhibitor NSD-1015 or anti-sense morpholino oligonucleotides (MO) reduced brain volume and body length. We observed increased brain cell apoptosis and loss of dipencephalic catecholaminergic cluster neurons in ddc morphants (ddc MO-injected embryos). Seizure-like activity was also detected in ddc morphants in a dose-dependent manner. ddc morphants had less sensitive touch response and impaired swimming activity that could be rescued by injection of ddc plasmids. In addition, eye movement was also significantly impaired in ddc morphants. Collectively, loss of Ddc appears to result in similar phenotypes as that of ADCC deficiency, thus zebrafish could be a good model for investigating pathogenetic mechanisms of AADC deficiency in children.


Common NFKBIL2 polymorphisms and susceptibility to pneumococcal disease: a genetic association study.
Streptococcus pneumoniae remains a major global health problem and a leading cause of death in children worldwide. The factors that influence development of pneumococcal sepsis remain poorly understood, although increasing evidence points towards a role for genetic variation in the host's immune response. Recent insights from the study of animal models, rare human primary immunodeficiency states, and population-based genetic epidemiology have focused attention on the role of the proinflammatory transcription factor NF-κB in pneumococcal disease pathogenesis. The possible role of genetic variation in the atypical NF-κB inhibitor IκB-R, encoded by NFKBIL2, in susceptibility to invasive pneumococcal disease has not, to our knowledge, previously been reported upon. An association study was performed examining the frequencies of nine common NFKBIL2 polymorphisms in two invasive pneumococcal disease case-control groups: European individuals from hospitals in Oxfordshire, UK (275 patients and 733 controls), and African individuals from Kilifi District Hospital, Kenya (687 patients with bacteraemia, of which 173 patients had pneumococcal disease, together with 550 controls). Five polymorphisms significantly associated with invasive pneumococcal disease susceptibility in the European study, of which two polymorphisms also associated with disease in African individuals. Heterozygosity at these loci was associated with protection from invasive pneumococcal disease (rs760477, Mantel-Haenszel 2 × 2 χ(2) = 11.797, P = 0.0006, odds ratio = 0.67, 95% confidence interval = 0.53 to 0.84; rs4925858, Mantel-Haenszel 2 × 2 χ(2) = 9.104, P = 0.003, odds ratio = 0.70, 95% confidence interval = 0.55 to 0.88). Linkage disequilibrium was more extensive in European individuals than in Kenyans. Common NFKBIL2 polymorphisms are associated with susceptibility to invasive pneumococcal disease in European and African populations. These findings further highlight the importance of control of NF-κB in host defence against pneumococcal disease.


N-terminal protein characterization by mass spectrometry after cyanogen bromide cleavage using combined microscale liquid- and solid-phase derivatization.
A sample preparation method for protein N-terminal peptide isolation from cyanogen bromide (CNBr) protein digests has been developed. In this strategy, the CNBr cleavage was preceded by protein α- and ε-amine acetylation and carboxyamidomethylation in a one-pot reaction scheme. The peptide mixture was adsorbed on ZipTipC18 pipette tips for reaction of the newly generated N-termini with sulfosuccinimidyl-2-(biotinamido) ethyl-1, 3-dithiopropionate. In the subsequent steps, the peptides were exposed in situ to hydroxylamine for reversal of potential hydroxyl group acylation, followed by reductive release of the disulfide-linked biotinamido moiety from the derivatives. The selectively thiol group-functionalized internal and C-terminal peptides were reversibly captured by covalent chromatography on activated thiol-sepharose, leaving the N-terminal fragment in the flow-through fraction. The use of the reversed-phase support as a venue for postcleavage serial modification proved instrumental to ensure throughput and completeness of derivatization. By this sequence of solid-phase reactions, the N-terminal peptide could be recognized uniquely in the MALDI-mass spectra of unfractionated digests by its unaltered mass signature. The use of the sample preparation method was demonstrated with low-picomole amounts of model protein. The N-terminal CNBr fragments were retrieved selectively from the affinity support. The sample preparation method provides for robustness and simplicity of operation using standard equipment available in most biological laboratories and is anticipated to be readily expanded to gel-separated proteins.


Non-aggregated Zn(ii)octa(2,6-diphenylphenoxy) phthalocyanine as a hole transporting material for efficient perovskite solar cells.
A non-aggregated Zn(ii)octa(2,6-diphenylphenoxy) phthalocyanine (coded as TT80) has been used as a hole-transporting material for perovskite solar cells. The cells were fabricated under three different configurations by changing the uptake solvent (chlorobenzene or toluene) and incorporating additives (bis(trifluoromethane) sulfonimide lithium salt (LiTFSI) and 4-tert-butylpyridine (TBP). A power conversion efficiency of 6.7% (AM1.5G standard conditions) was achieved for the best cell under optimized configuration.


Density Variation in the Expanded Polystyrene Foam of Bicycle Helmets and Its Influence on Impact Performance.
Bicycle helmets attenuate head impacts using expanded polystyrene (EPS) foam liners. The EPS density plays a key role in determining the helmet and head response during an impact. Prior pilot work in our lab showed that EPS density varied by up to 18 kg/m3 within a single helmet, and thus the purpose of this study was to quantify the regional density variations within and between helmets and to establish how these variations influence helmet impact performance. We evaluated 10-12 samples of two traditional and two bicycle motocross (BMX) bicycle helmets with EPS liners. The bulk liner density and density of 16-19 cores extracted from specific locations on each sample were measured. Additional samples of two of these helmet models were then impacted at 3.0, 6.3, and 7.8 m/s to determine the relationship between local EPS density and helmet impact performance. We found that density varied significantly within each sample in all helmet models and also varied significantly between samples in three helmet models. The density variations were not symmetric across the midline in two of the four helmet models. The observed density variations influenced the helmets' impact performance. Our data suggest that variations in peak headform acceleration during impacts to the same location on different samples of the same helmet model can be partially explained by density differences between helmet samples. These density variations and resulting impact performance differences may play a role in a helmet's ability to mitigate head injury.


MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls.
Our goal was to identify circulating micro RNA (miRNA) levels that could distinguish patients with low-stage pancreatic cancer from healthy and disease controls. We measured 735 miRNAs in pancreatic cancer case and control sera by QRTPCR using TaqMan MicroRNA Arrays. After array analysis, we selected 18 miRNA candidates for validation in an independent set of cases and control samples. Of the significantly elevated circulating miRNAs in patients with pancreatic cancer compared with controls, miR-1290 had the best diagnostic performance: receiver operating characteristic (ROC) analysis on miR-1290 serum level yielded curve areas (AUC) of 0.96 [95% confidence interval (CI), 0.91-1.00], 0.81 (0.71-0.91), and 0.80 (0.67-0.93), for subjects with pancreatic cancer (n = 41) relative to healthy controls (n = 19), subjects with chronic pancreatitis (n = 35), and pancreatic neuroendocrine tumors (n = 18), respectively. Serum miR-1290 levels were also significantly higher than healthy controls among patients with intraductal papillary mucinous neoplasm (IPMN; n = 20; AUC = 0.76, 0.61-0.91). Serum miR-1290 levels distinguished patients with low-stage pancreatic cancer from controls better than CA19-9 levels, and like CA19-9, higher miR-1290 levels predicted poorer outcome among patients undergoing pancreaticoduodenectomy. Greater numbers of miR-1290 transcripts were detected by FISH in primary pancreatic cancer and IPMN than normal pancreatic duct cells. miR-1290 influenced in vitro pancreatic cancer cell proliferation and invasive ability. Several other circulating miRNAs distinguished sera of patients with pancreatic cancer from those of healthy controls with AUCs >0.7, including miR-24, miR-134, miR-146a, miR-378, miR-484, miR-628-3p, and miR-1825. The detection of elevated circulating miR-1290 has the potential to improve the early detection of pancreatic cancer.


Improving Person-Centred Leadership: A Qualitative Study of Ward Managers' Experiences During the COVID-19 Crisis.
In order to provide guidance and prepare ward managers for future crisis situations similar to the COVID-19 pandemic, the aim of this study was to reflect and learn how person-centred nursing leadership may be strengthened in such situations. The pandemic has forced nurse leaders to face new challenges. Knowledge about their experiences may contribute to advancing leadership practices in times of future crises. A qualitative directed content analysis was chosen. The theoretical perspective was person-centred leadership. Thirteen ward managers from a Danish university hospital were included and interviewed using telephone interviews three months after the first national COVID-19 case was confirmed. The main findings of the study revealed that the ward managers often experienced a lack of timely, relevant information, involvement in decision-making and acknowledgement from the head nurse of department and the executive management. This was caused by the existing organizational cultures and the traditional hierarchy of communication. This meant that the ward managers' sense of own competences and leadership values and beliefs came under high pressure when they had to balance different stakeholders' needs. When the experience of ward managers results in them being unable to lead authentically and competently in a crisis like the COVID-19 pandemic, lack of engagement can occur, with serious consequences for patients, staff and the ward managers themselves. Traditional organizational cultures that are hierarchical and controlling needs to be challenged and reoriented towards collaborative, inclusive and participative practices of engagement and involvement. Leadership development must be an established and integrated component of organizations, so that ward managers are able to sustain person-centred ways of being and doing in times of crisis.


Osmotic injury of PC-3 cells by hypertonic NaCl solutions at temperatures above 0 degrees C.
Cell injury due to osmotic dehydration, which is regarded as a major cause of injury during freeze-thaw processes, was examined closely using a perfusion microscope. Human prostatic adenocarcinoma cells (PC-3), which were put in a chamber, were subjected to hyperosmotic stresses by perfusing NaCl solutions of varying concentrations into the chamber. Cells were exposed to 2.5 and 4.5M NaCl solutions for 1-60 min by changing the concentrations at 0.2, 1, and 10 M/min. Decrease in cell viability was biphasic: the viability decreased first after the increase in NaCl concentration due to dehydration and then after return to isotonic conditions due to rehydration. Rehydration was substantially more responsible for cell injury than dehydration, which was marked at lower NaCl concentrations and lower temperatures. Injury resulting from contraction was negligible at the 2.5 M NaCl solution. While the hypertonic cell survival, which was determined without a return to isotonic conditions, was almost independent of time of exposure to hyperosmotic concentrations, the post-hypertonic survival after returning to isotonic conditions decreased with increasing exposure time, suggesting that the rehydration-induced injury was a consequence of time-dependent alteration of the plasma membrane. The post-hypertonic survival was lower for higher NaCl concentrations and higher temperatures, which was qualitatively consistent with previous studies. Effects of the rate of concentration change on the post-hypertonic cell survival were observed at 4.5 M; the highest rate of survival was obtained by slower increase and faster decrease in the NaCl concentration. However, the effect was negligible at 2.5 M.


Asthma and ambient air pollution in Helsinki.
To study whether ambient air levels of sulphur dioxide (SO2), nitrogen dioxide (NO2), total suspended particulates (TSP), and ozone (O3) affect the number of hospital admissions for asthma. The associations between the daily number of admissions and air pollutants were analysed with Poisson regression, taking into account potential confounding factors by using the standardised protocol of the APHEA project. Helsinki, Finland, 1987-89. Patients admitted to hospitals through emergency rooms because of asthma (n = 2421). The daily mean concentration was 13-25 micrograms/m3 for SO2, 33-41 micrograms/m3 for NO2, 19-41 micrograms/m3 for O3, and 58-109 micrograms/m3 for TSP during the different seasons. Values are means for various stations. The daily mean temperature during the three year period was +5.4 degrees C (range -37-27 degrees C). Positive associations with admissions were observed for O3 levels in all children under 14 years, and for SO2 levels in 15-64 year olds and among those older than 64. Significant associations were also seen between admissions for digestive tract diseases (the control) and O3 levels. This suggests that the modelling, which proved to be problematic, was unsatisfactory, or it may be a statistical coincidence. A rise in temperature was associated with a low number of admissions for asthma among 0-14 year olds and among 15-64 year olds, whereas humidity did not have a significant effect on the number of admissions. It is possible than even low level pollution may increase hospital admissions for asthma. However, definitive conclusions will be justified only after meta-analysis comprising several studies. The methodology was seen to have a strong effect on the results and standardised methods, possibly differing from those for the study concerning mortality, are needed to investigate the association between morbidity and ambient air pollutants.


Assessing incentives to increase digital payment acceptance and usage: A machine learning approach.
An important step to achieve greater financial inclusion is to increase the acceptance and usage of digital payments. Although consumer adoption of digital payments has improved dramatically globally, the acceptance and usage of digital payments for micro, small, and medium-sized retailers (MSMRs) remain challenging. Using random forest estimation, we identify 14 key predictors out of 190 variables with the largest predictive power for MSMR adoption and usage of digital payments. Using conditional inference trees, we study the importance of sequencing and interactions of various factors such as public policy initiatives, technological advancements, and private sector incentives. We find that in countries with low POS terminal adoption, killer applications such as mobile phone payment apps increase the likelihood of P2B digital transactions. We also find the likelihood of digital P2B payments at MSMRs increases when MSMRs pay their employees and suppliers digitally. The level of ownership of basic financial accounts by consumers and the size of the shadow economy are also important predictors of greater adoption and usage of digital payments. Using causal forest estimation, we find a positive and economically significant marginal effect for merchant and consumer fiscal incentives on POS terminal adoption on average. When countries implement financial inclusion initiatives, POS terminal adoption increases significantly and MSMRs' share of P2B digital payments also increases. Merchant and consumer fiscal incentives also increase MSMRs' share of P2B electronic payments.


A global lipid map reveals host dependency factors conserved across SARS-CoV-2 variants.
A comprehensive understanding of host dependency factors for SARS-CoV-2 remains elusive. We mapped alterations in host lipids following SARS-CoV-2 infection using nontargeted lipidomics. We found that SARS-CoV-2 rewires host lipid metabolism, altering 409 lipid species up to 64-fold relative to controls. We correlated these changes with viral protein activity by transfecting human cells with each viral protein and performing lipidomics. We found that lipid droplet plasticity is a key feature of infection and that viral propagation can be blocked by small-molecule glycerolipid biosynthesis inhibitors. We found that this inhibition was effective against the main variants of concern (alpha, beta, gamma, and delta), indicating that glycerolipid biosynthesis is a conserved host dependency factor that supports this evolving virus.


Natural biased coin encoded in the genome determines cell strategy.
Decision making at a cellular level determines different fates for isogenic cells. However, it is not yet clear how rational decisions are encoded in the genome, how they are transmitted to their offspring, and whether they evolve and become optimized throughout generations. In this paper, we use a game theoretic approach to explain how rational decisions are made in the presence of cooperators and competitors. Our results suggest the existence of an internal switch that operates as a biased coin. The biased coin is, in fact, a biochemical bistable network of interacting genes that can flip to one of its stable states in response to different environmental stimuli. We present a framework to describe how the positions of attractors in such a gene regulatory network correspond to the behavior of a rational player in a competing environment. We evaluate our model by considering lysis/lysogeny decision making of bacteriophage lambda in E. coli.


Basal hepatic glucose production is regulated by the portal vein insulin concentration.
The ability of portal vein insulin to control hepatic glucose production (HGP) is debated. The aim of the present study was to determine, therefore, if the liver can respond to a selective decrease in portal vein insulin. Isotopic ([3H]glucose) and arteriovenous difference methods were used to measure HGP in conscious overnight fasted dogs. A pancreatic clamp (somatostatin plus basal portal insulin and glucagon) was used to control the endocrine pancreas. A 40-min control period was followed by a 180-min test period. During the latter, the portal vein insulin level was selectively decreased while the arterial insulin level was not changed. This was accomplished by stopping the portal insulin infusion and giving insulin peripherally at half the basal portal rate (PID, n=5). In a control group (n=5), the portal insulin infusion was not changed and glucose was infused to match the hyperglycemia that occurred in the PID group. A selective decrease of 120 pmol/l in portal vein insulin was achieved (basal, 150+/-36 to last 30 min, 30+/-12 pmol/l) in the absence of a change in the arterial insulin level (basal, 30+/-3 to last 30 min, 36+/-4 pmol/l). Neither arterial nor portal insulin levels changed in the control group (30+/-6 and 126+/-30 pmol/l, respectively). In response to the selective decrease in portal vein insulin, net hepatic glucose output (NHGO) increased significantly, from 8+/-1 (basal) to 30+/-6 and 14+/-2 micromol x kg(-1) x min(-1) by 15 min and the last 30 min (P < 0.05) of the experimental period, respectively. Arterial plasma glucose increased from 5.9+/-0.2 (basal) to 10.5+/-0.4 micromol/l (last 30 min). Three-carbon gluconeogenic precursor uptake fell from 11.2+/-2.9 (basal) to 5.9+/-0.7 micromol x kg(-1) x min(-1) (last 30 min), and thus a change in gluconeogenesis could not account for any of the increase in NHGO. With matched hyperglycemia (basal, 5.5+/-0.3 to last 30 min, 10.5+/-0.8 micromol/l) but no change in insulin, NHGO decreased from 12+/-1 (basal) to 0 (-1+/-6 micromol x kg(-1) x min(-1), last 30 min, P < 0.05) and hepatic gluconeogenic precursor uptake did not change (basal, 8.0+/-1.7 to last 30 min, 8.9+/-2.2 micromol x kg[-1] x min[-1]). Thus, the liver responds rapidly to a selective decrease in portal vein insulin by markedly increasing HGP as a result of increased glycogenolysis. These studies indicate that after an overnight fast, basal HGP (glycogenolysis) is highly sensitive to the hepatic sinusoidal insulin level.


The effectiveness of medical interventions aimed at preventing preterm birth: a literature review.
Preterm birth is a significant global health problem with serious short and long term consequences. This paper reviews the research literature to answer the question how effective are the medical interventions that aim to reduce the rates of preterm birth? A systematic search was carried out in CINAHL, Cochrane, Medline and Embase in relation to following medical treatments aimed at preventing preterm births: anti-infective medications, tocolytics, progesterone and cervical cerclage. The research underpinning each type of intervention is critically analysed in order to establish the validity of knowledge claims that are made for each type of intervention. In relation to reducing the rates of preterm births, anti-infectives are only effective in the presence of known infection. Screening for infections during pregnancy is ineffective. Tocolytic agents are not effective in decreasing the preterm birth rates. Progesterone seems to be effective in a select group of pregnant women at higher risk of preterm birth. Cervical cerclage plays a small and an occasional role in preventing some preterm births. This literature review demonstrates that medical interventions aimed at preventing, not just delaying, preterm birth, are not effective at a population level. Providing holistic, antenatal midwifery care for women living in socio-economic disadvantage and/or with an increased risk of preterm birth seems to be a promising strategy to address the negative effects of the social determinants of disease and thus to reduce the rate of preterm births at an individual and a population level.


Repair of full-thickness cartilage defects with cells of different origin in a rabbit model.
The purpose of this study was to evaluate the repaired tissues formed in full-thickness cartilage defects in a rabbit model implanted with 4 types of chondrogenic cells, including chondrocytes, mesenchymal stem cells (MSCs) and fibroblasts from rabbit, and human umbilical cord blood (hUCB) stem cells. Chondrocytes, MSCs, and fibroblasts were isolated from 6-week-old New Zealand rabbits; hUCB stem cells were isolated from the umbilical cord blood of newborn children. These 4 types of cells were cultured in vitro and embedded in polylactic acid (PLA) matrices. Full-thickness defects were produced in the femoral trochlear grooves of both knees in 36 adult New Zealand White rabbits. Cell/PLA composites were transplanted into cartilage defects. A total of 5 groups were formed according to implanted cell type: Group A, chondrocytes; Group B, MSCs; Group C, fibroblasts; Group D, hUCB stem cells; and Group E, no cells (control group). Repaired tissues were evaluated grossly, histologically, and immunohistochemically at 6 weeks and 12 weeks after implantation. In Groups A and B, defects were repaired with hyaline-like cartilage. In Group C, defects were repaired with fibrous tissue. In Group D, defects were repaired primarily with fibrous tissue and scattered chondrocytes; in some specimens, defects were repaired with a thin layer of hyaline-like cartilage at 12 weeks. In Group E, defects were repaired with fibrous tissue. Histologic scores in Groups A and B were significantly higher than those in Groups C, D, and E at 6 and 12 weeks after transplantation. Full-thickness cartilage defects treated with chondrocyte or MSC transplantation were repaired with hyaline-like cartilage tissue, and repair was significantly better than in tissues treated with fibroblasts and hUCB stem cells, as well as in the control group. Repaired tissues treated with MSCs appeared to have better cell arrangement, subchondral bone remodeling, and integration with surrounding cartilage than did repaired tissues generated by chondrocyte implantation. MSCs might be the most suitable cell source for cartilage repair. Further investigation into hUCB stem cell transplantation is needed. In our study of rabbits, MSCs supplied the most promising cell source for cartilage repair.


Apoptosis signal-regulating kinase 1 controls the proapoptotic function of death-associated protein (Daxx) in the cytoplasm.
Although Daxx (death-associated protein) was first reported to mediate the apoptotic signal from Fas to JNK in the cytoplasm, other data suggested that Daxx is mainly located in the nucleus as a transcriptional regulator. Here, we demonstrated that cellular localization of Daxx could be determined by the relative concentration of a proapoptotic kinase, apoptosis signal-regulating kinase 1 (ASK1) by using immunofluorescence and transcriptional reporter assay. ASK1 sequestered Daxx in the cytoplasm and inhibited the repressive activity of Daxx in transcription. In addition, Daxx was bound to the activated Fas only in the presence of ASK1, accelerating the Fas-mediated apoptosis. These results suggest that Daxx requires ASK1 for its cytoplasmic localization and Fas-mediated signaling. Taken together, we could conclude that ASK1 controls the dual function of Daxx as a transcriptional repressor in the nucleus and as a proapoptotic signal mediator in the cytoplasm.


Auxiliary probe design adaptable to existing probes for remote detection NMR, MRI, and time-of-flight tracing.
A versatile, detection-only probe design is presented that can be adapted to any existing NMR or MRI probe with the purpose of making the remote detection concept generally applicable. Remote detection suggests freeing the NMR experiment from the confinement of using the same radio frequency (RF) coil and magnetic field for both information encoding and signal detection. Information is stored during the encoding step onto a fluid sensor medium whose magnetization is later measured in a different location. The choice of an RF probe and magnetic field for encoding can be made based solely on the size and characteristics of the sample and the desired information quality without considering detection sensitivity, as this aspect is dealt with by a separate detector. While early experiments required building probes that included two resonant circuits, one for encoding and one for detection, a modular approach with a detection-only probe as presented here can be used along with any existing NMR probe of choice for encoding. The design of two different detection-only probes is presented, one with a saddle coil for milliliter-sized detection volumes, and the other one with a microsolenoid coil for sub-microliter fluid quantities. As example applications, we present time-of-flight (TOF) tracing of hyperpolarized (129)Xe spins in a gas mixture through coiled tubing using the microsolenoid coil detector and TOF flow imaging through a nested glass container where the gas flow changes its direction twice between inlet and outlet using the saddle coil detector.


Fertility and adjuvant treatment in young women with breast cancer.
Women of childbearing age with breast cancer are often concerned about whether they will become infertile after treatment, and for those who wish to bear children, whether a subsequent pregnancy will alter their risk of disease recurrence. The risk of chemotherapy-related amenorrhea (CRA), menopause, and infertility appear to be related to patient age and type of treatment received, though data regarding actual fertility following treatment are limited. There are options available for fertility preservation for young women who wish to have a biologic child after breast cancer and are at risk for infertility. Options include cryopreservation of embryos, oocytes, ovarian tissue prior to treatment, and ovarian suppression through chemotherapy. However, most of these are considered experimental, and there are limited data regarding the safety of such strategies. There has been concern that pregnancy after breast cancer may worsen prognosis in light of the endocrine manipulations used to treat breast cancer, particularly for women with hormone sensitive disease. Several studies addressing the potential risk of pregnancy after breast cancer have not revealed any negative effect on prognosis. However, these studies have significant limitations, and concerns about a negative impact for some remain. Ongoing and future prospective studies evaluating fertility and pregnancy issues for young breast cancer survivors are warranted for this vulnerable population facing this difficult issue.


Pediatric trainees' engagement in the online nutrition curriculum: preliminary results.
The Pediatric Nutrition Series (PNS) consists of ten online, interactive modules and supplementary educational materials that have utilized web-based multimedia technologies to offer nutrition education for pediatric trainees and practicing physicians. The purpose of the study was to evaluate pediatric trainees' engagement, knowledge acquisition, and satisfaction with nutrition modules delivered online in interactive and non-interactive formats. From December 2010 through August 2011, pediatric trainees from seventy-three (73) different U.S. programs completed online nutrition modules designed to develop residents' knowledge of counseling around and management of nutritional issues in children. Data were analyzed using SPSS version 19. Both descriptive and inferential statistics were used in comparing interactive versus non-interactive modules. Pretest/posttest and module evaluations measured knowledge acquisition and satisfaction. Three hundred and twenty-two (322) pediatric trainees completed one or more of six modules for a total of four hundred and forty-two (442) accessions. All trainees who completed at least one module were included in the study. Two-way analyses of variance (ANOVA) with repeated measures (pre/posttest by interactive/non-interactive format) indicated significant knowledge gains from pretest to posttest (p < 0.002 for all six modules). Comparisons between interactive and non-interactive formats for Module 1 (N = 85 interactive, N = 95 non-interactive) and Module 5 (N = 5 interactive, N = 16 non-interactive) indicated a parallel improvement from the pretest to posttest, with the interactive format significantly higher than the non-interactive modules (p < .05). Both qualitative and quantitative data from module evaluations demonstrated that satisfaction with modules was high. However, there were lower ratings for whether learning objectives were met with Module 6 (p < 0.03) and lecturer rating (p < 0.004) compared to Module 1. Qualitative data also showed that completion of the interactive modules resulted in higher resident satisfaction. This initial assessment of the PNS modules shows that technology-mediated delivery of a nutrition curriculum in residency programs has great potential for providing rich learning environments for trainees while maintaining a high level of participant satisfaction.


Ramachandran-type plots for glycosidic linkages: Examples from molecular dynamic simulations using the Glycam06 force field.
The goals of this article are to (1) provide further validation of the Glycam06 force field, specifically for its use in implicit solvent molecular dynamic (MD) simulations, and (2) to present the extension of G.N. Ramachandran's idea of plotting amino acid phi and psi angles to the glycosidic phi, psi, and omega angles formed between carbohydrates. As in traditional Ramachandran plots, these carbohydrate Ramachandran-type (carb-Rama) plots reveal the coupling between the glycosidic angles by displaying the allowed and disallowed conformational space. Considering two-bond glycosidic linkages, there are 18 possible conformational regions that can be defined by (alpha, phi, psi) and (beta, phi, psi), whereas for three-bond linkages, there are 54 possible regions that can be defined by (alpha, phi, psi, omega) and (beta, phi, psi, omega). Illustrating these ideas are molecular dynamic simulations on an implicitly hydrated oligosaccharide (700 ns) and its eight constituent disaccharides (50 ns/disaccharide). For each linkage, we compare and contrast the oligosaccharide and respective disaccharide carb-Rama plots, validate the simulations and the Glycam06 force field through comparison to experimental data, and discuss the general trends observed in the plots.


New Opportunities in Mid-Infrared Emission Control.
Tunable laser absorption spectroscopy (TLAS) has been well accepted as a preferred measurement technique for many industrial applications in recent years, especially for in situ applications. Previously, mainly near-infrared lasers have been used in TLAS sensors. The advent of compact mid-infrared light sources, like quantum cascade lasers and interband cascade lasers, has made it possible to detect gases with better sensitivity by utilizing fundamental absorption bands and to measure species that do not have any absorption lines in the near-infrared spectral region. This technological advancement has allowed developing new sensors for gases, such as nitric oxide and sulfur dioxide, for industrial applications. Detection limits of better than 1 ppm·m for nitric oxide and better than 10 ppm·m for sulfur dioxide are demonstrated in field experiments.


Outcomes of photorefractive keratectomy in patients with atypical topography.
Photorefractive keratectomy (PRK) is at risk of serious complications such as corneal ectasia, which can reduce corrected distance visual acuity. The rate of complications of PRK is higher in patients with atypical topography. To determine the outcomes of photorefractive keratectomy in patients with atypical topography. This cross-sectional study was done in 2015 in Shiraz in Iran. We included 85 eyes in this study. The samples were selected using a simple random sampling method. All patients were under evaluation for uncorrected distance visual acuity, corrected distance visual acuity, manifest refraction, corneal topography, central corneal thickness using pentacam, slit-lamp microscopy, and detailed fondus evaluation. The postoperative examination was done 1-7 years after surgery. Data were analyzed using IBM SPSS 21.0 version. To analyze the data, descriptive statistics (frequency, percentage, mean, and standard deviation), chi-square, and independent samples t-test were used. We studied 85 eyes. Among the patients, 23 (27.1%) were male and 62 (72.9%) were female. Mean age of the participants was 28.25±5.55 years. Mean postoperative refraction was - 0.37±0.55 diopters. Keratoconus or corneal ectasia was not reported in any patient in this study. There was no statistically significant difference between SI index before and after operation (p=0.736). Mean preoperative refraction was -3.84 ± 1.46 diopters in males and -4.20±1.96 diopters in females; thus there was not statistically significant difference (p = 0.435). PRK is a safe and efficient photorefractive surgery and is associated with low complication rate in patients with atypical topography.


Physicochemical aspects of lead bioaccumulation by Chlorella vulgaris.
The relationship between lead speciation and its bioaccumulation by the alga Chlorella vulgaris was studied in the absence and presence of nitrilotriacetic, iminodiacetic, malonic, and citric acids. Pb uptake fluxes were rigorously analyzed by considering the simultaneous effects of metal transport in the medium coupled with metal complex dissociation kinetics. Under the conditions examined here, lead biouptake by C. vulgaris was governed by the free lead ion activity. Potentially labile hydrophilic complexes such as lead citrate and lead malonate did not contribute to the internalization fluxes. Kinetic modeling of the mass transport, adsorption reactions, and internalization fluxes confirmed the rate limiting role of the internalization flux. Comparison of the internalization and diffusive fluxes revealed that even in the presence of a large excess of Pb complexes, the supply of free ion (Pb2+) was sufficient to account for the observed Pb uptake. Pb adsorption to the cell surface was described by Langmuir isotherm. A new method was proposed as a means to estimate the number of Pb occupied transport sites at steady state. The apparent stability constant for the interaction of Pb with transport sites was determined to be 10(5.5) M(-1) at pH 6. Low temperature decreased both the Pb uptake flux and the Pb adsorbed to the transport sites. Pb uptake in the presence of Ca was competitively inhibited, and the binding affinity constant for Ca and transport sites was estimated to be 10(4.67) M(-1) at pH 6. Results were discussed within the perspective of the free ion activity and biotic ligand models.


Investigation of the photoconductive properties of thiophene substituted metallo-phthalocyanines.
The synthesis of 4-(thiophen-3-ylethynyl)phthalonitrile was achieved via the Sonogashira cross-coupling reaction. Herein, we report the synthesis of symmetrical metallo-phthalocyanines with cobalt, zinc, and manganese as the metal ions, and tetrakis(ethynylthiophene) groups substituted at the peripheral positions. The new compounds have been characterized by using mass, 1H NMR, 13C NMR, FT-IR and UV-vis spectroscopy. Dark and photoconductivity measurements were carried out on spin coated thiophene substituted metallo-phthalocyanines at various temperatures fixed between 300 and 440 K. Photocurrent generation and charge transport mechanisms are discussed as well. The evaluation of the photoconductive properties of these compounds indicated that the photocurrent generation efficiency and charge transport mechanism exhibited a strong temperature dependence. On the other hand, conductivity measurements revealed that the temperature dependence of the conductivity can be described by the Arrhenius type exponential equation under dark conditions. Furthermore, it was found that the photoconductive behavior of the film can be described successfully by the variable range hopping model for the whole investigated temperature range.


Effect of long term-administration with Gymnema sylvestre R. BR on plasma and liver lipid in rats.
Extract of Gymnema sylvestre leaves was administered to rats receiving either a high fat diet or normal fat diet for 10 weeks to investigate its influence on plasma and liver lipids and on visceral fat accumulation. In addition, its effect was compared with those of chitosan and the influence of combined use of these two substances was also evaluated. Within the high fat diet groups, the extract suppressed body weight gain and accumulation of liver lipids to the same extent as chitosan and the combined use. In addition, intraperitoneal fat and fat drop vacuoles on the epithelium of renal tubules, noted in the high fat diet group, were scattered by administration of the extract with the same results as for chitosan and combined use. Within the normal fat diet groups, plasma triglyceride levels decreased by administration of the extract, with similar results as chitosan and combined use. Concerning plasma total cholesterol, there was no decreasing effects with the extract, as found with chitosan and combined use. However, the effect of chitosan on plasma total cholesterol tended to be enhanced when used in combination with the extract. In addition, long-term administration of the extract did not show any influence on hematological and blood chemical parameters.


Dietary habits of patients with coronary atherosclerosis: case-control study.
The aim of this study was to identify the dietary-related risk factors for coronary atherosclerosis among Hong Kong Chinese people. Prevalence and mortality figures for coronary atherosclerosis are increasing in Chinese communities, including those in Hong Kong. Changes in dietary patterns might explain the increased risk of coronary artery disease among the Hong Kong Chinese. A total of 145 consecutive patients scheduled to have coronary angiogram in a regional hospital in Hong Kong completed a self-reported questionnaire on their dietary intake for 1 week. A case-control design was used, and the data were collected from December 2000 to February 2001. Consumption of more than 1120 g of fish [28 tael (Chinese weight unit, 1 tael equals approximately 42 g)] per week (OR = 0.07) and soybean (OR = 0.17) had a beneficial effect in preventing coronary atherosclerosis. In addition, an increased waist-hip ratio (OR = 4.81) and consumption of more than 28 teaspoons of fat per week (OR = 42.36) were identified by logistic regression as independent risk factors for coronary atherosclerosis. Moreover, people who smoked (OR = 1.72), had a lower educational level (OR = 0.51) or higher family income (OR = 1.92) were more vulnerable to coronary atherosclerosis. Patients confirmed as having coronary atherosclerosis were more likely than those with normal coronary vessels to rank deep fry, stir fry, and pan fry as their preferred cooking methods over steaming or boiling. The results provide nurses with information on which to develop appropriate health education programmes for patients and the general public in Hong Kong to promote cardiovascular health. Efforts should be directed particularly to promoting boiling and steaming as major cooking methods, rather than frying or deep frying, as protective actions against coronary atherosclerosis.


Resident selection: a key to the future of orthopaedics.
Recognizing the challenges presented in the process of resident selection, in 1981 the American Orthopaedic Association formed a Steering Committee on Resident Selection. This Committee was charged with studying the processes involved in the selection of orthopaedic residents and developing guidelines and making suggestions to program directors. The activities of the Committee focused on five areas: (1) the mechanics of resident selection; (2) the assessment of cognitive skills; (3) the assessment of motor ability; (4) the assessment of noncognitive factors (the affective domain); (5) the assessment of "dropouts." The Committee made the following recommendations to help program directors in the selection of residents: (1) use of a standardized application form; (2) full disclosure to applicants; (3) careful selection of candidates to be interviewed; (4) careful planning and implementation of the interview and visit; (5) broad faculty representation and discussion at time of selection; (6) due diligence when necessary. We still believe these criteria important in resident selection.


Ultrasonography for neonatal brachial plexus palsy.
Ultrasonography has previously been reported for use in the evaluation of compressive or traumatic peripheral nerve pathology and for its utility in preoperative mapping. However, these studies were not performed in infants, and they were not focused on the brachial plexus. The authors report a case in which ultrasonography was used to improve operative management of neonatal brachial plexus palsy (NBPP). An infant boy was born at term, complicated by right-sided shoulder dystocia. Initial clinical evaluation revealed proximal arm weakness consistent with an upper trunk injury. Unlike MRI or CT myelography that focus on proximal nerve roots, ultrasonography of the brachial plexus in the supraclavicular fossa was able to demonstrate a small neuroma involving the upper trunk (C-5 and C-6) and no asymmetry in movement of the diaphragm or in the appearance of the rhomboid muscle when compared with the unaffected side. However, the supra- and infraspinatus muscles were significantly asymmetrical and atrophied on the affected side. Importantly, ultrasound examination of the shoulder revealed posterior glenohumeral laxity. Instead of pursuing the primary nerve reconstruction first, timely treatment of the shoulder subluxation prevented formation of joint dysplasia and formation of a false glenoid, which is a common sequela of this condition. Because the muscles innervated by proximal branches of the cervical nerve roots/trunks were radiographically normal, subsequent nerve transfers were performed and good functional results were achieved. The authors believe this to be the first report describing the utility of ultrasonography in the surgical treatment planning in a case of NBPP. Noninvasive imaging, in addition to thorough history and physical examination, reduces the intraoperative time required to determine the extent and severity of nerve injury by allowing improved preoperative planning of the surgical strategy. Inclusion of ultrasonography as a preoperative modality may yield improved outcomes for children with NBPP.


The nature of medical evidence and its inherent uncertainty for the clinical consultation: qualitative study.
To describe how clinicians deal with the uncertainty inherent in medical evidence in clinical consultations. Qualitative study. Clinical consultations related to hormone replacement therapy, bone densitometry, and breast screening in seven general practices and three secondary care clinics in the UK NHS. Women aged 45-64. 45 of the 109 relevant consultations included sufficient discussion for analysis. The consultations could be categorised into three groups: focus on certainty for now and this test, with slippage into general reassurance; a coherent account of the medical evidence for risks and benefits, but blurring of the uncertainty inherent in the evidence and giving an impression of certainty; and acknowledging the inherent uncertainty of the medical evidence and negotiating a provisional decision. Strategies health professionals use to cope with the uncertainty inherent in medical evidence in clinical consultations include the use of provisional decisions that allow for changing priorities and circumstances over time, to avoid slippage into general reassurance from a particular test result, and to avoid the creation of a myth of certainty.


Deletion of the BCSP31 gene of Brucella abortus by replacement.
The 31-kDa salt-extractable immunogenic protein, BCSP31, was deleted from several Brucella abortus strains by replacement with a marker gene encoding resistance to the antibiotics kanamycin and neomycin. The BCSP31 gene replacement plasmids, constructed with ColE1-derived vectors, were introduced by electroporation into B. abortus strain 19 (S19), into a rough variant of B. abortus S19, and into B. abortus S2308, and antibiotic-resistant transformants were isolated. B. abortus S19 is an attenuated strain used as a vaccine for prevention of bovine brucellosis in the United States, and B. abortus S2308 is a commonly used challenge strain. The antibiotic-resistant isolates were all obtained by recombination; none were spontaneous mutants. Loss of the gene encoding BCSP31 and presence of the marker gene were confirmed by Southern analysis. Vector sequences were either absent or linked to the genome, indicating that ColE1-derived plasmids are not maintained in B. abortus. Survival of B. abortus mutant strains in the macrophagelike cell line J774 and in HeLa cells was examined and shown to be indistinguishable from that of the parental strain.


Exploring neighborhoods in large metagenome assembly graphs using spacegraphcats reveals hidden sequence diversity.
Genomes computationally inferred from large metagenomic data sets are often incomplete and may be missing functionally important content and strain variation. We introduce an information retrieval system for large metagenomic data sets that exploits the sparsity of DNA assembly graphs to efficiently extract subgraphs surrounding an inferred genome. We apply this system to recover missing content from genome bins and show that substantial genomic sequence variation is present in a real metagenome. Our software implementation is available at https://github.com/spacegraphcats/spacegraphcats under the 3-Clause BSD License.


Quality of life in patients with Alzheimer's disease as reported by patient proxies.
To measure behaviors indicative of quality of life (QOL) in patients with Alzheimer's disease and to examine correlates of patient QOL. Cross-sectional investigation. Multi-center study. Sample of 130 diagnosed patients. PRINCIPAL OUTCOME MEASURES: Proxy ratings of (1) the frequency, opportunity, and enjoyment of 15 non-ADL activities potentially within the capacity of a demented person, and (2) the frequency of a series of positive and negative affects, evident in clearly demarcated facial and bodily expressions. QOL ratings were reliably elicited. Family and institutional caregivers differed only in reports of opportunity for patient activity. Frequency of activities declined with increasing severity of dementia. The frequency of negative affects increased and positive affects declined with increasing severity of dementia, but correlations were weak. High QOL, defined by frequent activity and positive affect, was evident in a quarter of the sample. In multivariate models, functional and cognitive status independently predicted QOL among community-resident older adults; only absence of antipsychotics was related to QOL among older people in nursing homes. Patient education, a marker of premorbid state, independently predicted some activity patterns. Although the subjective world of the demented patient is not directly accessible, readily observable behaviors offer a basis for assessing QOL.


A Rapid Primary Healthcare Response to COVID-19: An Equity-Based and Systems-Thinking Approach to Care Ensuring that No One Is Left Behind.
Recent data from across the globe show that COVID-19 is disproportionately affecting those who are already adversely impacted by social determinants of health. In this paper, we explore how members of the Alliance for Healthier Communities - comprehensive, salary-based primary care organizations in Ontario - anticipated the same and rapidly responded by adapting their services to ensure continued equitable access to primary care services. Lessons from this project could be adapted in other primary care team-based models or partnerships to ensure ongoing support for populations that are most at risk from COVID-19 and the consequences of restricted access to services.


Formation of a dynamic kinetochore- microtubule interface through assembly of the Dam1 ring complex.
How kinetochore proteins form a dynamic interface with microtubules is largely unknown. In budding yeast, the 10-protein Dam1 complex is an Aurora kinase target that plays essential roles maintaining the integrity of the mitotic spindle and regulating interactions with the kinetochore. Here, we investigated the biochemical properties of purified Dam1 complex. The complex oligomerized into rings around microtubules. Ring formation was facilitated by microtubules but could occur in their absence. Mutant alleles led to partially assembled complexes or reduced microtubule binding. The interaction between rings and microtubules is mediated by the C termini of both Dam1 and alphabeta-tubulin. Ring formation promotes microtubule assembly, stabilizes against disassembly, and promotes bundling. A GTP-tubulin lattice is the preferred binding partner for the complex, and Dam1 rings can exhibit lateral mobility on microtubules. These observations suggest a mechanism by which the kinetochore can recognize and stay attached to the plus ends of microtubules.


Sublethal Doses of Mefenoxam Enhance Pythium Damping-off of Geranium.
The effect of sublethal doses of fungicides on fungicide-resistant Pythium isolates is unknown but potentially relevant to disease management. Occasional grower reports of Pythium disease increases after fungicide applications and our observations of greater radial growth in vitro on fungicide-amended media than on nonamended media suggests that Pythium isolates may be stimulated by sublethal doses of fungicides. The objectives of this study were to determine whether Pythium isolates were stimulated by sublethal doses of mefenoxam in vitro and whether this stimulation had any influence on Pythium damping-off of geranium seedlings. A mefenoxam-resistant isolate of Pythium aphanidermatum displayed 10% mean radial growth increase in vitro with mefenoxam at 1 × 10-10 μg/ml compared with growth on nonamended agar (nonsignificant). Geranium seedlings treated with one of eight mefenoxam concentrations were inoculated with 5-mm-diameter colonized agar plugs and evaluated for disease severity every 24 h. The area under the disease progress curve and the survival curve were estimated for each treatment and compared. Significant increases in damping-off were observed with mefenoxam at 1 × 10-6 and 1 × 10-10 μg/ml. Our data indicate that a Pythium isolate with resistance to mefenoxam can be stimulated by sublethal doses of the fungicide, and that this stimulation can result in significantly higher rates of Pythium damping-off of geranium seedlings.


Technologies for the Directed Evolution of Cell Therapies.
The next generation of therapies is moving beyond the use of small molecules and proteins to using whole cells. Compared with the interactions of small-molecule drugs with biomolecules, which can largely be understood through chemistry, cell therapies act in a chemical and physical world and can actively adapt to that world, amplifying complexity but also the potential for truly breakthrough impact. Although there has been success in introducing targeting proteins into cells to achieve a therapeutic effect, for example, chimeric antigen receptor (CAR) T cells, our ability to engineer cells is generally limited to introducing proteins, but not modulating large-scale traits or structures of cellular "machines," which play critical roles in disease. Example traits include the ability to secrete compounds, deform through tissue, adhere to surrounding cells, apply force to phagocytose targets, or move through extracellular matrix. There is an opportunity to increase the efficacy of cell therapies through the use of quantitative automation tools, to analyze, sort, and select rare cells with beneficial traits. Combined with methods of genetic or epigenetic mutagenesis to create diversity, such approaches can enable the directed cellular evolution of new therapeutically optimal populations of cells and uncover genetic underpinnings of these optimal traits.


para-Hydrogen-induced polarization in heterogeneous hydrogenation reactions.
We demonstrate the creation and observation of para-hydrogen-induced polarization in heterogeneous hydrogenation reactions. Wilkinson's catalyst, RhCl(PPh3)3, supported on either modified silica gel or a polymer, is shown to hydrogenate styrene into ethylbenzene and to produce enhanced spin polarizations, observed through NMR, when the reaction was performed with H2 gas enriched in the para spin isomer. Furthermore, gaseous phase para-hydrogenation of propylene to propane with two catalysts, the Wilkinson's catalyst supported on modified silica gel and Rh(cod)(sulfos) (cod = cycloocta-1,5-diene; sulfos = -O3S(C6H4)CH2C(CH2PPh2)3) supported on silica gel, demonstrates heterogeneous catalytic conversion resulting in large spin polarizations. These experiments serve as a direct verification of the mechanism of heterogeneous hydrogenation reactions involving immobilized metal complexes and can be potentially developed into a practical tool for producing catalyst-free fluids with highly polarized nuclear spins for a broad range of hyperpolarized NMR and MRI applications.


Impulsivity in overweight children.
This study investigates whether or not obese children have a stronger tendency to act on impulse than normal weight children, taking into account the multidimensionality and complexity of the impulsivity construct. A performance based test (Matching Familiar Figure Test, MFFT), a child interview and questionnaire, and parental reports were obtained from 56 overweight children and 53 normal weight children aged 10-18 years. Overweight children responded in a more impulsive way on the MFFT (P < .01). On the child questionnaire, overweight boys reported more problems with focussing attention (P < .05) and both overweight boys and girls reported being worse at shifting their attention compared with normal weight children (P < .05). In particular, overweight boys showed more impulsivity (P < .05), hyperactivity (P < .01), and inattention symptoms (P < .001) as measured via the clinical interview. Parents of overweight children reported an equal amount of impulsivity and hyperactivity symptoms as parents of normal weight children, but scored their children lower on the Conscientiousness personality dimension (P < .01). A subgroup of overweight children appears to have a stronger tendency to act on impulse than normal weight children, and demonstrated an impulsivity prone personality. Hence, overweight children should be screened for impulse control deficiencies. More research is needed to clear out the robustness of gender differences, the existence of a specific personality profile and possibly common underlying mechanisms of childhood obesity and Attention Deficit Hyperactivity Disorder.


Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy.
Arrhythmogenic cardiomyopathy (ACM) is a heritable disease characterized by fibrofatty replacement of cardiomyocytes, has a prevalence of approximately 1 in 5000 individuals, and accounts for approximately 20% of sudden cardiac death in the young (≤35 years). ACM is most often inherited as an autosomal dominant trait with incomplete penetrance and variable expression. While mutations in several genes that encode key desmosomal proteins underlie about half of all ACM, the remainder is elusive genetically. Here, whole exome sequencing (WES) was performed with genomic triangulation in an effort to identify a novel explanation for a phenotype-positive, genotype-negative multi-generational pedigree with a presumed autosomal dominant, maternal inheritance of ACM. WES and genomic triangulation was performed on a symptomatic 14-year-old female proband, her affected mother and affected sister, and her unaffected father to elucidate a novel ACM-susceptibility gene for this pedigree. Following variant filtering using Ingenuity® Variant Analysis, gene priority ranking was performed on the candidate genes using ToppGene and Endeavour. The phylogenetic and physiochemical properties of candidate mutations were assessed further by 6 in silico prediction tools. Species alignment and amino acid conservation analysis was performed using the Uniprot Consortium. Tissue expression data was abstracted from Expression Atlas. Following WES and genomic triangulation, CDH2 emerged as a novel, autosomal dominant, ACM-susceptibility gene. The CDH2-encoded N-cadherin is a cell-cell adhesion protein predominately expressed in the heart. Cardiac dysfunction has been demonstrated in prior CDH2 knockout and over-expression animal studies. Further in silico mutation prediction, species conservation, and protein expression analysis supported the ultra-rare (minor allele frequency <0.005%) p.Asp407Asn-CDH2 variant as a likely pathogenic variant. Herein, it is demonstrated that genetic mutations in CDH2-encoded N-cadherin may represent a novel pathogenetic basis for ACM in humans. The prevalence of CDH2-mediated ACM in heretofore genetically elusive ACM remains to be determined.


The golden age: gold nanoparticles for biomedicine.
Gold nanoparticles have been used in biomedical applications since their first colloidal syntheses more than three centuries ago. However, over the past two decades, their beautiful colors and unique electronic properties have also attracted tremendous attention due to their historical applications in art and ancient medicine and current applications in enhanced optoelectronics and photovoltaics. In spite of their modest alchemical beginnings, gold nanoparticles exhibit physical properties that are truly different from both small molecules and bulk materials, as well as from other nanoscale particles. Their unique combination of properties is just beginning to be fully realized in range of medical diagnostic and therapeutic applications. This critical review will provide insights into the design, synthesis, functionalization, and applications of these artificial molecules in biomedicine and discuss their tailored interactions with biological systems to achieve improved patient health. Further, we provide a survey of the rapidly expanding body of literature on this topic and argue that gold nanotechnology-enabled biomedicine is not simply an act of 'gilding the (nanomedicinal) lily', but that a new 'Golden Age' of biomedical nanotechnology is truly upon us. Moving forward, the most challenging nanoscience ahead of us will be to find new chemical and physical methods of functionalizing gold nanoparticles with compounds that can promote efficient binding, clearance, and biocompatibility and to assess their safety to other biological systems and their long-term term effects on human health and reproduction (472 references).


Effects of preservation methods of muscle tissue from upper-trophic level reef fishes on stable isotope values (δ (13)C and δ (15)N).
Research that uses stable isotope analysis often involves a delay between sample collection in the field and laboratory processing, therefore requiring preservation to prevent or reduce tissue degradation and associated isotopic compositions. Although there is a growing literature describing the effects of various preservation techniques, the results are often contextual, unpredictable and vary among taxa, suggesting the need to treat each species individually. We conducted a controlled experiment to test the effects of four preservation methods of muscle tissue from four species of upper trophic-level reef fish collected from the eastern Gulf of Mexico (Red Grouper Epinephelus morio, Gag Mycteroperca microlepis, Scamp Mycteroperca phenax, and Red Snapper Lutjanus campechanus). We used a paired design to measure the effects on isotopic values for carbon and nitrogen after storage using ice, 95% ethanol, and sodium chloride (table salt), against that in a liquid nitrogen control. Mean offsets for both δ (13)C and δ (15)N values from controls were lowest for samples preserved on ice, intermediate for those preserved with salt, and highest with ethanol. Within species, both salt and ethanol significantly enriched the δ (15)N values in nearly all comparisons. Ethanol also had strong effects on the δ (13)C values in all three groupers. Conversely, for samples preserved on ice, we did not detect a significant offset in either isotopic ratio for any of the focal species. Previous studies have addressed preservation-induced offsets in isotope values using a mass balance correction that accounts for changes in the isotope value to that in the C/N ratio. We tested the application of standard mass balance corrections for isotope values that were significantly affected by the preservation methods and found generally poor agreement between corrected and control values. The poor performance by the correction may have been due to preferential loss of lighter isotopes and corresponding low levels of mass loss with a substantial change in the isotope value of the sample. Regardless of mechanism, it was evident that accounting for offsets caused by different preservation methods was not possible using the standard correction. Caution is warranted when interpreting the results from specimens stored in either ethanol or salt, especially when using those from multiple preservation techniques. We suggest the use of ice as the preferred preservation technique for muscle tissue when conducting stable isotope analysis as it is widely available, inexpensive, easy to transport and did not impart a significant offset in measured isotopic values. Our results provide additional evidence that preservation effects on stable isotope analysis can be highly contextual, thus requiring their effects to be measured and understood for each species and isotopic ratio of interest before addressing research questions.


Why it Worked: Participants' Insights into an mHealth Antiretroviral Therapy Adherence Intervention in China.
Few Antiretroviral Therapy (ART) adherence trials investigate the reasons for intervention success or failure among HIV-positive individuals. To conduct qualitative research to explore the reasons for effectiveness of a 6-month mHealth (mobile health) trial that improved adherence among ART patients in China. The intervention utilized Wireless Pill Containers (WPCs) to provide, real-time SMS reminders, WPC-generated adherence reports, and report-informed counseling. We conducted in-depth interviews with 20 intervention-arm participants immediately following the trial. Sampling was purposeful to ensure inclusion of participants with varied adherence histories. Questions covered adherence barriers and facilitators, and intervention experiences. We analyzed data in nVivo using a thematic approach. Of participants, 14 (70%) were male; 7 (35%) had used injectable drugs. Pre-intervention, 11 were optimal adherers and 9 were suboptimal adherers, using a 95% threshold. In the final intervention month, all but 3 (85%) attained optimal adherence. Participants identified a range of adherence barriers and facilitators, and described various mechanisms for intervention success. Optimal adherers at baseline were motivated by positive adherence reports at monthly clinic visits-similar to receiving A+ grades. For suboptimal adherers, reminders facilitated the establishment of adherence-promoting routines; data-guided counseling helped identify strategies to overcome specific barriers. Different behavioral mechanisms appear to explain the success of an mHealth adherence intervention among patients with varying adherence histories. Positive reinforcement was effective for optimal adherers, while struggling patients benefitted from reminders and data-informed counseling. These findings are relevant for the design and scalability of mHealth interventions and warrant further investigation.


The relationship between television advertising, children's viewing and their requests to Father Christmas.
Children's letters to Father Christmas provide an opportunity to use naturalistic methods to investigate the influence of television advertising. This study investigates the number of toy requests in the letters of children aged between 6 and 8 (n = 98) in relation to their television viewing and the frequency of product advertisements prior to Christmas. Seventy-six hours of children's television were sampled, containing over 2,500 advertisements for toys. Children's viewing frequency, and a preference for viewing commercial channels, were both related to their requests for advertised goods. Gender effects were also found, with girls requesting more advertised products than boys. Exploring the children's explicit understanding of advertising showed that children in this age group are not wholly aware of the advertisers' intent and that, together with their good recall of advertising, this may account for their vulnerability to its persuasive messages.


Evaluation of cardiovascular risk in school children.
Atherosclerosis is a pathological condition that begins in early childhood, but clinically the disease manifests in older age. The aim of work was to determine frequency of atherosclerosis risk factors in healthy school children. Cross-sectional study included 214 children in mean age 10,99+/-2,52 years, within range 7 to 15 years. Patients body mass index, blood pressure, lipid status, dietary habits, physical activity and sedentary habits have been evaluated. Cardiovascular risk factors are significantly present in children (P<0,05) i.e. one cardiovascular risk factor is present in 47/214 (21,96%) children, two risk factors had 25/214 (11,68%) children, while 17/214 (7,94%) children had three or more cardiovascular risk factors. Obesity was present in 20/214 (9,34%) children, while overweight was present in 23/214 (10,74%) children. Hypertension was present in 10/214 (4,67%) children, and it was significantly present (p<0,05) in obese and overweight children. Total cholesterol was increased in 17/214 (7,94%) children, LDL-cholesterol was increased in 11/214 (5,14%) [corrected], increased triglycerides had 4/214 (1,86%) children, while decreased HDL-cholesterol was found in (3/214, 1,40%) children. Unhealthy dietary habits were present in 45/214 (21,02%) children, 42/214 (19,62%) children is physically inactive, while sedentary habits were shown in 39/214 (18,22%) children. Research shows that a large number within study group has one or more cardiovascular risk factors that can lead to premature atherosclerosis. Using massive screening of cardiovascular risk factors, along with adequate physical activity, healthy dietary habits, reduced sedentary habits, doctors and teacher's education, parents and children can reduce premature clinical sequels in atherosclerotic process.


Layer-oriented adaptive optics for solar telescopes.
First multiconjugate adaptive-optical (MCAO) systems are currently being installed on solar telescopes. The aim of these systems is to increase the corrected field of view with respect to conventional adaptive optics. However, this first generation is based on a star-oriented approach, and it is then difficult to increase the size of the field of view beyond 60-80 arc sec in diameter. We propose to implement the layer-oriented approach in solar MCAO systems by use of wide-field Shack-Hartmann wavefront sensors conjugated to the strongest turbulent layers. The wavefront distortions are averaged over a wide field: the signal from distant turbulence is attenuated and the tomographic reconstruction is thus done optically. The system consists of independent correction loops, which only need to account for local turbulence: the subapertures can be enlarged and the correction frequency reduced. Most importantly, a star-oriented MCAO system becomes more complex with increasing field size, while the layer-oriented approach benefits from larger fields and will therefore be an attractive solution for the future generation of solar MCAO systems.


The influence of dinoprostone on uterine cervix ripening and the course of labor.
The aim of the study was to estimate the influence of dinoprostone in two different forms on the ripening of uterine cervix and the course of labor. 128 pregnant women with indications for labor induction and uterine cervix Bishop's scores <6, divided into 2 groups: I--62 patients who had dinoprostone in the form of a gel applied for labor preinduction; II--66 women who were administered dinoprostone in the form of vaginal inserts. The effectiveness of both forms of dinoprostone were estimated and compared. No differences in Bishop's score changes were noticeable between the groups after 6-8 hours from application, however they were significant at the beginning of induction: I - 7.8+/-1.3 vs. II - 6.9+/-1.6 (p=0.0007). Almost half of the patients from group II had spontaneous contractions and required no labor induction at all. The average time from dinoprostone application till delivery was shorter in group II. Dinoprostone vaginal inserts seem to influence both uterine cervix and muscle, while gel-prepare uterine cervix for delivery more effectively.


1,1'-Biaceanthrylene and 2,2'-Biaceanthrylene: Models for Linking Larger Polycyclic Aromatic Hydrocarbons via Five-Membered Rings.
We show that polycyclic aromatic hydrocarbon (PAH) chromophores that are linked between two five-membered rings can access planarized structures with reduced optical gaps and redox potentials. Two aceanthrylene chromophores were connected into dimer model systems with the chromophores either projected outward (2,2'-biaceanthrylene) or inward (1,1'-biaceanthrylene), and the optical and electronic properties were compared. Only the planar 2,2'-biaceanthrylene system showed significant reductions of the optical gaps (1 eV) and redox potentials in relation to the aceanthrylene monomer. Organic field effect transistors based on 2,2'-biaceanthrylene were prepared and were found to operate in the hole transport regime with an average charge carrier mobilities of 1.8 × 10-4 cm2 V-1 s-1.


NK Cells Expressing the Inhibitory Killer Immunoglobulin-Like Receptors (iKIR) KIR2DL1, KIR2DL3 and KIR3DL1 Are Less Likely to Be CD16+ than Their iKIR Negative Counterparts.
Natural Killer (NK) cell education, which requires the engagement of inhibitory NK cell receptors (iNKRs) by their ligands, is important for generating self-tolerant functional NK cells. While the potency of NK cell education is directly related to their functional potential upon stimulation with HLA null cells, the influence of NK cell education on the potency of the antibody dependent cellular cytotoxicity (ADCC) function of NK cells is unclear. ADCC occurs when the Fc portion of an immunoglobulin G antibody bridges the CD16 Fc receptor on NK cells and antigen on target cells, resulting in NK cell activation, cytotoxic granule release, and target cell lysis. We previously reported that education via the KIR3DL1/HLA-Bw4 iNKR/HLA ligand combination supported higher KIR3DL1+ than KIR3DL1- NK cell activation levels but had no impact on ADCC potency measured as the frequency of granzyme B positive (%GrB+) targets generated in an ADCC GranToxiLux assay. A lower frequency of KIR3DL1+ compared to KIR3DL1- NK cells were CD16+, which may in part explain the discrepancy between NK cell activation and target cell effects. Here, we investigated the frequency of CD16+ cells among NK cells expressing other iNKRs. We found that CD16+ cells were significantly more frequent among NK cells negative for the inhibitory KIR (iKIR) KIR2DL1, KIR2DL3, and KIR3DL1 than those positive for any one of these iKIR to the exclusion of the others, making iKIR+ NK cells poorer ADCC effectors than iKIR- NK cells. The education status of these iKIR+ populations had no effect on the frequency of CD16+ cells.


Efficacy and safety of pramipexole in restless legs syndrome.
To evaluate the efficacy and safety of pramipexole in patients with moderate to severe restless legs syndrome (RLS) METHODS: The authors conducted a 12-week, double-blind, randomized, placebo-controlled trial of fixed doses of pramipexole (0.25, 0.50, and 0.75 mg/day). Patients (N = 344) were up-titrated to their randomized dose over 3 weeks. The primary efficacy endpoints were patient ratings of symptom severity on the International RLS Study Group Rating Scale (IRLS) and clinician ratings of improvement on the Clinical Global Impressions-Improvement (CGI-I) scale. Secondary efficacy endpoints included visual analogue ratings of sleep and quality of life (QOL) RESULTS: By both primary measures, pramipexole was superior to placebo. For IRLS, the adjusted mean (SE) change from baseline to week 12 was -9.3 (1.0) for placebo, -12.8 (1.0) for 0.25 mg/day, -13.8 (1.0) for 0.50 mg/day, and -14.0 (1.0) for 0.75 mg/day (all p < 0.01). Similarly, pramipexole increased the percentage of patients with a CGI-I rating of "very much improved" or "much improved" at the end of the trial (51.2% for placebo and 74.7%, 67.9%, and 72.9% for pramipexole; all p < 0.05). Pramipexole significantly improved ratings of symptom severity, day and night, and also ratings of sleep satisfaction and QOL. Pramipexole was well tolerated: The most frequent adverse events with higher occurrence in the pramipexole group were nausea (19.0% vs 4.7%) and somnolence (10.1% vs 4.7%) As rated by patients and by clinicians, pramipexole was efficacious and safe in reducing the symptoms of restless legs syndrome.


Specific adsorption of IgM antibody onto H-2-activated mouse T lymphocytes.
Evidence is presented to support the contention that IgM demonstrable by surface immunofluorescent staining on H-2-activated T cells represents specifically adsorbed B-cell-derived alloantibody. T cells activated to H-2 determinants expressed surface IgM only when the progenitor cell populations contained B lymphocytes. IgM was not detected on T cells activated to determinants which fail to stimulate alloantibody production (e.g., M-locus determinants). In addition, IgM-negative H-2 activated T cells (derived from B-cell-depleted lymphoid cells), unlike M-locus-activated T cells, adsorbed IgM in a specific manner when incubated in vitro with "early bleed" antisera raised against the activating H-2 determinants.


Solvent retention in electrospun fibers affects scaffold mechanical properties.
Electrospinning is a robust material fabrication method allowing for fine control of mechanical, chemical, and functional properties in scaffold manufacturing. Electrospun fiber scaffolds have gained prominence for their potential in a variety of applications such as tissue engineering and textile manufacturing, yet none have assessed the impact of solvent retention in fibers on the scaffold's mechanical properties. In this study, we hypothesized that retained electrospinning solvent acts as a plasticizer, and gradual solvent evaporation, by storing fibers in ambient air, will cause significant increases in electrospun fiber scaffold brittleness and stiffness, and a significant decrease in scaffold toughness. Thermogravimetric analysis indicated solvent retention in PGA, PLCL, and PET fibers, and not in PU and PCL fibers. Differential scanning calorimetry revealed that polymers that were electrospun below their glass transition temperature (T g ) retained solvent and polymers electrospun above T g did not. Young's moduli increased and yield strain decreased for solventretaining PGA, PLCL, and PET fiber scaffolds as solvent evaporated from the scaffolds over a period of 14 days. Toughness and failure strain decreased for PGA and PET scaffolds as solvent evaporated. No significant differences were observed in the mechanical properties of PU and PCL scaffolds that did not retain solvent. These observations highlight the need to consider solvent retention following electrospinning and its potential effects on scaffold mechanical properties.


Staging of primary breast cancer is not indicated in asymptomatic patients with early tumor stages.
The routinely practiced staging for distant metastasis in patients with primary breast cancer has been increasingly questioned. Data from 742 patients with breast cancer who had completed staging (chest x-ray, liver ultrasound, and bone scan) were retrospectively analyzed. Present findings were transferred to a dataset of a voluntarily monitored benchmarking project by the West German Breast Center that included patient data of 179 breast cancer centers. Routine staging examinations revealed in 1.2% (n = 9) distant metastasis and in 38.8% (n = 288) suspicious results. In total, 15 patients (2%) had distant metastases confirmed by additional diagnostics. The existence of distant metastases correlated with tumor size, nodal state, and lymphatic vessel spread. Tumor size and nodal state were independent predictors for disseminated disease. The risk of exhibiting distant metastases was 0.77% for patients with tumor stage pT1 pN1. Based on these findings, in 159,310 patients 41,728 chest x-rays, 43,950 liver ultrasounds, and 39,037 bone scans could have been avoided. Asymptomatic patients with tumor stages ≤ pT1 pN1 do not benefit from staging of primary breast cancer. Suspending staging examinations for these patients could reduce cost without restricting oncologic safety.