Ascaris suum: role of ecdysteroids in molting.
Three studies were conducted to examine the function of ecdysteroids in the development of parasitic nematodes. Ecdysone and 20-hydroxyecdysone were extracted, separated chromatographically, and measured in the reproductive tracts of adult female Ascaris suum. Perienteric fluid and the body wall did not contain measurable levels of these steroids. Levels of 20-hydroxyecdysone were correlated with the third and fourth molts of larvae grown in vitro from the third stage. In a bioassay, addition of ecdysteroid extracted from the female reproductive tract or synthetic ecdysteroid increased the proportion of third-stage larvae that molted after 4 days in culture. This evidence supports the role of ecdysteroids in molting in A. suum, as well as suggesting a function in gametogenesis and embryogenesis.


A novel process for ethanol or biogas production from cellulose in blended-fibers waste textiles.
A novel process has been developed for separation of the cellulose, i.e. cotton and viscose, from blended-fibers waste textiles. An environmentally friendly cellulose solvent, N-methylmorpholine-N-oxide (NMMO) was used in this process for separation and pretreatment of the cellulose. This solvent was mixed with blended-fibers textiles at 120 °C and atmospheric pressure to dissolve the cellulose and separate it from the undissolved non-cellulosic fibers. Water was then added to the solution in order to precipitate the cellulose, while both water and NMMO were reused after separation by evaporation. The cellulose was then either hydrolyzed by cellulase enzymes followed by fermentation to ethanol, or digested directly to produce biogas. The process was verified by testing 50/50 polyester/cotton and 40/60 polyester/viscose-blended textiles. The polyesters were purified as fibers after the NMMO treatments, and up to 95% of the cellulose fibers were regenerated and collected on a filter. A 2-day enzymatic hydrolysis and 1-day fermentation of the regenerated cotton and viscose resulted in 48 and 50 g ethanol/g regenerated cellulose, which were 85% and 89% of the theoretical yields, respectively. This process also resulted in a significant increase of the biogas production rate. While untreated cotton and viscose fibers were converted to methane by respectively, 0.02% and 1.91% of their theoretical yields in 3 days of digestion, the identical NMMO-treated fibers resulted into about 30% of yield at the same period of time.


Revisiting the MotionWatch8©: Calibrating Cut-Points for Measuring Physical Activity and Sedentary Behavior Among Adults With Stroke.
Reduced moderate-to-vigorous physical activity (MVPA) and increased sedentary behavior (SB) are common following stroke, which can limit stroke recovery and contribute to greater cognitive decline. Hence, the MVPA and SB of adults with stroke should be measured concurrently using objective methods. One currently available method for objectively measuring MVPA and SB is the MotionWatch8© (MW8). However, adults with stroke can have significant mobility restrictions (depending on stroke severity) and thus it is important to determine separate MVPA and SB cut-points for adults with stroke, as well as validate separate cut-points: (1) when the MW8 is worn on the stroke affected side compared to the non-affected side; and (2) for adults with mild stroke versus adults with moderate-to-severe stroke. In the current study, we concurrently measured MW8 actigraphy (worn on both the stroke affected side and the non-affected side) and indirect calorimetry during 10 different activities of daily living for 43 adults with stroke (aged 55-87 years). Using intra-class correlations (ICC), we first investigated the agreement of the MW8 when placed on the affected side as compared to the non-affected side for: (1) all participants irrespective of stroke severity; (2) participants with mild stroke, classified as a Fugl Meyer motor score of ≥79/100; and (3) participants with moderate-to-severe stroke (i.e., Fugl Meyer < 79/100). We then determined cut-points for all participants-as well as separate cut-points based on stroke severity-on both the stroke affected side and non-affected side for SB and MVPA using receiver operating characteristic curves. The results of our analyses indicate that the agreement in MW8 output between the stroke affected and non-affected sides was moderate across all participants (ICC = 0.67), as well as for each sub-group (mild stroke: ICC = 0.64; moderate-to-severe stroke: ICC = 0.77). Additionally, the results of our cut-point analyses support using different cut-points for different levels of stroke severity and also for the stroke affected side. We determined the following cut-points: (1) for the affected side, adults with mild stroke have cut-points of SB ≤134 counts per minute (CPM) and MVPA ≥704 CPM, while adults with moderate-to-severe stroke have cut-points of SB ≤281 CPM and MVPA ≥468 CPM; and (2) the non-affected side, adults with mild stroke have cut-points of SB ≤162 CPM and MVPA ≥661 CPM, while adults with moderate-to-severe stroke have cut-points of SB ≤281 CPM and MVPA ≥738 CPM. Hence, these data provide a new measure for concurrently examining the dynamic relationships between MVPA and SB among adults with stroke.


Larval excretory-secretory products from the parasite Schistosoma mansoni modulate HSP70 protein expression in defence cells of its snail host, Biomphalaria glabrata.
Synthesis of heat shock proteins (HSPs) following cellular stress is a response shared by many organisms. Amongst the HSP family, the approximately 70 kDa HSPs are the most evolutionarily conserved with intracellular chaperone and extracellular immunoregulatory functions. This study focused on the effects of larval excretory-secretory products (ESPs) from the parasite Schistosoma mansoni on HSP70 protein expression levels in haemocytes (defence cells) from its snail intermediate host Biomphalaria glabrata. S. mansoni larval stage ESPs are known to interfere with haemocyte physiology and behaviour. Haemocytes from two different B. glabrata strains, one which is susceptible to S. mansoni infection and one which is resistant, both showed reduced HSP70 protein levels following 1 h challenge with S. mansoni ESPs when compared to unchallenged controls; however, the reduction observed in the resistant strain was less marked. The decline in intracellular HSP70 protein persisted for at least 5 h in resistant snail haemocytes only. Furthermore, in schistosome-susceptible snails infected by S. mansoni for 35 days, haemocytes possessed approximately 70% less HSP70. The proteasome inhibitor, MG132, partially restored HSP70 protein levels in ESP-challenged haemocytes, demonstrating that the decrease in HSP70 was in part due to intracellular degradation. The extracellular signal-regulated kinase (ERK) signalling pathway appears to regulate HSP70 protein expression in these cells, as the mitogen-activated protein-ERK kinase 1/2 (MEK1/2) inhibitor, U0126, significantly reduced HSP70 protein levels. Disruption of intracellular HSP70 protein expression in B. glabrata haemocytes by S. mansoni ESPs may be a strategy employed by the parasite to manipulate the immune response of the intermediate snail host.


Experience of Health Care Services After a Suicide Attempt: Results from an Online Survey.
Failure to provide follow-up care after a suicide attempt is associated with increased risk of reattempt. This online survey examined the experiences of patients of the Australian health system after a suicide attempt. Just over half of the participants had a psychiatric assessment within 1 week of their attempt. Fewer than half believed they had been offered enough help. Low service satisfaction was associated with lower help-seeking intentions. Support for individuals who have made a suicide attempt needs to be enhanced, and an integrated approach to care is required, including improved referral pathways and staff attitudinal change.


Humoral antibody response of the tilapia Oreochromis niloticus against Cichlidogyrus spp. (Monogenea).
The humoral immune response of the tilapia Oreochromis niloticus was evaluated using a direct ELISA. Serum was tested from fish infected with Cichlidogyrus spp. (Monogenea) and from fish injected intraperitoneally with the Cichlidogyrus spp. antigenic extract, i.e., 150 microl of the Cichlidogyrus spp. saline extract diluted in Freund's complete adjuvant (FCA) (1:1) were inoculated intraperitoneally at day 0, followed by 2 dosages of 50 microl of the same Cichlidogyrus spp. saline extract diluted in Freund's incomplete adjuvant (FIA) (1:1) at weeks 2 and 4, respectively. The humoral response was also evaluated by the double immunodiffusion test (DID) and by serum protein and total immunoglobulin (Ig) determinations. The IgM OD values in the hyperimmune fish were significantly higher than in the infected and uninfected fish groups. In the DID test, a precipitation (antigen-antibody) band was observed between the Cichlidogyrus spp. saline extract and hyperimmune sera, but not with the other groups. Increases in serum protein concentration and total Igs were observed in the immunized fish at weeks 2 and 10 postinjection. Results from this study suggest that tilapia is capable of producing an induced humoral immune response against an antigenic extract of Cichlidogyrus spp.


Management and Follow-up Practices of Children with Unclassified Fever in Rural Ethiopia: Experiences of Health Extension Workers and Caregivers.
Different health-care management guidelines by the World Health Organization exist to help health workers in resource-limited settings treat patients. However, for children with unclassified fever and no danger signs, management guidelines are less clear and follow-up recommendations differ. Both a "universal follow-up" for all children, irrespective of health status, and a "conditional follow-up" only for children whose fever persists are recommended in different guidelines. It is unclear how feasible and acceptable these two different follow-up guidelines are among community health workers and caregivers of the sick child. This qualitative study was conducted in Ethiopia and was nested within a cluster-randomized controlled trial (cRCT). It aimed to determine health extension workers' (HEWs') and caregivers' experiences of the management of febrile children and their perceptions of universal versus conditional follow-up recommendations. Seventeen HEWs and 20 caregivers were interviewed. The interviews revealed that HEWs' understanding of how to handle an unclassified fever diagnosis increased with the implementation of the cRCT in both study arms (universal versus conditional follow-up). This enabled HEWs to withhold medicines from children with this condition and avoid referral to health centers. Both follow-up recommendations had perceived advantages, while the universal follow-up provided an opportunity to see the child's health progress, the conditional follow-up advice allowed saving time and costs. The findings suggest that improved awareness of the unclassified fever condition can make HEWs feel more comfortable in managing these febrile children themselves and omitting unnecessary medication. Future community-level management guidelines should provide clearer instructions on managing fever where no malaria, pneumonia, diarrhea, or danger signs are present.


Allergy to polyethylene glycol and polysorbates in a patient cohort: Diagnostic work-up and decision points for vaccination during the COVID-19 pandemic.
During the COVID-19 pandemic focus has been on polyethylene glycol (PEG) and polysorbate as these excipients are constituents in the first vaccines and possible elicitors of allergic reactions to the vaccines. We aimed to evaluate the possibility of vaccinating patients with PEG and/or polysorbate allergy against COVID-19. Twenty-five patients with a history of an allergic reaction to drugs, vaccines and mouth hygiene products containing PEG or polysorbate and sensitization (skin test or in vitro test) or a positive challenge were included. We re-evaluated 19 of 21 patients diagnosed before 2021 and four new patients by skin prick tests (SPT) and Basophil Histamine Release (BaHR) for PEGs, polysorbates and approved COVID-19 vaccines as well as measurement of specific IgE (PEG 2000, 10,000). Patients were offered vaccination based on decision points from the primary diagnosis and re-evaluation. Most common primary elicitors were depot-steroids and laxatives. Most patients had experienced more than one reaction. SPT was superior to BaHR test although many SPTs became negative over time. After careful re-evaluation three patients were successfully vaccinated with the Pfizer/BioNTech vaccine. Three were vaccinated before referral. Eleven were offered the Johnson-Johnson vaccine; four were vaccinated successfully, seven abstained. Six patients could not be vaccinated with PEG or polysorbate containing vaccines. Hypersensitivity to excipients in COVID-19 vaccines constitutes a risk to patients with allergy to PEG or polysorbates. After diagnostic evaluation, a safe COVID-19 vaccine could be offered to most patients, the remainders will await new vaccines containing different excipients.


Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis.
Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics. However, the exact status and causal role of CLDN3 in IBD and regulation of gut dysbiosis remain unknown. Analysis of mouse and human IBD cohorts helped examine CLDN3 expression in IBD. The causal role was determined by modeling CLDN3 loss of expression during experimental colitis. 16S sequencing and in silico analysis helped examine gut microbiota diversity between Cldn3KO and WT mice and potential host metabolic responses. Fecal microbiota transplant (FMT) studies were performed to assess the role of gut dysbiosis in the increased susceptibility of Cldn3KO mice to colitis. A significant decrease in CLDN3 expression characterized IBD and CLDN3 loss of expression promoted colitis. 16S sequencing analysis suggested gut microbiota changes in Cldn3KO mice that were capable of modulating fatty acid metabolism and oxidative stress response. FMT from naïve Cldn3KO mice promoted colitis susceptibility in recipient germ-free mice (GFM) compared with GFM-receiving microbiota from WT mice. Our data demonstrate a critical role of CLDN3 in maintaining normal gut microbiota and inflammatory responses, which can be harnessed to develop novel therapeutic opportunities for patients with IBD.


The effect of dexmedetomidine on agitation during weaning of mechanical ventilation in critically ill patients.
Ventilated patients receiving opioids and/or benzodiazepines are at high risk of developing agitation, particularly upon weaning towards extubation. This is often associated with an increased intubation time and length of stay in the intensive care unit and may cause long-term morbidity. Anxiety, fear and agitation are amongst the most common non-pulmonary causes of failure to liberate from mechanical ventilation. This prospective, open-label observational study examined 28 ventilated adult patients in the intensive care unit (30 episodes) requiring opioids and/or sedatives for >24 hours, who developed agitation and/or delirium upon weaning from sedation and failed to achieve successful extubation with conventional management. Patients were ventilated for a median (interquartile range) of 115 [87 to 263] hours prior to enrolment. Dexmedetomidine infusion was commenced at 0.4 microg/kg/hour for two hours, after which concurrent sedative therapy was preferentially weaned and titrated to obtain target Motor Activity Assessment Score score of 2 to 4. The median (range) maximum dose and infusion time of dexmedetomidine was 0.7 microg/kg/hour (0.4 to 1.0) and 62 hours (24 to 252) respectively. The number of episodes at target Motor Activity Assessment Score score at zero, six and 12 hours after commencement of dexmedetomidine were 7/30 (23.3%), 28/30 (93.3%) and 26/30 (86.7%), respectively (P < 0.001 for 6 and 12 vs. 0 hours). Excluding unrelated clinical deterioration, 22 episodes (73.3%) achieved successful weaning from ventilation with a median (interquartile range) ventilation time of 70 (28 to 96) hours after dexmedetomidine infusion. Dexmedetomidine achieved rapid resolution of agitation and facilitated ventilatory weaning after failure of conventional therapy. Its role as first-line therapy in ventilated, agitated patients warrants further investigation.


Microfluidic device for coupling isotachophoretic sample focusing with nanopore single-molecule sensing.
Solid-state nanopores (NPs) are label-free single-molecule sensors, capable of performing highly sensitive assays from a small number of biomolecule translocation events. However, single-molecule sensing is challenging at extremely low analyte concentrations due to the limited flux of analytes to the sensing volume. This leads to a low event rate and increases the overall assay time. In this work, we present a method to enhance the event rate at low analyte concentrations by using isotachophoresis (ITP) to focus and deliver analytes to a nanopore sensor. Central to this method is a device capable of performing ITP focusing directly on a solid-state NP chip, while preventing the focusing electric field from damaging the nanopore membrane. We discuss considerations and trade-offs related to the design of the focusing channel, the ITP electrolyte system and electrical decoupling between the focusing and sensing modes. Finally, we demonstrate an integrated device wherein the concentration enhancement due to ITP focusing leads to an increase in event rate of >300-fold in the ITP-NP device as compared to the NP-only case.


A Senolytic-Eluting Coronary Stent for the Prevention of In-Stent Restenosis.
The vast majority of drug-eluting stents (DES) elute either sirolimus or one of its analogues. While limus drugs stymie vascular smooth muscle cell (VSMC) proliferation to prevent in-stent restenosis, their antiproliferative nature is indiscriminate and limits healing of the endothelium in stented vessels, increasing the risk of late-stent thrombosis. Oxidative stress, which is associated with vascular injury from stent implantation, can induce VSMCs to undergo senescence, and senescent VSMCs can produce pro-inflammatory cytokines capable of inducing proliferation of neighboring nonsenescent VSMCs. We explored the potential of senolytic therapy, which involves the selective elimination of senescent cells, in the form of a senolytic-eluting stent (SES) for interventional cardiology. Oxidative stress was modeled in vitro by exposing VSMCs to H2O2, and H2O2-mediated senescence was evaluated by cytochemical staining of senescence-associated β-galactosidase activity and qRT-PCR. Quiescent VSMCs were then treated with the conditioned medium (CM) of H2O2-treated VSMCs. Proliferative effects of CM were analyzed by staining for proliferating cell nuclear antigen. Senolytic effects of the first-generation senolytic ABT263 were observed in vitro, and the effects of ABT263 on endothelial cells were also investigated through an in vitro re-endothelialization assay. SESs were prepared by dip coating. Iliofemoral arteries of hypercholesteremic rabbits were implanted with SES, everolimus-eluting stents (EESs), or bare-metal stents (BMSs), and the area of stenosis was measured 4 weeks post-implantation using optical coherence tomography. We found that a portion of H2O2-treated VSMCs underwent senescence, and that CM of H2O2-treated senescent VSMCs triggered the proliferation of quiescent VSMCs. ABT263 reverted H2O2-mediated senescence and the proliferative capacity of senescent VSMC CM. Unlike everolimus, ABT263 did not affect endothelial cell migration and/or proliferation. SES, but not EES, significantly reduced stenosis area in vivo compared with bare-metal stents (BMSs). This study shows the potential of SES as an alternative to current forms of DES.


Causal estimation using semiparametric transformation models under prevalent sampling.
This article presents methods and inference for causal estimation in semiparametric transformation models for the prevalent survival data. Through the estimation of the transformation models and covariate distribution, we propose a few analytical procedures to estimate the causal survival function. As the data are observational, the unobserved potential outcome (survival time) may be associated with the treatment assignment, and therefore there may exist a systematic imbalance between the data observed from each treatment arm. Further, due to prevalent sampling, subjects are observed only if they have not experienced the failure event when data collection began, causing the prevalent sampling bias. We propose a unified approach, which simultaneously corrects the bias from the prevalent sampling and balances the systematic differences from the observational data. We illustrate in the simulation study that standard analysis without proper adjustment would result in biased causal inference. Large sample properties of the proposed estimation procedures are established by techniques of empirical processes and examined by simulation studies. The proposed methods are applied to the Surveillance, Epidemiology, and End Results (SEER) and Medicare-linked data for women diagnosed with breast cancer.


Identification of a novel compound with antiviral activity against influenza A virus depending on PA subunit of viral RNA polymerase.
Influenza viruses have developed resistance to current drugs, creating a need for new antiviral targets and new drugs to treat influenza virus infections. In this study, computational and experimental screening of an extensive compound library identified THC19, which was able to suppress influenza virus replication. This compound had no cytotoxic effects and did not disrupt cell cycle progression or induce apoptosis in MDCK cells as confirmed by WST-1 assays, flow cytometry analysis, and caspase-3 assays. Time-of-addition experiments showed that THC19 acts at a relatively early stage of the viral lifecycle. Subsequent mini-genome assays revealed that THC19 inhibited viral genome replication and/or transcription, suggesting that it interferes with one or more of the viral components that form the ribonucleoprotein complexes, namely polymerase basic 2 (PB2), polymerase basic 1 (PB1), polymerase acidic (PA), nucleoprotein (NP) and viral RNA. Finally, mini-genome assays where PB2, PB1, PA or NP from A/WSN/33 (H1N1) virus were replaced with those from A/Udorn/307/1972 (H3N2) virus effectively demonstrated that THC19 inhibited viral multiplication in a manner dependent upon the PA subunit. Taken together, these results suggest that influenza virus PA protein is a potential target for, and may aid the development of, novel compounds that inhibit influenza A virus replication.


Eukaryotic ribosomal proteins lacking a eubacterial counterpart: important players in ribosomal function.
The ribosome is a macromolecular machine responsible for protein synthesis in all organisms. Despite the enormous progress in studies on the structure and function of prokaryotic ribosomes, the respective molecular details of the mechanism by which the eukaryotic ribosome and associated factors construct a polypeptide accurately and rapidly still remain largely unexplored. Eukaryotic ribosomes possess more RNA and a higher number of proteins than eubacterial ribosomes. As the tertiary structure and basic function of the ribosomes are conserved, what is the contribution of these additional elements? Elucidation of the role of these components should provide clues to the mechanisms of translation in eukaryotes and help unravel the molecular mechanisms underlying the differences between eukaryotic and eubacterial ribosomes. This article focuses on a class of eukaryotic ribosomal proteins that do not have a eubacterial homologue. These proteins play substantial roles in ribosomal structure and function, and in mRNA binding and nascent peptide folding. The role of these proteins in human diseases and viral expression, as well as their potential use as targets for antiviral agents is discussed.


Prevalence and clinical characteristics of perinatal chronic lung disease by infant gestational age.
Children with perinatal chronic lung disease (CLD) are at elevated risk for severe respiratory syncytial virus (RSV) disease in the first two years of life. The American Academy of Pediatrics policy does not recommend RSV immunoprophylaxis for infants with CLD born at ≥32 weeks' gestational age (wGA). The objective of this study was to describe the number and clinical characteristics of US infants in this population. Birth hospitalization data from the Kids' Inpatient Database were utilized to estimate the prevalence of CLD (International Classification of Diseases, Ninth Revision [ICD-9] = 770.7) in 2003-2012 overall and by gestational age (ICD-9 = 765.21-765.29). CLD birth hospitalizations were evaluated by length of stay, costs, ventilatory support, and inpatient mortality. A total of 33,537 infants were diagnosed with CLD, representing 0.2% of US births; 79% had wGA coded in the database. Among infants with CLD with wGA, 3.5% were born at >32 wGA, representing 7 of every 100,000 US births, or approximately 300 infants annually. Across all wGA categories, birth hospitalization length of stay and costs were elevated, and mechanical ventilation use ranged from 73% to 97%. All-cause inpatient mortality was highest among those <27 wGA and >32 wGA. Approximately 300 infants born at >32 wGA are diagnosed with CLD annually in the United States. The all-cause perinatal mortality rate is high in this population. The rationale for excluding this small but high-risk group of infants from the recommendations for RSV immunoprophylaxis is unclear.


PURE mRNA display and cDNA display provide rapid detection of core epitope motif via high-throughput sequencing.
The reconstructed in vitro translation system known as the PURE system has been used in a variety of cell-free experiments such as the expression of native and de novo proteins as well as various display methods to select for functional polypeptides. We developed a refined PURE-based display method for the preparation of stable messenger RNA (mRNA) and complementary DNA (cDNA)-peptide conjugates and validated its utility for in vitro selection. Our conjugate formation efficiency exceeded 40%, followed by gel purification to allow minimum carry-over of components from the translation system to the downstream assay enabling clean and efficient random peptide sequence screening. We chose the commercially available anti-FLAG M2 antibody as a target molecule for validation. Starting from approximately 1.7 × 1012 random sequences, a round-by-round high-throughput sequencing showed clear enrichment of the FLAG epitope DYKDDD as well as revealing consensus FLAG epitope motif DYK(D/L/N)(L/Y/D/N/F)D. Enrichment of core FLAG motifs lacking one of the four key residues (DYKxxD) indicates that Tyr (Y) and Lys (K) appear as the two key residues essential for binding. Furthermore, the comparison between mRNA display and cDNA display method resulted in overall similar performance with slightly higher enrichment for mRNA display. We also show that gel purification steps in the refined PURE-based display method improve conjugate formation efficiency and enhance the enrichment rate of FLAG epitope motifs in later rounds of selection especially for mRNA display. Overall, the generalized procedure and consistent performance of two different display methods achieved by the commercially available PURE system will be useful for future studies to explore the sequence and functional space of diverse polypeptides.


Applications of machine learning to undifferentiated chest pain in the emergency department: A systematic review.
Chest pain is amongst the most common reason for presentation to the emergency department (ED). There are many causes of chest pain, and it is important for the emergency physician to quickly and accurately diagnose life threatening causes such as acute myocardial infarction (AMI). Multiple clinical decision tools have been developed to assist clinicians in risk stratifying patients with chest. There is growing recognition that machine learning (ML) will have a significant impact on the practice of medicine in the near future and may assist with diagnosis and risk stratification. This systematic review aims to evaluate how ML has been applied to adults presenting to the ED with undifferentiated chest pain and assess if ML models show improved performance when compared to physicians or current risk stratification techniques. We conducted a systematic review of journal articles that applied a ML technique to an adult patient presenting to an emergency department with undifferentiated chest pain. Multiple databases were searched from inception through to November 2020. In total, 3361 articles were screened, and 23 articles were included. We did not conduct a metanalysis due to a high level of heterogeneity between studies in both their methods, and reporting. The most common primary outcomes assessed were diagnosis of acute myocardial infarction (AMI) (12 studies), and prognosis of major adverse cardiovascular event (MACE) (6 studies). There were 14 retrospective studies and 5 prospective studies. Four studies reported the development of a machine learning model retrospectively then tested it prospectively. The most common machine learning methods used were artificial neural networks (14 studies), random forest (6 studies), support vector machine (5 studies), and gradient boosting (2 studies). Multiple studies achieved high accuracy in both the diagnosis of AMI in the ED setting, and in predicting mortality and composite outcomes over various timeframes. ML outperformed existing risk stratification scores in all cases, and physicians in three out of four cases. The majority of studies were single centre, retrospective, and without prospective or external validation. There were only 3 studies that were considered low risk of bias and had low applicability concerns. Two studies reported integrating the ML model into clinical practice. Research on applications of ML for undifferentiated chest pain in the ED has been ongoing for decades. ML has been reported to outperform emergency physicians and current risk stratification tools to diagnose AMI and predict MACE but has rarely been integrated into practice. Many studies assessing the use of ML in undifferentiated chest pain in the ED have a high risk of bias. It is important that future studies make use of recently developed standardised ML reporting guidelines, register their protocols, and share their datasets and code. Future work is required to assess the impact of ML model implementation on clinical decision making, patient orientated outcomes, and patient and physician acceptability. International Prospective Register of Systematic Reviews registration number: CRD42020184977.


[Changes in blood tyrosine levels during stress in adrenalectomized and intact rats].
On the 10th day after operation adrenalectomized male rats and non-operated animals of the control group were exposed to immobilization stress lasting 30 min and 4 h. The blood content of tyrosine and 11-HCS was measured before and during I day after stress. It has been demonstrated that blood tyrosine changes may be used as an index of adrenocortical reserves.


Fructose 1:6 bisphosphatase activity in the liver and testis of rats and goats.
1. The activity of the enzyme Fructose 1:6 Bisphosphatase (FDPase) was studied in the liver and testis of adult goats and rats. No significant difference in the enzyme activity was observed between liver and testis of rats. Highly significant differences (P less than 0.01) were observed between the activity of goat liver and goat testis, goat liver and rat liver, goat testis and rat testis; the activities being higher in goat tissues. 2. Homogenization of the tissues with water, 0.05 M lactate buffer (pH 3.5), 150 mM KCl and 0.34 M sucrose yielded highest activity with water and lactate buffer followed by Sucrose and KCl. 3. 10 microM of Fe2+ and 45 microM of Zn2+ decreased the enzyme activity of rat testis by 39% and 93% respectively. 4. The rate of hydrolysis of FDP with respect to time in rat liver and testis was a first order reaction. Linear kinetics of the substrate hydrolysis was observed up to 90 min. No substrate inhibition of the enzyme activity was observed up to 50 microM of the substrate. Km of rat liver and testis FDPase were 8.3 microM and 10.5 microM respectively.


Immunization with a tissue vaccine enhances the effect of irradiation on prostate tumors.
Recent studies on immunotherapy as a means to treat prostate cancer presents an interesting opportunity for combination therapy with radiation. This work was undertaken to determine if immunization with a prostate cancer tissue vaccine could enhance the effect of radiation treatment. Groups of Lobund-Wistar (LW) rats were subcutaneously administered PAIII prostate cancer cells (Day 0). Tumor-bearing rats were then either left untreated, vaccinated on Days 11 and 14 with a vaccine composed of glutaraldehyde-fixed harvested tumor tissue (GFT), irradiated with 15 Gy on Days 21 and 23 (Irr), or vaccinated with the GFT vaccine on Days 11 and 14 and irradiated on Days 21 and 23 (GFT/Irr). The tumors were measured on Day 11 and at the time of euthanasia (Day 30) and tumor volume was calculated. On Day 30, the tumors were harvested, weighed and fixed for histopathological evaluation. The mean tumor weight was significantly less (p < or = 0.05) in the Irr rats (7.21 g) compared to the untreated (13.04 g) and GFT-treated (10.64 g) rats. In contrast, the mean tumor weight of the GFT/Irr rats (3.37 g) was significantly less than the untreated and the GFT-treated tumors (p < or = 0.001), as well as the Irr tumors (p < or = 0.01). The GFT/Irr rats were the only group in which the tumor volume decreased during the study (14% decrease) compared to the untreated (147% increase), the GFT-treated (115% increase), and the Irr (12% increase) rats. Immunization with a tissue vaccine prior to radiation treatment enhances the therapeutic effect of radiation.


Biomarker profiling of plasma from acute coronary syndrome patients. Application of ProteinChip Array analysis.
Acute coronary syndrome (ACS) is one of the leading causes of death in the world and remains a complex pathophysiologic process involving inflammatory, hemostatic and vascular processes. The purpose of this study was to identify unique proteomic biomarkers present in patients with ACS using a newly developed proteomic profiling technique, surface enhanced laser desorption/ionization (SELDI). Citrated plasma samples obtained from clinically confirmed cases of ACS (n=100) and age matched controls (n=25) were profiled using SELDI-time of flight (TOF)-mass spectrometry (Ciphergen Biosystems, Freemont, CA, USA). A strong anion exchange (SAX) ProteinChip Array was used to profile these samples. In addition to spectra profiles, protein density plots were be obtained from the generated molecular profile. The SELDI profile in the molecular weight (MW) range of 0-150 kDa revealed a prominent 66.3 kDa albumin peak along with several distinct components at 28 kDa, 13.7 kDa and 6.5 kDa. Additional minor molecular components were also noted in the lower MW range (<6 kDa). There was a cluster of peaks between 10 and 12 kDa that were unique to the patients with ACS; about 1/3 of the ACS patients exhibited these peaks as evident in the ProteinChip Array spectrum. None of the age-matched controls exhibited the peaks in this MW range, nor did the normal human plasma pool that was used as an additional control. The relative intensity of these novel molecular components in the range of 10-12 kDa represent unique proteins/peptides which are generated in specific pathologic states associated with ACS. These observations suggest that patients with ACS have a unique cluster of molecular components that are present in their SELDI profile. It might be possible to use these patterns to identify high-risk patients who may be more susceptible to the development of unstable plaque, which may eventually lead to myocardial infarction. Identification and characterization of these molecular components will also help in the understanding of the pathogenesis of ACS. These unique peaks may represent pathologic proteins, novel inflammatory mediators or protease cleavage products. Further studies need to be done to better characterize and identify these molecular components and their pathologic role in ACS.


A Scoping Review of Studies Evaluating the Healthiness of Street Food Vendors.
This scoping review investigates the available tools for monitoring the healthiness of the food sold at street food outlets globally. Several tools were identified that have been used to evaluate the healthiness of street food outlets; however, these tools are not applicable globally, do not provide simple measures for evaluating the healthiness of foods sold, and generally have not been used across more than one study. The development of a comprehensive tool for measuring the healthiness of the street food environment that can be used across different jurisdictions and with different levels of resourcing is essential in order to understand the current street food environment and how it changes over time. As a major source of food in low- and middle-income countries globally, the street food environment is important to understand in order to know how it might help address the growing burden of diet-related diseases.


Curcumol induces apoptosis via caspases-independent mitochondrial pathway in human lung adenocarcinoma ASTC-a-1 cells.
Curcumol isolated from Rhizoma Curcumae, a common traditional Chinese medicine, has been reported to possess antitumor effects, but little is known about the molecular mechanism. The current study tried to explore the molecular mechanism of curcumol-induced cell death in human lung adenocarcinoma (ASTC-a-1) cells. Cell counting kit (CCK-8) assay, fluorescence resonance energy transfer (FRET), confocal fluorescence microscopy imaging, emission spectral analysis, and flow cytometry (FCM) technologies were used to assess the characteristics of curcumol-induced cell death. FCM analysis showed that curcumol induced G(2)/M phase arrest, nuclear fragmentation and phosphatidylserine externalization, implying that curcumol dominantly induced apoptotic cell death. Dynamical imaging showed that curcumol induced a rapid translocation of Bax from cytosol into mitochondria within 6 h, leading to a rapid dissipation of mitochondrial membrane potential (∆Ψm), implying that mitochondria play an important role in the curcumol-induced apoptosis. The fact that Z-VAD-fmk, a broad-spectrum inhibitor of caspases, did not reduce the curcumol-induced apoptosis showed that caspases were not involved in curcumol-induced apoptosis, which was further verified by monitoring the caspase-3 activation inside living cells stably expressing SCAT3, a FRET plasmid. Collectively, we for the first time demonstrated that curcumol induced cell death in a dominant apoptotic fashion via the caspases-independent mitochondrial pathway in ASTC-a-1 cells.


Knowledge and utilization of the partograph among midwives in the Niger Delta Region of Nigeria.
This cross-sectional study assessed knowledge and utilization of the partograph among midwives in two tertiary health facilities in the Niger Delta Region of Nigeria. A descriptive survey design was utilized, using a structured questionnaire administered to 165 midwives purposively selected from the Federal Medical Center (FMC) (79) and Niger Delta University Teaching Hospital (NDUTH) (86). Results revealed that 84% of midwives knew what the partograph was and 92.7% indicated that the use of the partograph reduces maternal and child mortality. About 50.6% midwives in FMC and 98.8% in NDUTH indicated that it was routinely utilized in their centers. Assessment of utilized partograph charts revealed that only 18 (37.5%) out of 48 in FMC and 17 (32.6%) out of 52 in NDUTH were properly filled. Factors in the utilization of the partograph were:-non-availability of the partograph (30.3%), shortage of staff (19.4%), little or no knowledge in the use of the partograph (22.2%), and 8.6 percent indicated it was time consuming. A significant relationship existed between knowledge of the partograph and its utilization (chi2 = 32.298. Df = 1; P < 0.05) and between midwives years of experience and its utilization (chi2 = 4.818, Df = 4; P < 0.05). However, this study also showed that despite midwives good knowledge of the partograph, there was poor utilization in labor monitoring in both centers. Training of midwives on the use of the partograph with periodic workshops and seminars and a mandatory hospital policy are recommended and vital to the safety of women in labor in the Niger Delta region of Nigeria.


High-throughput expression of C. elegans proteins.
Proteome-scale studies of protein three-dimensional structures should provide valuable information for both investigating basic biology and developing therapeutics. Critical for these endeavors is the expression of recombinant proteins. We selected Caenorhabditis elegans as our model organism in a structural proteomics initiative because of the high quality of its genome sequence and the availability of its ORFeome, protein-encoding open reading frames (ORFs), in a flexible recombinational cloning format. We developed a robotic pipeline for recombinant protein expression, applying the Gateway cloning/expression technology and utilizing a stepwise automation strategy on an integrated robotic platform. Using the pipeline, we have carried out heterologous protein expression experiments on 10,167 ORFs of C. elegans. With one expression vector and one Escherichia coli strain, protein expression was observed for 4854 ORFs, and 1536 were soluble. Bioinformatics analysis of the data indicates that protein hydrophobicity is a key determining factor for an ORF to yield a soluble expression product. This protein expression effort has investigated the largest number of genes in any organism to date. The pipeline described here is applicable to high-throughput expression of recombinant proteins for other species, both prokaryotic and eukaryotic, provided that ORFeome resources become available.


AWARENESS AND KNOWLEDGE OF OBSTRUCTIVE SLEEP APNEA AMONG THE POPULATION OF THE AL-BAHA REGION OF SAUDI ARABIA: A CROSS-SECTIONAL STUDY.
Obstructive sleep apnea (OSA) is a known sleep-disordered breathing, with known morbidity and mortality, that affects a lot of people worldwide. In Saudi Arabia, the prevalence of OSA is estimated to be around 8.8% among adult males and 5.1% among adult females. The research is a cross-sectional study design conducted in the Al-Baha region; Saudi Arabia in 385 participants. To evaluate the knowledge and awareness of OSA, the study utilized a validated and reliable adapted Arabic version of the OSA questionnaire. The degree of consciousness and understanding regarding OSA demonstrated a noteworthy connection with varying levels of education and a favorable family history of OSAS (p<0.05). The regression analyses unveiled that people with a familial OSA background had a 2.565-fold increased likelihood of identifying daytime fatigue as a symptom of OSA (p<0.05). The study reported an insufficient level of awareness and knowledge of OSA among the Saudi Arabian population. Various factors, including gender, education, and family history of OSA, may affect the awareness and knowledge of this condition.


Citizens and scientists: toward a gendered history of scientific practice in post-revolutionary France.
Because the French Revolution failed to produce a widely acceptable definition of citizenship, the limits of manhood suffrage in the early nineteenth century were uncertain. Social practices, in particular scientific activity, served as claims to the status of citizen. By engaging in scientific pastimes, bourgeois Frenchmen asserted that they possessed the rationality and autonomy that liberal theorists associated both with manliness and with civic capacity. However, bourgeois science was never a stable signifier of masculinity or of competence. As professional science emerged, the bourgeois amateur increasingly became the feminised object of satire rather than the sober and meritorious citizen-scientist.


Decoupling copolymer, lipid and carbon nanotube interactions in hybrid, biomimetic vesicles.
Bilayer vesicles that mimic a real biological cell can be tailored to carry out a specific function by manipulating the molecular composition of the amphiphiles. These bio-inspired and bio-mimetic structures are increasingly being employed for a number of applications from drug delivery to water purification and beyond. Complex hybrid bilayers are the key building blocks for fully synthetic vesicles that can mimic biological cell membranes, which often contain a wide variety of molecular species. While the assembly and morpholgy of pure phospholid bilayer vesicles is well understood, the functionality and structure dramaticlly changes when copolymer and/or carbon nanotube porins (CNTP) are added. The aim of this study is to understand how the collective molecular interactions within hybrid vesicles affect their nanoscale structure and properties. In situ small and wide angle X-ray scattering (SAXS/WAXS) and molecular dynamics simulations (MD) are used to investigate the morphological effect of molecular interactions between polybutadiene polyethylene oxide, lipids and carbon nanotubes (CNT) within the hybrid vesicle bilayer. Within the lipid/copolymer system, the hybrid bilayer morphology transitions from phase separated lipid and compressed copolymer at low copolymer loadings to a mixed bilayer where opposing lipids are mostly separated from the inner region. This transition begins between 60 wt% and 70 wt%, with full homogenization observed by 80 wt% copolymer. The incorporation of CNT into the hybrid vesicles increases the bilayer thickness and enhances the bilayer symmetry. Analysis of the WAXS and MD indicate that the CNT-dioleoyl interactions are much stronger than the CNT-polybutadiene.


Ultrasound- and MR-guided focused ultrasound surgery for prostate cancer.
Prostate cancer (PC) is one of the most frequently diagnosed cancers in men. There are a number of treatment options for PC with a different therapeutic approach between USA and Europe. Radical prostatectomy is one of the most used therapies but focal gland therapy is an emerging approach, especially for localized tumors. In this scenario, high intensity focused ultrasound (HIFU) has been incorporated in certain medical association guidelines. HIFU has been employed for about 10 years especially for localized PC. Results are promising with a 5-year biochemical survival rate ranging from 45% to 84%. Collateral events are rare and HIFU retreatment is not common. Magnetic resonance guided focused ultrasound surgery (MRgFUS) was recently presented as a method for ablation with focused ultrasound under magnetic resonance imaging guidance. It has the advantage of improved targeting and real time temperature monitoring but only a few studies have been conducted with human patients. The aim of this review is to describe the current status of HIFU and MRgFUS in the therapy of PC.


Proteomic characterization of specific minor proteins in the human milk casein fraction.
Human milk contains many bioactive proteins that are likely to support the early development of the newborn. The aim of this study was to identify whether there are specific minor proteins associated with the human milk casein micelle prepared by the acid precipitation method. Protein identification was performed by liquid chromatography tandem mass spectrometry analysis. Eighty-two proteins were identified in the casein micelle, 18 of which are not present in their whey compartment. Thirty-two of these proteins specifically associated with the casein micelle have not previously been identified in human milk or colostrum. Proteins involved in immune function comprised the major part (28%) of total proteins, and another significant part is involved in metabolism/energy production (22%). Most of the proteins were of extracellular or cytoplasmic origin (accounting for 50 and 29%, respectively). This study indicates that various soluble proteins should be considered as part of the casein compartment, prepared by the acid precipitation method. The data provide new insight not only into the proteomic profile of the human milk casein micelle and its physiological significance, but also into the proper proportion of casein and casein-associated proteins to use in infant formula.


Bilateral simultaneous laparoscopic adrenalectomy in Cushing's syndrome: safe, effective, and curative.
Surgical morbidity and mortality rates are high in patients with Cushing's syndrome. Nevertheless, simultaneous bilateral laparoscopic adrenalectomy (LA) is feasible in these patients with less morbidity and good long-term results. Consecutive 22 patients who underwent LA for Cushing's syndrome between 2003 and 2010 in our institute were retrospectively studied. Ninteen patients underwent bilateral simultaneous and three underwent unilateral LA. Seven patients had Cushing's syndrome after failed pituitary surgery and five each had ectopic adrenocorticotrophic hormone dependent syndrome and bilateral macronodular hyperplasia respectively. LA was bilaterally done by lateral transabdominal adrenalectomy in 15 patients and retroperitoneal endoscopic adrenalectomy in 4 on the right side. Mean operative time for simultaneous bilateral cases was 199.45±72.43 minutes with mean blood loss of 72.72±48.6 mL. Patients were fit for discharge by the fifth postoperative day from the surgical aspect. Surgical complication rate was 26% that included wound infections in two, port site hernia, pleural effusion, and atelectasis in one each. One patient died of sepsis (5% mortality). Satisfactory metabolic control was achieved in all observable patients in the long term although Addisonian crisis and Nelson syndrome were seen in 26% and 15% respectively. LA has all advantages of minimal access surgery in patients with Cushing's syndrome who are immunocompromised and at high risk of delayed wound healing and infections. Magnification decreases the risk of retained adrenal remnants. Despite advances in minimal access surgery, perioperative morbidity continues to be significant for the procedure.


Supracricoid partial laryngectomies after radiation failure: a multi-institutional series.
Radiation therapy (RT) is one of the gold standard treatments for early laryngeal cancer, and total laryngectomy is still the most applied surgical procedure after failure. Selected recurrences can be managed by supracricoid partial laryngectomies (SCPLs). A multi-institutional retrospective analysis was carried out in 78 consecutive patients treated by SCPLs for the recurrence of glottic-supraglottic cancer after RT. Cricohyoidoepiglottopexy was performed in 62, and cricohyoidopexy (CHP) in 16 cases. Disease-free survival at 3 and 5 years were 95.5%. Early and late postoperative complications occurred in 27% and 17.9% of cases. Decannulation and satisfactory swallowing were achieved in 97.4% of cases. SCPLs represent effective surgical organ-preservation strategies in the treatment of selected recurrences after RT failure, resulting in a good local control as well as functional recovery with acceptable morbidity, despite a complication rate which is not negligible.


Effects of electrically coupled inhibitory networks on local neuronal responses to intracortical microstimulation.
Using in vivo multielectrode electrophysiology in mice, we investigated the underpinnings of a local, long-lasting firing rate suppression evoked by intracortical microstimulation. Synaptic inhibition contributes to this suppression as it was reduced by pharmacological blockade of gamma-aminobutyric acid type B (GABAB) receptors. Blockade of GABAB receptors also abolished the known sublinear addition of inhibitory response duration after repetitive electrical stimulation. Furthermore, evoked inhibition was weaker and longer in connexin 36 knockout (KO) mice that feature decoupled cortical inhibitory networks. In supragranular layers of KO mice even an unusually long excitatory response (< or = 50 ms) appeared that was never observed in wild-type (WT) mice. Furthermore, the spread and duration of very fast oscillations (> 200 Hz) evoked by microstimulation at a short latency were strongly enhanced in KO mice. In the spatial domain, lack of connexin 36 unmasked a strong anisotropy of inhibitory spread. Although its reach along layers was almost the same as that in WT mice, the spread across cortical depth was severely hampered. In summary, the present data suggest that connexin 36-coupled networks significantly shape the electrically evoked cortical inhibitory response. Electrical coupling renders evoked cortical inhibition more precise and strong and ensures a uniform spread along the two cardinal axes of neocortical geometry.


The sexual lives of residents and fellows in graduate medical education programs: a single institution survey.
The prevalence of sexual problems among resident physicians has not been investigated. To explore the sexual behavior of residents and fellows in training and to determine the incidence of sexual dysfunction in this population. Residents and fellows at our institution were invited to complete a demographic questionnaire, as well as two to three gender-specific validated instruments for the assessment of human sexuality. The validated survey instruments selected were the International Index of Erectile Function (IIEF), the Index of Premature Ejaculation (IPE), and the Self-Esteem and Relationship Quality (SEAR) survey for male residents, and the Female Sexual Function Index (FSFI) and the Index of Sex Life (ISL) for female residents. Results were compared with established normative data and validated cut-off scores that were available. Pearson correlation coefficient was used to assess for relationships between variables. There were 180 responses (83 female, 97 male, mean age 29 years), for a response rate of 20%. Among men, 90%, 67%, and 98% were in a relationship, married, and heterosexual, respectively. Among women, the same numbers were 80%, 55%, and 96%, respectively. Based on validated cut-off scores for the IIEF and FSFI, 13% of men reported ED (3% reported mild ED, 4% reported moderate ED, and 6% reported severe ED) and 60% of women were classified as "at high risk" for sexual problems, with desire disorders the most prevalent and orgasmic disorders the second most prevalent. There were significant gender differences with respect to the associations between sexual and relationship problems. Sexual problems may be prevalent among residents in training, particularly female residents. Additional, larger studies that assess other quality of life measures and query sexual partners of residents are needed.


Culturing Planarians in the Laboratory.
Planaria, particularly Schmidtea mediterranea and Dugesia japonica, are now established as research organisms in many laboratories across the life sciences community. Planarians are cheap and easy to keep in the lab. This chapter provides techniques and guidelines for establishing and maintaining a planarian colony. We provide sections on food preparation, housing, feeding, cleaning, culture expansion by amputation, and recognizing and responding to culture problems.


Fluorescence lifetime evaluation of whole soils from the Amazon rainforest.
Time-resolved fluorescence spectroscopy (TRFS) is a new tool that can be used to investigate processes of interaction between metal ions and organic matter (OM) in soils, providing a specific analysis of the structure and dynamics of macromolecules. To the best of our knowledge, there are no studies in the literature reporting the use of this technique applied to whole/non-fractionated soil samples, making it a potential method for use in future studies. This work describes the use of TRFS to evaluate the fluorescence lifetimes of OM of whole soils from the Amazon region. Analysis was made of pellets of soils from an oxisol-spodosol system, collected in São Gabriel da Cachoeira (Amazonas, Brazil). The fluorescence lifetimes in the oxisol-spodosol system were attributed to two different fluorophores. One was related to complexation of an OM fraction with metals, resulting in a shorter fluorophore lifetime. A short fluorescence lifetime (2-12 ns) could be associated with simpler structures of the OM, while a long lifetime (19-66 ns) was associated with more complex OM structures. This new TRFS technique for analysis of the fluorescence lifetime in whole soil samples complies with the principles of green chemistry.


Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins.
The DNA binding activities of some basic region and putative helix-loop-helix (bHLH)-containing transcriptional factors can be inhibited by the Id protein. Because Id contains the HLH motif for dimerization but not the basic amino acid region for DNA binding, heterodimers of Id with bHLH transcriptional factors may not bind to DNA. We have isolated and characterized the gene and cDNA clones for a new Id protein, designated Id2. The Id2 protein contains a helix-loop-helix motif similar to that of the previously described Id protein (referred to here as Id1), but the two proteins are different elsewhere. Id1 and Id2 are encoded by two unlinked genes, as shown by chromosome mapping. The two Id proteins have similar inhibitory activities. They selectively bind to and inhibit the function of one set of bHLH proteins, typified by E2A.E47 and E2B.m3, but not that of the other set, including TFE3, USF, and AP4. The Id proteins also homodimerize poorly. Expression of both Id genes is down-regulated during differentiation in a variety of cell types.


Mathematical modelling of competitive labelled-ligand assay systems. Theoretical re-evaluation of optimum assay conditions and precision data for some experimentally established radioimmunoassay systems.
A mathematical theory of competitive labelled-ligand assays was developed with the intention of theoretically re-evaluating the optimal assay conditions and precision data of assay systems established by experiment. Our theory is based upon the assumptions of a simple bimolecular reaction mechanism, homogeneous reactants, as well as kinetically indistinguishable labelled and non-labelled ligands. The general case of two-step (non-equilibrium) assay was considered including the one-step (equilibrium) assay as a special case. The solution of the system of corresponding kinetic differential equations was used to mathematically construct standard curves. Furthermore, intraassay precision profiles and indices as well as detection limits were calculated considering solely the pipetting error, epsilon, as a source of experimental error. A procedure was outlined to mathematically determine the optimal incubation conditions for any assay system targeted to a given analyte concentration, P, at which the standard deviation of assay results is to be minimized. Estimates of both the content of binding sites and the equilibrium constant, K, of the specific binding agent are necessary, and these can be derived from Scatchard plots. For six RIA systems, of which three were one-step and three were two-step assays, experimental assay conditions and precision data were compared with theoretical predictions. Experimentally determined antibody binding site concentrations agreed fairly well with those independently evaluated by mathematical optimization. Mean precision indices, defined as constituting an average over the complete precision profile, were found to be within the theoretically predicted range, i.e. two- to threefold the pipetting error.(ABSTRACT TRUNCATED AT 250 WORDS)


The cytokine-mediated imbalance between coagulant and anticoagulant mechanisms in sepsis and endotoxaemia.
Disseminated intravascular coagulation (DIC) is a frequently occurring complication of sepsis and may contribute to multiple organ failure. More insight into the pathogenesis of this derangement of the coagulation system is necessary to develop more effective therapeutic strategies for this condition. Recently, more detailed knowledge on the pathogenetic pathways involved in DIC has been obtained by the study of models of experimental bacteraemia and endotoxaemia in human subjects and non-human primates. The mechanisms that lead to activation of coagulation, potentiated by the simultaneous depression of physiological inhibitory systems and to impaired function of the fibrinolytic system, are outlined in this review. In addition, the mediatory role of various cytokines in the derangement of coagulation is discussed.


Metastatic metanephric adenoma in a child.
Metanephric adenoma is a recently characterized renal tumor that generally occurs in adults and has an excellent prognosis. To date, only one atypical metanephric adenoma has been reported to metastasize. The authors report a case of typical metanephric adenoma that arose in the left kidney of a 7-year-old girl that was associated with metastases to the para-aortic, hilar, and aortic bifurcation lymph nodes. The tumor was 9.5 cm and was composed entirely of epithelial elements arranged in tubules, short papillae, and glomeruloid bodies with scattered psammoma bodies. No atypia and only rare mitotic activity were present. Immunohistochemically, the tumor was negative for epithelial membrane antigen, negative for keratin AE1, and focally positive for both keratin CAM5.2 and cytokeratin 7. Tumor cytogenetics revealed a normal diploid karyotype, and disomy of chromosomes 7 and 17 was confirmed by fluorescence in situ hybridization. The authors conclude that tumors with histologic, immunohistochemical, and genetic features characteristic of typical metanephric adenoma can present with metastatic disease.


Distinct Muscle Biopsy Findings in Genetically Defined Adult-Onset Motor Neuron Disorders.
The objective of this study was to characterize and compare muscle histopathological findings in 3 different genetic motor neuron disorders. We retrospectively re-assessed muscle biopsy findings in 23 patients with autosomal dominant lower motor neuron disease caused by p.G66V mutation in CHCHD10 (SMAJ), 10 X-linked spinal and bulbar muscular atrophy (SBMA) and 11 autosomal dominant c9orf72-mutated amyotrophic lateral sclerosis (c9ALS) patients. Distinct large fiber type grouping consisting of non-atrophic type IIA muscle fibers were 100% specific for the late-onset spinal muscular atrophies (SMAJ and SBMA) and were never observed in c9ALS. Common, but less specific findings included small groups of highly atrophic rounded type IIA fibers in SMAJ/SBMA, whereas in c9ALS, small group atrophies consisting of small-caliber angular fibers involving both fiber types were more characteristic. We also show that in the 2 slowly progressive motor neuron disorders (SMAJ and SBMA) the initial neurogenic features are often confused with considerable secondary "myopathic" changes at later disease stages, such as rimmed vacuoles, myofibrillar aggregates and numerous fibers reactive for fetal myosin heavy chain (dMyHC) antibodies. Based on our findings, muscle biopsy may be valuable in the diagnostic work-up of suspected motor neuron disorders in order to avoid a false ALS diagnosis in patients without clear findings of upper motor neuron lesions.


Reduced Renal Methylarginine Metabolism Protects against Progressive Kidney Damage.
Nitric oxide (NO) production is diminished in many patients with cardiovascular and renal disease. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and elevated plasma levels of ADMA are associated with poor outcomes. Dimethylarginine dimethylaminohydrolase-1 (DDAH1) is a methylarginine-metabolizing enzyme that reduces ADMA levels. We reported previously that a DDAH1 gene variant associated with increased renal DDAH1 mRNA transcription and lower plasma ADMA levels, but counterintuitively, a steeper rate of renal function decline. Here, we test the hypothesis that reduced renal-specific ADMA metabolism protects against progressive renal damage. Renal DDAH1 is expressed predominately within the proximal tubule. A novel proximal tubule-specific Ddah1 knockout (Ddah1(PT-/-)) mouse demonstrated tubular cell accumulation of ADMA and lower NO concentrations, but unaltered plasma ADMA concentrations. Ddah1(PT-/-) mice were protected from reduced kidney tissue mass, collagen deposition, and profibrotic cytokine expression in two independent renal injury models: folate nephropathy and unilateral ureteric obstruction. Furthermore, a study of two independent kidney transplant cohorts revealed higher levels of human renal allograft methylarginine-metabolizing enzyme gene expression associated with steeper function decline. We also report an association among DDAH1 expression, NO activity, and uromodulin expression supported by data from both animal and human studies, raising the possibility that kidney DDAH1 expression exacerbates renal injury through uromodulin-related mechanisms. Together, these data demonstrate that reduced renal tubular ADMA metabolism protects against progressive kidney function decline. Thus, circulating ADMA may be an imprecise marker of renal methylarginine metabolism, and therapeutic ADMA reduction may even be deleterious to kidney function.


Working memory and blood lactate levels.
The accumulation of lactate in the blood after a high-intensity exercise is associated with an increase of lactate extractions by the brain. Previously, a negative influence of blood lactate on attentional processes has been observed. The present study was carried out to examine the association of high blood lactate levels, induced with a maximal cycling, with another cognitive domain: working memory. For evaluation of working memory two different protocols were used: the first (Self-Ordered Pointing Task) capable of analyzing non-spatial working memory requiring the ability to generate and monitor a sequence of responses and the second for evaluating motor working memory necessary to perform a motor task. The study was carried out in 30 students (15 males and 15 females) who performed exhaustive exercise. In each subject, blood lactate was measured and motor as well as non-motor forms of working memory were evaluated before the exercise, at its end as well as 15 min after the exhaustion. It was observed that an increase of blood lactate levels is associated with a worsening of both types of working memory.


BRCA1/2 genetic testing uptake and psychosocial outcomes in men.
Few studies have quantitatively evaluated the uptake and outcomes of BRCA1/2 genetic counseling and testing in men. We conducted a prospective longitudinal study to describe and compare uptake of and psychosocial outcomes following BRCA1/2 testing in a sample of men and women at high-risk for carrying a BRCA1/2 mutation. Men (n = 98) and women (n = 243) unaffected with cancer completed baseline assessments prior to genetic counseling and testing and then 6- and 12-months post-testing. Most men (n = 94; 95.9%) opted to have genetic testing, of whom 44 received positive BRCA1/2 genetic test results and 50 received true negative results. Among women, 93.4% had genetic testing, of whom 79 received positive results and 148 received negative results. In multivariate models, male BRCA1/2 carriers reported significantly higher genetic testing distress (6-months: Z = 4.48, P < 0.0001; 12-months: Z = 2.78, P < 0.01) than male non-carriers. After controlling for baseline levels of distress, no statistically significant differences emerged between male and female BRCA1/2 carriers in psychological distress at 12-months post-testing, although absolute differences were evident over time. Predictors of distress related to genetic testing among male carriers at 12-months included higher baseline cancer-specific distress (Z = 4.73, P < 0.0001) and being unmarried (Z = 2.18, P < 0.05). Similarly, baseline cancer-specific distress was independently associated with cancer-specific distress at 6- (Z = 3.66, P < 0.001) and 12-months (Z = 4.44, P < 0.0001) post-testing among male carriers. Clinically, our results suggest that pre-test assessment of distress and creation of educational materials specifically tailored to the needs and concerns of male carriers may be appropriate in this important but understudied high-risk group.


A tailored flexible vaginal pessary treatment for pelvic organ prolapse in older women.
To present a flexible protocol of vaginal pessaries for older women with significant pelvic organ prolapse (POP). A prospective cohort study of 140 consecutive older women (aged ≥65 years) with significant POP treated with individually fitted vaginal pessaries. After initial insertion, each patient was invited for a first evaluation after 1 month and subsequent follow-ups at increasing intervals of 1 month. During each examination, the pessary was removed and the vagina was inspected for infection, bleeding, or erosions. All patients were advised to use a vaginal estrogen cream twice a week. The study was conducted during 2020 in the urogynecology clinic of a tertiary medical center. The study cohort included 140 consecutive older women with significant and symptomatic POP treated with vaginal pessaries. Primary outcomes included time intervals between follow-up visits, pessary-associated complications, need to change the pessary, need to remove the pessary temporarily, and whether the patients eventually underwent POP surgery. The mean age of the patients at the time of pessary fitting was 76.7 ± 9.2 years (range 65-100 years). Mean interval between follow-up examinations was 3.3 ± 1.1 months (range 1-6 months). Most patients (83.6%) used a ring pessary with support, but only a small number of patients were able to maintain the pessary by themselves. Of the 140 patients, five (3.6%) patients only eventually underwent POP surgery, and in 11 (7.9%) patients, the vaginal pessary had to be removed for 2-4 weeks because of significant vaginal discharge or superficial erosions. Additionally, 12 (8.6%) patients developed stress urinary incontinence following pessary insertion. Customized management with vaginal pessary for symptomatic POP in older women is effective and safe, and is a suitable therapeutic alternative for older women who are unable or unwilling to undergo reconstructive pelvic surgery.


Quantifying Contributions of Different Factors to Canopy Photosynthesis in 2 Maize Varieties: Development of a Novel 3D Canopy Modeling Pipeline.
Crop yield potential is intrinsically related to canopy photosynthesis; therefore, improving canopy photosynthetic efficiency is a major focus of current efforts to enhance crop yield. Canopy photosynthesis rate (Ac) is influenced by several factors, including plant architecture, leaf chlorophyll content, and leaf photosynthetic properties, which interact with each other. Identifying factors that restrict canopy photosynthesis and target adjustments to improve canopy photosynthesis in a specific crop cultivar pose an important challenge for the breeding community. To address this challenge, we developed a novel pipeline that utilizes factorial analysis, canopy photosynthesis modeling, and phenomics data collected using a 64-camera multi-view stereo system, enabling the dissection of the contributions of different factors to differences in canopy photosynthesis between maize cultivars. We applied this method to 2 maize varieties, W64A and A619, and found that leaf photosynthetic efficiency is the primary determinant (17.5% to 29.2%) of the difference in Ac between 2 maize varieties at all stages, and plant architecture at early stages also contribute to the difference in Ac (5.3% to 6.7%). Additionally, the contributions of each leaf photosynthetic parameter and plant architectural trait were dissected. We also found that the leaf photosynthetic parameters were linearly correlated with Ac and plant architecture traits were non-linearly related to Ac. This study developed a novel pipeline that provides a method for dissecting the relationship among individual phenotypes controlling the complex trait of canopy photosynthesis.


Pristine gelatin incorporation as a strategy to enhance the biofunctionality of poly(vinyl alcohol)-based hydrogels for tissue engineering applications.
Synthetic polymers, such as poly(vinyl alcohol) (PVA), are popular biomaterials for the fabrication of hydrogels for tissue engineering and regenerative medicine (TERM) applications, as they provide excellent control over the physico-chemical properties of the hydrogel. However, their bioinert nature is known to limit cell-biomaterial interactions by hindering cell infiltration, blood vessel recruitment and potentially limiting their integration with the host tissue. Efforts in the field have therefore focused on increasing the biofunctionality of synthetic hydrogels, without limiting the advantages associated with their tailorability and controlled release capacity. The aim of this study was to investigate the suitability of pristine gelatin to enhance the biofunctionality of tyraminated PVA (PVA-Tyr) hydrogels, by promoting cell infiltration and host blood vessel recruitment for TERM applications. Pure PVA-Tyr hydrogels and PVA-Tyr hydrogels incorporated with vascular endothelial growth factor (VEGF), a well-known pro-angiogenic stimulus, were used for comparison. Incorporating increasing concentrations of VEGF (0.01-10 μg mL-1) or gelatin (0.01-5 wt%) did not influence the physical properties of PVA-Tyr hydrogels. However, their presence within the polymer network (>0.1 μg mL-1 VEGF and >0.1 wt% gelatin) promoted endothelial cell interactions with the hydrogels. The covalent binding of unmodified gelatin or VEGF to the PVA-Tyr network did not hamper their inherent bioactivity, as they both promoted angiogenesis in a chick chorioallantoic membrane (CAM) assay, performing comparably with the unbound VEGF control. When the PVA-Tyr hydrogels were implanted subcutaneously in mice, it was observed that cell infiltration into the hydrogels was possible in the absence of gelatin or VEGF at 1- or 3-weeks post-implantation, highlighting a clear difference between in vitro an in vivo cell-biomaterial interaction. Nevertheless, the presence of gelatin or VEGF was necessary to enhance blood vessel recruitment and infiltration, although no significant difference was observed between these two biological molecules. Overall, this study highlights the potential of gelatin as a standalone pro-angiogenic cue to enhance biofunctionality of synthetic hydrogels and provides promise for their use in a variety of TERM applications.


hnRNPM guides an alternative splicing program in response to inhibition of the PI3K/AKT/mTOR pathway in Ewing sarcoma cells.
Ewing sarcomas (ES) are biologically aggressive tumors of bone and soft tissues for which no cure is currently available. Most ES patients do not respond to chemotherapeutic treatments or acquire resistance. Since the PI3K/AKT/mTOR axis is often deregulated in ES, its inhibition offers therapeutic perspective for these aggressive tumors. Herein, by using splicing sensitive arrays, we have uncovered an extensive splicing program activated upon inhibition of the PI3K/AKT/mTOR signaling pathway by BEZ235. Bioinformatics analyses identified hnRNPM as a key factor in this response. HnRNPM motifs were significantly enriched in introns flanking the regulated exons and proximity of binding represented a key determinant for hnRNPM-dependent splicing regulation. Knockdown of hnRNPM expression abolished a subset of BEZ235-induced splicing changes that contained hnRNPM binding sites, enhanced BEZ235 cytotoxicity and limited the clonogenicity of ES cells. Importantly, hnRNPM up-regulation correlates with poor outcome in sarcoma patients. These findings uncover an hnRNPM-dependent alternative splicing program set in motion by inhibition of the mTOR/AKT/PI3K pathway in ES cells that limits therapeutic efficacy of pharmacologic inhibitors, suggesting that combined inhibition of the PI3K/AKT/mTOR pathway and hnRNPM activity may represent a novel approach for ES treatment.


The Very Important Partner program: integrating family and friends into the health care experience.
The hospital experience, especially in critical care units, can be perceived by patients and their family as unwelcoming, intimidating, and anxiety producing. Patients desire the presence of loved ones and family members and may commonly express feelings of helplessness and not feeling valued or important. The Very Important Partner (VIP) program integrates family and friends into the health care experience in order to create an environment that provides opportunities for patients and their loved ones to truly experience healing of the mind, body, and spirit. Patient satisfaction survey results and anecdotal comments demonstrate that the VIP program has a significantly positive effect on the perception of the overall hospital stay. The program is a simple, common sense approach to optimizing the overall healing of patients and family. The implementation of similar programs is recommended in hospitals nationwide.


The management of medically unexplained symptoms.
Medically unexplained symptoms occur in up to 50% of new medical out-patients. Health care seeking may not be related to the presence of physical disease but may reflect social problems, psychological disturbance, or frank psychiatric disorder. Management of unexplained physical symptoms depends on the duration of symptoms. If acute, exclusion of physical disease, as well as providing symptomatic care, is a priority. The patient's fears of illness need to be addressed and an explanation in simple terms of the symptoms provided. Adverse life situations should be identified and, where possible, rectified. Psychiatric disorders require appropriate treatment. When symptoms are chronic, conservative management is required to contain the symptoms and avoid iatrogenic problems.


HAART-related effects on morphological connectivity in HIV: an individual-level morphological brain network study.
Suboptimal concentration of the antiretroviral drug is insufficient to inhibit HIV destruction on brain structure and function due to the resistance of blood brain barrier. We aimed to investigate HAART-related effects on the morphological connectivity in people with HIV (PWH). Case-control study. Fifty-five HAART-treated for more than 3 months and 54 untreated PWH, as well as 66 demographically matched healthy controls underwent a high-resolution 3D T1-weighted MRI. Individual-level morphological brain network based on gray matter volume of 90 brain regions was constructed and network topological properties were analyzed. Network-based statistics (NBS) was performed to identify sub-networks showing significant differences in morphological connectivity. Correlation and mediation analyses were employed to evaluate associations between the morphological properties and clinical variables of PWH. Although PWH exhibited small-world architecture in their morphological brain networks, untreated PWH demonstrated altered network properties while HAART-treated PWH showed relatively similar network properties compared to healthy controls. Furthermore, HAART-related effects were mainly involved the bilateral putamen and left thalamus. The findings of NBS further indicated the cortico-striatum-thalamic-cortical loop was involved in the therapeutic-associated morphological network. The positive correlations between the duration of treatment and nodal degree and efficiency of the putamen were mediated by the number of CD4+ T lymphocytes. The topological properties are recovered to normal in PWH after HAART and the effects induced by HAART are mostly within the cortical-subcortical circuit.


Maternal morbidity: neglected dimension of safe motherhood in the developing world.
In safe motherhood programming in the developing world, insufficient attention has been given to maternal morbidity, which can extend well beyond childbirth. For every woman who dies of pregnancy-related causes, an estimated 20 women experience acute or chronic morbidity. Maternal morbidity adversely affects families, communities and societies. Maternal morbidity has multiple causes, with duration ranging from acute to chronic, severity ranging from transient to permanent and with a range of diagnosis and treatment options. This article addresses six selected relatively neglected aspects of maternal morbidity to illustrate the range of acute and chronic morbidities that can affect women related to pregnancy and childbearing that are prevalent in developing countries: anaemia, maternal depression, infertility, fistula, uterine rupture and scarring and genital and uterine prolapse. Based on this review, recommendations to reduce maternal morbidity include: expand the focus of safe motherhood to explicitly include morbidity; improve data on incidence and prevalence of maternal morbidity; link mortality and morbidity outcomes and programming; increase access to facility- and community-based maternal health care and reproductive health care; and address the antecedents to poor maternal health through a lifecycle approach.


Conserved RNA structures in the non-canonical Hac1/Xbp1 intron.
The unconventional splicing of Hac1 by the ribonuclease Ire1 is a key event in the activation of the unfolded protein response (UPR) in Saccharomyces cerevisiae. This splicing is independent of the spliceosome and is mediated by a secondary structure at the intron-exon boundaries of the mRNA. Similar unconventional splicing was also described for the gene Xbp1 in human, mouse, C. elegans and D. melanogaster, and for Hac1 in five other fungi. We used reported RNA structures to build a multiple sequence alignment and the Infernal package to search for homologous structures. We identified homologous non-canonical intron structures in 128 out of 156 searched eukaryotic genomes. Our results show that the sequence of the Hac1/Xbp1 intron is highly conserved only around the splice sites recognized by Ire1. The consensus structure of the Hac1/Xbp1 mRNA is well conserved in Fungi and Metazoa and resembles structures previously described. We show that a typical Hac1/Xbp1 intron is very short, only 20-26 bases, whereas yeast species have a long intron (> 100 bases). We identified six species with unambiguous Hac1/Xbp1 homologs that have lost the non-canonical intron structure. We propose that these species use a different mechanism to regulate the UPR.


The WD40 Domain Protein MSI1 Functions in a Histone Deacetylase Complex to Fine-Tune Abscisic Acid Signaling.
MSI1 belongs to a family of histone binding WD40-repeat proteins. Arabidopsis thaliana contains five genes encoding MSI1-like proteins, but their functions in diverse chromatin-associated complexes are poorly understood. Here, we show that MSI1 is part of a histone deacetylase complex. We copurified HISTONE DEACETYLASE19 (HDA19) with MSI1 and transcriptional regulatory SIN3-like proteins and provide evidence that MSI1 and HDA19 associate into the same complex in vivo. These data suggest that MSI1, HDA19, and HISTONE DEACETYLATION COMPLEX1 protein form a core complex that can integrate various SIN3-like proteins. We found that reduction of MSI1 or HDA19 causes upregulation of abscisic acid (ABA) receptor genes and hypersensitivity of ABA-responsive genes. The MSI1-HDA19 complex fine-tunes ABA signaling by binding to the chromatin of ABA receptor genes and by maintaining low levels of acetylation of histone H3 at lysine 9, thereby affecting the expression levels of ABA receptor genes. Reduced MSI1 or HDA19 levels led to increased tolerance to salt stress corresponding to the increased ABA sensitivity of gene expression. Together, our results reveal the presence of an MSI1-HDA19 complex that fine-tunes ABA signaling in Arabidopsis.


Gradation of microcapsule wall porosity by deposition of polymer mixtures (Eudragit RL and Eudragit RS). Phase separation of polymer mixtures and effects of external media and conditions on release.
With the aim of increasing flexibility in controlling release from microcapsules, mixtures of wall polymers varying in porosity were investigated by phase separation. Eudragit RL and RS (polymethylmethacrylate linear backbone polymers) mixtures differing in polar substituent content and porosity were used as the wall material and were deposited using a non-solvent addition method. Release rates increased with polar group content of the mixtures, using theophylline, potassium dichromate or sodium chloride as model core materials. Theophylline release rate had the same relationship to polar group content as found earlier for urea permeation of cast mixed-polymer films. Release was generally accelerated in these systems when the external medium contained sodium lauryl sulphate as a wetting agent but not consistently, decreasing unexpectedly for RL-theophylline microcapsules. Localized dissolution of core substance was visible microscopically during release from single microcapsules. The release rate was sensitive to agitation intensity only at low wall to core ratios. Temperature change revealed only a single release mechanism for sodium chloride by Arrhenius equation treatment. Buffer ions penetrated coatings readily, changing theophylline release rates and providing clear evidence of diffusion via a pore-capillary mechanism.


PARENTAL AND SIBLING MIGRATION AND HIGH BLOOD PRESSURE AMONG RURAL CHILDREN IN CHINA.
This study examines the associations between parental and sibling rural-to-urban migration and blood pressure (BP) of rural left-behind children (LBC) in rural China. Analysis was based on the 2000, 2004, 2006 and 2009 waves of longitudinal data from the China Health and Nutrition Survey, which is an ongoing prospective survey covering nine provinces with an individual-level response rate of 88%. Blood pressure levels were measured by trained examiners at three consecutive times on the same visit and the means of three measurements were used as the final BP values. An ordinal BP measure was then created using a recently validated age-sex-specified distribution for Chinese children and adolescents, distinguishing normal BP, pre-hypertension and hypertension. Random effect modelling was performed. Different migration circumstances play different roles in LBC's BP with mother-only and both-parent migration being particularly detrimental and father-only and sibling-only migration either having no association or a negative association with LBC's BP levels or odds of high BP. In conclusion, the link between family migration and left-behind children's blood pressure is complex, and depends on who is the person out-migrating.


Postural control strategy during standing is altered in patients with multiple sclerosis.
Disturbances in balance are one of the first reported symptoms of Multiple Sclerosis (MS), yet limited research has been performed to classify the postural control deficits in this population. This study investigated the variability present in the sway patterns during quiet standing in patients with MS (PwMS) and healthy controls. Subjects were assessed (eyes open, closed) standing on a force platform. Variability of the sway patterns was quantified using a measure of amount of variability (root mean square; RMS) and two measures of temporal structure of variability (Lyapunov Exponent - LyE; Approximate Entropy - ApEn). RMS results revealed significantly higher amount of variability in the sway patterns of PwMS. PwMS also exhibit increased regularity (decreased ApEn) and decreased divergence (decreased LyE) during standing compared to healthy controls. Removing vision resulted in significantly decreased divergence (decreased LyE) in the MS subject group. These changes in the temporal structure correspond well with the theoretical model of the optimal movement variability hypothesis and the results support using variability measures to understand the mechanisms that underline postural control in PwMS and possibly other neurodegenerative disease pathologies.


Effects of particle size of corn and stocking densities on the performance, carcass traits and gastrointestinal tract development of Muscovy ducks in housing.
The current investigation was conducted to investigate the effects of different particle sizes of corn and stocking densities on performance, carcass traits and gastrointestinal tract (GIT) development of Muscovy ducks in housing. 200 Muscovy ducks were distributed in a factorial scheme (2 × 2) where the treatments were constituted by two stocking densities (2 or 3 birds/m2) and two particle sizes of corn (6 or 8 mm), with five replicates of 10 birds each. At 1, 35, 70, and 90 days old, Muscovy ducks were slaughtered to evaluate the development of heart and GIT. Muscovy ducks managed in the density of 3 birds/m2 presented higher (P < 0.05) GIT development, performance and carcass traits regardless of age evaluated. In the same way, Muscovy ducks fed diets using a particle size of corn of 6 mm (Mean Geometric Diameter (MGD) = 781 μm) presented higher (P < 0.05) GIT development, performance and carcass traits regardless of age evaluated. Conclusively, the stocking density of 3 birds/m2 and the particle size of corn of 6 mm (MGD = 781 μm) were considered ideal recommendations for Muscovy ducks, providing higher GIT development, which resulted in better performance and carcass traits.


Current Role of Intraoperative Frozen Section Examination of Sentinel Lymph Node in Early Breast Cancer.
The aim of this study was to evaluate the current role of frozen section in identifying patients who could benefit from an immediate axillary lymph node dissection (ALND), following the criteria of the ASOCOG Z0011 and IBCSG 23-10 trials. A retrospective review was performed involving 2,079 patients with early breast cancer who underwent conservative surgery or total mastectomy with sentinel lymph node biopsy. Sensitivity and diagnostic accuracy were 63.8% and 90.3%, respectively. Sensitivity was significantly higher (p<0.001) in finding macrometastases (81.8%) compared to micrometastases (11.9%). Frozen section was useful only in 7.7% of the patients who met the criteria of the IBCSG 23-01 and ACOSOG Z0011 trials. Frozen section continues to be very useful in the intraoperative assessment of the SLN, offering a high sensitivity and diagnostic accuracy. Omission of ALND in 24.4% of patients who met the ACOSOG Z0011 criteria would have resulted in their undertreatment.


Optical communication at the source bandwidth limit.
The possible limiting components on optical communication bandwidth are the source, the modulator, the propagation medium, and the detector. It is easy to show that the source bandwidth is the fundamental limit. The possibility of source bandwidth limited communication is demonstrated theoretically and experimentally. The basic principles involved are readily extendable to more practical partial approaches to this limit.


Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma.
To assess whether urea-based cream (UBC) has prophylactic benefits on sorafenib-induced hand-foot skin reaction (HFSR) in patients with advanced hepatocellular carcinoma (HCC). In this randomized, open-label trial, 871 patients with advanced HCC throughout China were treated with 10% UBC three times per day plus best supportive care (BSC; n = 439) or BSC alone excluding all creams (n = 432), starting on day 1 of sorafenib treatment, for up to 12 weeks. HFSR was assessed every 2 weeks and at 14 weeks for patients completing the study. Once HFSR occurred, patients were allowed any cream, including a UBC. The 12-week incidence of any grade HFSR was significantly lower in the UBC group versus the BSC-alone group (56.0% v 73.6%, respectively; odds ratio [OR], 0.457; 95% CI, 0.344 to 0.608; P < .001), as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004). Median time to first occurrence of HFSR was significantly longer in the UBC group than the BSC-alone group (84 v 34 days, respectively; hazard ratio, 0.658; 95% CI, 0.541 to 0.799; P < .001). Elevated AST was associated with increased risk of HFSR but did not alter the treatment effect of UBC. UBC plus BSC, compared with BSC alone, did not affect the sorafenib dose reduction or interruption rate (9.1% v 11.8%, respectively; P = .1937), response rate (11.1% v 10.1%, respectively; P = .6674), or disease control rate (98.8% v 98.2%, respectively; P = .5350) at week 12. UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC. Blinded, randomized, placebo-controlled trials to determine the role of UBC on the incidence and severity of HFSR are warranted.


GCLiPP: global crosslinking and protein purification method for constructing high-resolution occupancy maps for RNA binding proteins.
GCLiPP is a global RNA interactome capture method that detects RNA-binding protein (RBP) occupancy transcriptome-wide. GCLiPP maps RBP-occupied sites at a higher resolution than phase separation-based techniques. GCLiPP sequence tags correspond with known RBP binding sites and are enriched for sites detected by RBP-specific crosslinking immunoprecipitation (CLIP) for abundant cytosolic RBPs. Comparison of human Jurkat T cells and mouse primary T cells uncovers shared peaks of GCLiPP signal across homologous regions of human and mouse 3' UTRs, including a conserved mRNA-destabilizing cis-regulatory element. GCLiPP signal overlapping with immune-related SNPs uncovers stabilizing cis-regulatory regions in CD5, STAT6, and IKZF1.


Dietary fat and insulin action in humans.
A high intake of fat may increase the risk of obesity. Obesity, especially abdominal obesity, is an important determinant of the risk of developing insulin resistance and non-insulin-dependent diabetes mellitus. It is suggested that a high proportion of fat in the diet is associated with impaired insulin sensitivity and an increased risk of developing diabetes, independent of obesity and body fat localization, and that this risk may be influenced by the type of fatty acids in the diet. Cross-sectional studies show significant relationships between the serum lipid fatty acid composition, which at least partly mirrors the quality of the fatty acids in the diet, and insulin sensitivity. Insulin resistance, and disorders characterized by insulin resistance, are associated with a specific fatty acid pattern of the serum lipids with increased proportions of palmitic (16:0) and palmitoleic acids (16:1 n-7) and reduced levels of linoleic acid (18:2 n-6). The metabolism of linoleic acid seems to be disturbed with increased proportions of dihomo-gamma linolenic acid (20:3 n-6) and a reduced activity of the delta 5 desaturase, while the activities of the delta 9 and delta 6 desaturases appear to be increased. The skeletal muscle is the main determinant of insulin sensitivity. Several studies have shown that the fatty acid composition of the phosholipids of the skeletal muscle cell membranes is closely related to insulin sensitivity. An increased saturation of the membrane fatty acids and a reduced activity of delta 5 desaturase have been associated with insulin resistance. There are several possible mechanisms which could explain this relationship. The fatty acid composition of the lipids in serum and muscle is influenced by diet, but also by the degree of physical activity, genetic disposition, and possibly fetal undernutrition. However, controlled dietary intervention studies in humans investigating the effects of different types of fatty acids on insulin sensitivity have so far been negative.


Ketone-Based Alert System for Insulin Pump Failures.
An increasing number of individuals with type 1 diabetes (T1D) manage glycemia with insulin pumps containing short-acting insulin. If insulin delivery is interrupted for even a few hours due to pump or infusion site malfunction, the resulting insulin deficiency can rapidly initiate ketogenesis and diabetic ketoacidosis (DKA). To detect an event of accidental cessation of insulin delivery, we propose the design of ketone-based alert system (K-AS). This system relies on an extended Kalman filter based on plasma 3-beta-hydroxybutyrate (BOHB) measurements to estimate the disturbance acting on the insulin infusion/injection input. The alert system is based on a novel physiological model capable of simulating the ketone body turnover in response to a change in plasma insulin levels. Simulated plasma BOHB levels were compared with plasma BOHB levels available in the literature. We evaluated the performance of the K-AS on 10 in silico subjects using the S2014 UVA/Padova simulator for two different scenarios. The K-AS achieves an average detection time of 84 and 55.5 minutes in fasting and postprandial conditions, respectively, which compares favorably and improves against a detection time of 193 and 120 minutes, respectively, based on the current guidelines. The K-AS leverages the rapid rate of increase of plasma BOHB to achieve short detection time in order to prevent BOHB levels from rising to dangerous levels, without any false-positive alarms. Moreover, the proposed novel insulin-BOHB model will allow us to understand the efficacy of treatment without compromising patient safety.