A hierarchical method for generating low-energy conformers of a protein-ligand complex.
A novel dynamical protocol for finding the low-energy conformations of a protein-ligand complex is described. The energy functions examined consist of an empirical force field with four different dielectric screening models; the generalized Born/surface area model also is examined. Application of the method to three complexes of known crystal structure provides insights into the energy functions used for selecting low-energy docked conformations and into the structure of the binding-energy surface. Evidence is presented that the local energy minima of a ligand in a binding site are arranged in a hierarchical fashion. This observation motivates the construction of a hierarchical docking algorithm that substantially enriches the population of ligand conformations close to the crystal conformation. The algorithm is also adapted to permit docking into a flexible binding site and preliminary tests of this method are presented.


Chronic effects of occupational exposure to mineral fibres and recurrent chest infections in insulators.
Exposure to mineral fibres (man-made forms of vitreous fibres often used as insulating material) is a risk factor for recurrent chest infections among workers, underscoring the necessity of workplace surveillance for protection from hazardous substances https://bit.ly/38cUpmA.


Medical care costs at the end of life among older adults with cancer: a national health insurance data-based cohort study.
Along with aging, the elderly population with cancers is increasing. The costs of end-of-life (EOL) care are particularly high among cancer patients. The purpose of this study was to investigate the trends in medical costs in the last year of life among older adults with cancer. Using the Health Insurance Review and Assessment Services (HIRA) database for the period 2016-2019, we identified older adults aged ≥ 65 years who had a primary diagnosis of cancers and high-intensity treatment at least once in the intensive care unit (ICU) of tertiary hospitals. High-intensity treatment was defined as receiving at least one of the following treatments: cardiopulmonary resuscitation, mechanical ventilation, extracorporeal membrane oxygenation, hemodialysis, and transfusion. The EOL medical treatment costs were calculated by dividing periods 1, 2, 3, 6, and 12 months from the time of death, respectively. The mean total EOL medical expense per older adult during the year before death was $33,712. The cost of EOL medical expenses for three months and one month before subjects' death accounted for 62.6% ($21,117) and 33.8% ($11,389) of total EOL costs, respectively. Among subjects who died while receiving high-intensity treatment in the ICU, the costs associated with medical treatments that occurred during the last month before death were 42.4% ($13,841) of the total EOL expenses during the year. The findings indicate that EOL care expenditures for the older population with cancer are highly concentrated until the last month. The intensity of medical care is an important and challenging issue in terms of care quality and cost suitability. Efforts are needed to properly use medical resources and provide optimal EOL care for older adults with cancer.


Iridoid and phenylethanoid glycosides in the New Zealand sun hebes (Veronica; Plantaginaceae).
The sun hebes are a small clade of New Zealand Veronica formerly classified as Heliohebe. The water-soluble compounds of Veronica pentasepala, Veronica raoulii and Veronica hulkeana were studied and 30 compounds including 15 iridoid glucosides, 12 phenylethanoid glycosides, the acetophenone glucoside pungenin, the mannitol ester hebitol II and mannitol were isolated. Of these, five were previously unknown in the literature: dihydroverminoside and 3,3',4,4'-tetrahydroxy-α-truxillic acid 6-O-catalpyl diester, named heliosepaloside, as well as three phenylethanoid glycoside esters heliosides D, E and F, all derivatives of aragoside. The esters of cinnamic acid derivatives with iridoid and phenylethanoid glycosides and an unusually high concentration of verminoside were found to be the most distinctive chemotaxonomic characters of the sun hebes. The chemical profiles of the species were compared and used to assess the phylogenetic relationships in the group.


Metal complex-DNA binding: Insights from molecular dynamics and DFT/MM calculations.
Molecular dynamics (MD) simulations, followed by density functional theory/molecular mechanics (DFT/MM) calculations, provided a detailed structure of the binding site between the cationic metallointercalator (dipyrido [3,2-a:2',3'-c]phenazine)(glycinato)copper(II), [Cu(gly)(dppz)](+), and the two dodeca-deoxynucleotide duplexes [dodeca(dG-dC)]2 and [dodeca(dA-dT)]2. Three simultaneous DNA binding types were detected in the fully optimized DFT/MM structures: 1) metal coordination through exocyclic oxygen atoms of nitrogen bases; 2) intercalation of the dppz chromophore between stacked Watson-Crick AT-AT and GC-GC bases; and 3) hydrogen bonding between the glycinato ligand and amine groups or heterocyclic nitrogen atoms of DNA bases. Standard enthalpy and Gibbs free energy values were used to evaluate, in vacuo and in solution, the formation energy of both [Cu(gly)(dppz)]/dodecanucleotide complexes. The latter were in excellent agreement with the recently reported value of the experimental DNA-binding constant, providing a physical interpretation of the enthalpy, entropy and solvent contributions in the binding mechanism.


Evaluation of immunomodulatory chemicals: alteration of macrophage function in vitro.
In an effort to develop a useful screening procedure for detecting potential modulators of macrophage function, 25 chemicals were tested for their ability to alter the nonspecific phagocytosis and killing of Saccharomyces cerevisiae by elicited mouse peritoneal macrophages (PM). Parallel studies monitored PM viability so as to distinguish between effective modulation of phagocytic function and changes due solely to cytotoxicity. Dextran sulfate, iota-carrageenan, lambda-carrageenan, dipropyltin dichloride, and di-n-octyltin dichloride, at concentrations which did not produce overt toxicity, significantly reduced the percentage of PM capable of ingesting yeast. The carrageenans also decreased the average number of yeast ingested per PM, while increasing the ability of PM to kill yeast. Microbicidal activity was suppressed in PM treated with indomethacin and dextran sulfate. Di-n-octyltin dichloride and dextran sulfate diminished the adherence of PM, whereas levamisole enhanced PM adherence. Vanillin, propyl gallate, lead acetate, hydrocortisone 21-phosphate, and hydrocortisone 21-hemisuccinate decreased the percentage of PM capable of ingesting yeast, but not below 50% of the control. Gallic acid, methyl paraben, mercuric chloride, cadmium chloride, nickel chloride, chromic chloride, dimethyltin dichloride, diethyltin dichloride, dibutyltin dichloride, tetra-n-octyltin, gibberellic acid, cyclophosphamide, and azathioprine did not alter PM phagocytic function at noncytotoxic doses. The results indicate that chemicals can be grouped into three broad categories as either ineffective, weak modulators, or effective modulators of PM function.


A Preliminary Examination of the Impact of Working Memory Training on Syntax and Processing Speed in Children with ASD.
In addition to deficits in pragmatics, children with autism spectrum disorders (ASD) have weaknesses in complex syntax and working memory (WM). These two deficits may be closely related. Previous work investigated the effects of WM training in developmental language disorders and showed significant improvement in both WM and syntax. The current study tests the impact of 12 h of WM training across 8 weeks in 30 children with ASD, aged 5 to 11. Results showed direct improvements on untrained WM tasks, as well as transfer effects to syntax and processing speed. Stronger WM led to better syntactic abilities. While they must be replicated, these exciting results provide impetus for further studies of WM interventions.


Hippocampal insulin resistance and cognitive dysfunction.
Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as a potential mediator of cognitive dysfunction in T2DM, as well as in Alzheimer disease (AD). This Review highlights these observations and discusses intervention studies which suggest that the restoration of insulin activity in the hippocampus may be an effective strategy to alleviate the cognitive decline associated with T2DM and AD.


Structural and functional insights into the spike protein mutations of emerging SARS-CoV-2 variants.
Since the emergence of the first case of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), the viral genome has constantly undergone rapid mutations for better adaptation in the host system. These newer mutations have given rise to several lineages/ variants of the virus that have resulted in high transmission and virulence rates compared to the previously circulating variants. Owing to this, the overall caseload and related mortality have tremendously increased globally to > 233 million infections and > 4.7 million deaths as of Sept. 28th, 2021. SARS-CoV-2, Spike (S) protein binds to host cells by recognizing human angiotensin-converting enzyme 2 (hACE2) receptor. The viral S protein contains S1 and S2 domains that constitute the binding and fusion machinery, respectively. Structural analysis of viral S protein reveals that the virus undergoes conformational flexibility and dynamicity to interact with the hACE2 receptor. The SARS-CoV-2 variants and mutations might be associated with affecting the conformational plasticity of S protein, potentially linked to its altered affinity, infectivity, and immunogenicity. This review focuses on the current circulating variants of SARS-CoV-2 and the structure-function analysis of key S protein mutations linked with increased affinity, higher infectivity, enhanced transmission rates, and immune escape against this infection.


Preliminary applicability tests of different methacrylic acid copolymers, type C NF, particularly relevant to spreading and film formation.
The intention of this study was to show under which conditions a film forming methacrylic acid copolymer coating excipient, corresponding to the requirements of pharmacopoeia, but obtained from different sources, can be substituted without severe problems. The mechanical properties of the film coats were investigated by dynamic-mechanical thermo-analysis (DMTA) experiments to determine with respect to the glass transition the storage modulus E', the loss modulus E'', and the loss factor tan delta. Further determinations concerned the surface tensions of the different coating dispersions. This attribute plays an important role in spreading, distribution and coalescence of the film forming preparations. Finally by a series of small experimental fluidized bed batches cores containing a model drug were coated with the different methacrylic acid copolymers. The resistance of these coated tablets in 0.1 N HC1 as well as their dissolution rates in artificial intestinal juice were tested. The coatings proved themselves so similar that in this case substitutions of products of different provenance are possible. The determinations of surface tension and the DMTA measurements seem to be useful and reliable preliminary applicability tests.


An interesting case of incidental solitary pulmonary nodule.
Doubling time, clinical prediction models of malignancy and positive bronchus sign are useful in stepwise evaluation of SPN to avoid thoracotomy. GeneXpert can be used as initial diagnostic test for tuberculosis and detection of rifampicin resistance. http://ow.ly/N37030mB8Fi.


Cross-talk between Akt, p53 and Mdm2: possible implications for the regulation of apoptosis.
The p53 tumor suppressor protein and the Akt/PKB kinase play important roles in the transduction of pro-apoptotic and anti-apoptotic signals, respectively. We provide evidence that conflicting signals transduced by Akt and p53 are integrated via negative feedback between the two pathways. On the one hand, the combination of ionizing radiation and survival factor deprivation, which leads to rapid apoptosis of IL-3 dependent DA-1 cells, entails a caspase- and p53-dependent destruction of Akt. This destruction of Akt is not a secondary consequence of apoptosis, since it is not seen when the same cells are triggered to undergo apoptosis under different conditions. On the other hand upon serum stimulation, when Akt becomes active and enhances cell survival, phosphorylation occurs at an Akt consensus site (serine 166) within the Mdm2 protein, a key regulator of p53 function. Taken together, our findings suggest that depending on the balance of signals, p53-dependent downregulation of Akt may promote an irreversible commitment to apoptotic cell death, whereas effective recruitment of Akt by appropriate survival signals may lead to activation of Mdm2, inactivation of p53, and eventually inhibition of p53-dependent apoptosis.


Extracervical approaches to endoscopic thyroid surgery.
There is increasing demand for surgical procedures which avoid visible scars while maintaining optimal functional and ideal cosmetic results, without compromising the safety or effectiveness of the procedure. Endoscopic techniques have been adapted to abdominal and pelvic surgery and increasingly employed over the past three decades. Although hampered by the absence of a natural cavity, endoscopic techniques have been adapted to surgery in the neck for the past 15 years, particularly for the thyroid gland. While earlier attempts at endoscopic thyroid surgery were performed through incisions in or near the midline of the neck, recent techniques have been developed to place the incisions and endoscopic ports extracervically, or at least away from the midline region of the neck, rendering the cosmetic result more acceptable. Most of these approaches are through the axilla, breast, chest wall or a combination of approaches. Visualization of the thyroid and rate of complications with these approaches are equal to those attained with older endoscopic approaches. Careful patient selection is important for endoscopic surgery. Complications unique to the endoscopic approach are mostly related to insufflation of cervical tissues with pressurized CO(2).


Cardiobacterium hominis bioprosthetic mitral valve endocarditis presenting as septic arthritis.
We report an unusual case of Cardiobacterium hominis bioprosthetic valve endocarditis presenting as septic arthritis. This remarkable presentation had clinical features consistent with endocarditis generally associated with highly virulent pathogens. A literature search has failed to disclose a report of septic arthiritis as a manifestation of C. hominis endocarditis.


Dynamical aspects of P systems.
A dynamical analysis of P systems is given that is focused on basic phenomena of biological relevance. After a short presentation of a new kind of P systems (PB systems), membrane systems with environment, called PBE systems, are introduced that are more suitable for modeling complex membrane interactions. Some types of periodicity and non-periodicity are considered for PBE systems by showing some "minimal" examples of systems that exhibit these properties. In particular, a discrete formulation of the Belousov-Zhabotinsky (BZ) reaction is given in terms of PBE systems. Some questions and open problems for future research are indicated.


Impacts of sleeve gastrectomy on gastroesophageal reflux disease in severely obese Korean patients.
Laparoscopic sleeve gastrectomy (LSG) has established popularity as a bariatric and metabolic surgery. However, the incidence of gastroesophageal reflux disease (GERD) following LSG is controversial. This study aims to describe the prevalence of de novo GERD after LSG. A retrospective chart review was performed for 130 patients who underwent a routine endoscopic surveillance before and after LSG between January 2013 and October 2018. The diagnosis of GERD was determined by presence of symptoms, history of PPI treatment, and endoscopic findings. The esophagogastroduodenoscopy (EGD) was performed annually after LSG and/or when the patients complained of severe reflux symptoms. The prevalence of GERD before surgery was 18.5%. At 1 year after LSG, GERD was present in 70 (53.8%) of the 130 patients. GERD consisted of 55 patients with newly developed GERD, and 15 with preexisting GERD. 9 (37.5%) out of pre-existing GERD patients were free of symptoms and abnormal finding at EGD following LSG. During the LSG, 66 (50.8%) patients with hiatal hernia underwent re-approximation of the diaphragmatic crura. There was no significant relationship between hiatal hernia repair and postoperative GERD (p = 0.39). Number of patients taking PPI medication before and after LSG were 34 (26.2%) and 49 (37.7%). Out of 56 (43.1%) patients with endoscopic lesions, LA grade A was 31 (23.9%), B = 15 (11.5%), C = 4 (3.1%), and D = 6 (4.6%). In this study, 42.3% (n = 55) of total patients developed newly developed GERD, and 7.7% (n = 10) had LA grade C or D esophagitis.


Diagnosis of Periprosthetic Infection: Novel Developments.
The diagnosis of periprosthetic joint infection (PJI) has been performed by obtaining a history and physical examination, blood tests, and analysis of the synovial fluid and tissue samples. The measurement of serum biomarkers are routinely used to diagnose PJI. These markers may be elevated in other inflammatory conditions, necessitating the need for more specific biomarkers to diagnose PJI. Serum biomarkers may be more specific to PJI. Synovial CRP, α-defensin, human β-defensin-2 and -3, leukocyte esterase, and cathelicidin LL-37 biomarkers hold promise for the diagnosis of PJI.


Using machine learning for process improvement in sepsis management.
In the U.S., sepsis afflicts 1.7 million adults, causing 270,000 deaths each year. Early detection of sepsis could decrease the number of deaths by 92,000 annually and decrease hospital expenditures by 1.5 billion USD. Few prior studies and reviews have presented a holistic understanding of the relationship between machine learning and existing process improvement measures. This study, in addition to discussing machine learning and existing process improvements measures, elaborates on the disadvantages and the barriers to integrating machine learning into the clinic. This article synthesizes previous studies to educate healthcare professionals on effectively managing sepsis by leveraging the benefits of machine learning. This study used the PubMed database. Search terms include sepsis antibiotics, sepsis process improvement, sepsis machine learning. Our search criteria included previous studies published between January 1, 2017, and February 1, 2022. Although machine learning algorithms have better predictive capabilities, their effectiveness in the clinical setting is limited as studies show mixed results because the medical staff often fails to intervene. To overcome poor interventional response, clinicians need to work with the facility's IT department to ensure integration into clinical workflow and minimize alert-fatigue. Algorithms should enhance the productivity of clinical teams, not attempt to replace them entirely. Hospitals can employ process improvement measures that effectively utilize machine learning algorithms to ensure integration into clinical workflows. Healthcare professionals can utilize workflow tools in addition to the predictive capabilities of machine learning to enhance clinical decisions in sepsis.


Myocardial contusion: when does it have clinical significance?
A retrospective review of 53 patients with blunt chest trauma admitted to a monitored hospital bed demonstrated a single elderly patient with multiple injuries who developed dysrhythmias requiring treatment. The remainder of the relatively young group had no significant cardiac sequelae. We conclude that the routine use of expensive monitoring and extensive diagnostic tests in the young blunt chest trauma victim should be reconsidered.


Optimizing atrio-ventricular delay in pacemakers using potentially implantable physiological biomarkers.
Hemodynamically optimal atrioventricular (AV) delay can be derived by echocardiography or beat-by-beat blood pressure (BP) measurements, but analysis is labor intensive. Laser Doppler perfusion monitoring measures blood flow and can be incorporated into future implantable cardiac devices. We assess whether laser Doppler can be used instead of BP to optimize AV delay. Fifty eight patients underwent 94 AV delay optimizations with biventricular or His-bundle pacing using laser Doppler and simultaneous noninvasive beat-by-beat BP. Optimal AV delay was defined using a curve of hemodynamic response to switching from AAI (reference state) to DDD (test state) at several AV delays (40-320 ms), with automatic quality control checking precision of the optimum. Five subsequent patients underwent an extended protocol to test the impact of greater numbers of alternations on optimization quality. 55/94 optimizations passed quality control resulting in an optimal AV delay on laser Doppler similar to that derived by BP (median absolute deviation 12 ms). An extended protocol with increasing number of replicates consistently improved quality and reduced disagreement between laser Doppler and BP optima. With only five replicates, no optimization passed quality control, and the median absolute deviation would be 29 ms. These improved progressively until at 50 replicates, all optimizations passed quality control and the median absolute deviation was only 13 ms. Laser Doppler perfusion produces hemodynamic optima equivalent to BP. Quality control can be automatic. Adding more replicates, consistently improves quality. Future implantable devices could use such methods to dynamically and reliably optimize AV delays.


[An unusual complication after the partial resection of the ascending duodenum of a cow].
In a heifer portions of the ascending duodenum, which had been perforated by an obstructing phytobezoar, were resected. This resulted in an unexpected complication. The shortened ligamentum duodenocolicum exerted steady traction on the descending colon. This traction caused a kink and finally resulted in a total obstruction of the colon. The pathogenesis of this complication is illustrated. Surgical--possibly preventive--procedures are discussed.


The roles of Dippu-allatostatin in the modulation of hormone release in Locusta migratoria.
Dippu-allatostatins (ASTs) have pleiotropic effects in Locusta migratoria. Dippu-ASTs act as releasing factors for adipokinetic hormone I (AKH I) from the corpus cardiacum (CC) and also alter juvenile hormone (JH) biosynthesis and release from the corpus allatum (CA). Dippu-AST-like immunoreactivity is found within lateral neurosecretory cells (LNCs) of the brain and axons within the paired nervi corporis cardiaci II (NCC II) to the CC and the CA, where there are extensive processes and nerve endings over both of these neuroendocrine organs. There was co-localization of Dippu-AST-like and proctolin-like immunoreactivity within these regions. Dippu-ASTs increase the release of AKH I in a dose-dependent manner, with thresholds below 10(-11)M (Dippu-AST 7) and between 10(-13) and 10(-12)M (Dippu-AST 2). Both proctolin and Dippu-AST 2 caused an increase in the cAMP content of the glandular lobe of the CC. Dippu-AST 2 also altered the release of JH from the locust CA, but this effect depended on the concentration of peptide and the basal release rates of the CA. These physiological effects for Dippu-ASTs in Locusta have not been shown previously.


1H, 15N and 13C resonance assignments of light organ-associated fatty acid-binding protein of Taiwanese fireflies.
Fatty acid-binding proteins (FABPs) are a family of proteins that modulate the transfer of various fatty acids in the cytosol and constitute a significant portion in many energy-consuming cells. The ligand binding properties and specific functions of a particular type of FABP seem to be diverse and depend on the respective binding cavity as well as the cell type from which this protein is derived. Previously, a novel FABP (lcFABP; lc: Luciola cerata) was identified in the light organ of Taiwanese fireflies. The lcFABP was proved to possess fatty acids binding capabilities, especially for fatty acids of length C14-C18. However, the structural details are unknown, and the structure-function relationship has remained to be further investigated. In this study, we finished the (1)H, (15)N and (13)C chemical shift assignments of (15)N/(13)C-enriched lcFABP by solution NMR spectroscopy. In addition, the secondary structure distribution was revealed based on the backbone N, H, Cα, Hα, C and side chain Cβ assignments. These results can provide the basis for further structural exploration of lcFABP.


Diagnostic challenges of an unusually large schwannoma of the mandible: Report of a case.
Schwannomas are slow-growing, benign neoplasms arising from the Schwann cells and are commonly reported as peripheral tumors in the head and neck region. Central intramandibular schwannomas are extremely rare lesions. We report a case of intramandibular schwannoma in a 70 year old male patient. Panoramic radiography revealed a large, multilocular radiolucent lesion with distinct borders involving the right mandibular body and ramus. A complete excision was achieved by removing the tumor followed by reconstruction of the mandible. The clinical, radiological, and histopathological features are discussed within the context of this case.


Contamination of autologous peripheral blood progenitor cell grafts predicts overall survival after high-dose chemotherapy in multiple myeloma.
Despite of the introduction of novel treatment modalities for multiple myeloma, high-dose chemotherapy with hematopoietic stem-cell rescue is still considered the standard of care for eligible patients <65 years of age. As we have previously reported, stem-cell grafts regularly contain quantities of plasma cells measurable by flow cytometry. However, the pathogenetic significance of this finding remains unknown. Multiple myeloma patients (n = 60) were mobilized with chemotherapy and filgrastim. Peripheral blood stem cell grafts were obtained by standard leukapheresis, and the number of CD38++/CD138+ cells/kg was determined by flow cytometry. Plasma cell contamination above a threshold of 4.5 x 10(5) plasma cells/kg was considered "high", whereas lower quantities of plasma cells or absent plasma cells in the graft were considered "low". Progression-free survival: the median statistical progression-free survival was 33.5 months (range 11-99 months) in the high-contamination group (n = 16) versus 47 months (range 8-148 months) in the low-contamination group (n = 44). This difference turned out not to be statistically significant (P = 0.15). However, the difference was highly significant regarding overall survival with 53 months (range 11-119 months) in the high-contamination group and with 114 months (range 8-158 months) in the low-contamination group (P = 0.012). Patients with >4.5 x 10(5) plasma cells/kg contaminating the peripheral blood stem cell graft received after high-dose chemotherapy have a significantly reduced overall survival. Whether high contamination of grafts with plasma cells might reflect residual in vivo tumor mass prior to stem cell transplantation and a generally more aggressive behavior of malignant myeloma cells in these patients, or whether reinfused plasma cells contribute to an unfavorable course of disease remains to be determined.


Expression of functional scorpion neurotoxin Lqq-V in E.coli.
We report the results on the expression in Escherichia coli of a functional neurotoxin LqqV from the scorpion Leiurus quinquestriatus quinquestriatus. The gene for LqqV was synthesized using recursive PCR and expressed as a poly-histidine-tagged fusion protein in thioredoxin mutant E. coli strain [AD494(DE3)pLysS], thus permitting disulfide-bond formation. When cultured at 37 degrees C, about 50% of the expressed protein is contained as a monomer in the soluble fraction of the E. coli extract. The fusion protein from the soluble fraction was purified and the His-tag was cleaved by thrombin, resulting in a yield of about 1.5 mg/liter. The globular structure of the purified protein was confirmed by NMR and CD spectroscopy. Patch-clamp measurements using native sodium channels in guinea pig ventricular myocytes reveal (1) a slowing of inactivation and (2) a decrease in peak current upon application of toxin, thus confirming the alpha-toxin activity of the purified recombinant protein.


[Limitations and possibilities of applying the positive effects of human/animal relations in the treatment of psychological ailments].
For the 72nd Psychiatric Saar-Lorr-Lux Symposium (Sept. 2004 at the Neuropsychiatric Hospital (CHNP) in Ettelbruck, LUXEMBOURG), Dr. Jean-Marie Spautz, director, brought together professionals of varied disciplines, each involved in Animal Assisted Therapy (AAT).


How visual inputs to the ponto-bulbar reticular formation are used in the synthesis of premotor signals during orienting.
The primate superior colliculus (SC) is known as a structure subserving the transformation of visual information into "commands" for orienting eye movements. Collicular burst neurons discharging with short lead times in relation to visually triggered or spontaneous saccades are supposed to be the output elements linking the SC to immediately premotor pattern generators. In this paper we summarize some data available for the cat's SC neurones, identified as tecto-reticulo-spinal projection cells (TRSN), and reticulospinal neurones (RSN), identified as receiving excitatory collicular input. Some TRSNs respond to visual stimuli in the absence of orienting movements and, hence, their signals cannot be regarded as motor "commands", in spite of their proven connections with premotor pools in the brain stem and with the spinal cord. Moreover, a small fraction of RSNs belonging to polysynaptic descending collicular pathways also displays visual responses dissociated from movement, in addition to discharges related to the performance of orienting eye-head synergies. The processes of visual to motor transformation, assumed by current models as being definitively accomplished in the SC, appear thus to be partially performed in the reticular network incorporating the overlapping collaterals of tectal projection cells and their target neurons in the reticular core. It is concluded that, at least as for visuomotor transformations underlying orienting movements in the cat, the deep division of the SC and the brain stem reticular formation represent an ensemble, rather than a sequence of hierarchically arranged levels of processing.


Acyclovir in the treatment of neonatal varicella.
We describe two cases of neonatal varicella and the role of acyclovir in their treatment.


Antigen presentation in cancer - mechanisms and clinical implications for immunotherapy.
Over the past decade, the emergence of effective immunotherapies has revolutionized the clinical management of many types of cancers. However, long-term durable tumour control is only achieved in a fraction of patients who receive these therapies. Understanding the mechanisms underlying clinical response and resistance to treatment is therefore essential to expanding the level of clinical benefit obtained from immunotherapies. In this Review, we describe the molecular mechanisms of antigen processing and presentation in tumours and their clinical consequences. We examine how various aspects of the antigen-presentation machinery (APM) shape tumour immunity. In particular, we discuss genomic variants in HLA alleles and other APM components, highlighting their influence on the immunopeptidomes of both malignant cells and immune cells. Understanding the APM, how it is regulated and how it changes in tumour cells is crucial for determining which patients will respond to immunotherapy and why some patients develop resistance. We focus on recently discovered molecular and genomic alterations that drive the clinical outcomes of patients receiving immune-checkpoint inhibitors. An improved understanding of how these variables mediate tumour-immune interactions is expected to guide the more precise administration of immunotherapies and reveal potentially promising directions for the development of new immunotherapeutic approaches.


Different prevalence of T2DM risk alleles in Roma population in comparison with the majority Czech population.
The Czech governmental study suggests up to a 25% higher prevalence of type 2 diabetes mellitus (T2DM) in the Roma population than within the majority population. It is not known whether and to what extent these differences have a genetic background. To analyze whether the frequencies of the alleles/genotypes of the FTO, TCF7L2, CDKN2A/2B, MAEA, TLE4, IGF2BP2, ARAP1, and KCNJ11 genes differ between the two major ethnic groups in the Czech Republic, we examined them in DNA samples from 302 Roma individuals and 298 Czech individuals. Compared to the majority population, Roma are more likely to carry risk alleles in the FTO (26% vs. 16% GG homozygotes, p < .01), IGF2BP2 (22% vs. 10% TT homozygotes, p < .0001), ARAP1 (98% vs. 95% of A allele carriers, p < .005), and CDKN2A/2B (81% vs. 66% of TT homozygotes, p < .001) genes; however, less frequently they are carriers of the TCF7L2 risk allele (34% vs. 48% of the T allele p < .0005). Finally, we found significant accumulation of T2DM-associated alleles between the Roma population in comparison with the majority population (25.4% vs. 15.2% of the carriers of at least 12 risk alleles; p < .0001). The increased prevalence of T2DM in the Roma population may have a background in different frequencies of the risk alleles of genes associated with T2DM development.


Locomotion and nightwaking.
In this study we addressed the association between two major achievements of infancy: independent locomotion and 'sleeping through the night'. Mothers of 107 healthy infants aged between five and eight months completed a sleep questionnaire and a motor checklist. Infants who were already crawling had more bedtime difficulties and nightwaking than did pre-crawlers. Among 7- and 8-month-old infants, locomotion predicted 17% of nightwaking variance, after controlling for age and gender. In discussing the developmental implications of locomotion we suggest that crawling may not only 'broaden the mind' but also 'cost' sleep. More studies, across time, on how motor development and sleep-wake regulation interrelate are recommended.


Choosing an intraocular lens for patients with large pupils.
Optical aberration from the positioning holes of a posterior chamber intraocular lens was encountered in three patients with wide spontaneous dilation of the pupil in scotopic conditions. One patient had a cataract extraction in his fellow eye with implantation of a posterior chamber lens without positioning holes in its optical portion and has not encountered any aberrations in that eye. We suggest that in such patients, careful preoperative measurement of the pupillary size in a dark room should be done and lenses without positioning holes on the optic should be used to prevent optical aberrations.


Pharmacological properties, functional alterations and gene expression of muscarinic receptors in young and old type 2 Goto-Kakizaki diabetic rat bladders.
We investigated pharmacological properties, functional alterations and gene expression of the muscarinic receptor system in young and old Goto-Kakizaki rat bladders. Male 12 and 70-week-old Goto-Kakizaki rats and age matched male Wistar rats were used in this study. Bladder function was estimated by voiding behavior, cystometric and functional studies using KCl, carbachol and various concentrations of subtype selective muscarinic antagonists, ie pirenzepine, methoctramine, 4-DAMP (Sigma) and atropine (Wako Pure Chemical Industries, Osaka, Japan). The participation levels of M(2) and M(3) receptor mRNA in the bladder were investigated by real-time polymerase chain reaction. In voiding behavior studies there were no significant differences in urine output, although an age related decrease in micturition frequency and an age related increase in single voided volume were observed in Goto-Kakizaki and Wistar rats. In cystometric studies there were no significant differences in maximum detrusor pressure or bladder capacity, although residual urine volume was significantly increased in 70-week-old Goto-Kakizaki rats. In functional studies carbachol induced detrusor contractility was significantly increased in Goto-Kakizaki rats in each age group. Estimated pA(2) values for atropine, pirenzepine, methoctramine and 4-DAMP (Sigma) indicated that the carbachol induced contractile response was mediated through the M(3) receptor subtype in all groups. Furthermore, muscarinic M(2) and M(3) receptor mRNA was significantly up regulated in 70-week-old Goto-Kakizaki rat bladders. Our data indicate that noninsulin dependent diabetes induces alterations in the muscarinic receptor system, which may contribute to the development of diabetic cystopathy.


The sexually differentiated delta 4-3-ketosteroid 5 beta-reductase of rat liver. Purification, characterization, and quantitation.
delta 4-3-Ketosteroid 5 beta-reductase was purified from male rat liver cytosol. The purification scheme consisted of column chromatographies on hydroxylapatite and DEAE-Sepharose, chromatofocusing, and Sephadex G-75 gel filtration followed by sodium dodecyl sulfate-gel electrophoresis. The column chromatography steps gave a 100-fold purification and resulted in a 90% pure preparation as judged by sodium dodecyl sulfate-gel electrophoresis. Kinetic properties with 4-androstene-3,17-dione as substrate were established for the enzyme, and its activity regarding three other delta 4-3-ketosteroids, testosterone, progesterone, and cortisol, was investigated. The relative rates of reduction of these steroids were 1.0, 0.8, 0.7, and 0.62, respectively. The electrophoretically purified 5 beta-reductase, with an Mr of 38,000, was used for immunization of rabbits. The antiserum was shown to be monospecific as judged from immunoblotting of electrophoretically separated rat liver cytosolic proteins. Immunological reactive protein and enzymatic 5 beta-reductase activity co-purified in the chromatographic steps. The sex difference in enzyme activity, 0.26 versus 0.10 nmol of product/mg of proteins/min for males and females, respectively, was shown to be due to a difference in concentration of enzyme protein. The 5 beta-reductase was calculated to constitute 1% of the total cytosolic proteins in male livers, whereas the corresponding figure for female livers was 0.3%.


The contribution of high-resolution multiplanar reformats of the skull base to the detection of skull-base fractures.
To investigate the contribution of routine review of submillimetric multiplanar reformats to the diagnosis of skull-base fractures. A prospective analysis was performed of 407 cases referred over a 6-month period for CT of the skull following cranial trauma. The reformatted 5-mm axial sections and subsequently the high-resolution multiplanar reformats (HRMPRs) were viewed on an ADW 4.1 workstation using bone windows and algorithm. All skull-base fractures and related features, recorded by the consensus of two radiologists, were classified as anatomically significant or non-significant on the basis of eight criteria. The clinical features of skull-base injury and any subsequent treatment were noted in all cases of skull-base fracture. HRMPRs detected 80 separate skull-base fractures in 36/407 cases. Of these 80 fractures, 57 were visible on 5-mm axial sections. In 8 of the 36 cases, the significant anatomical features were only evident on review of the HRMPRs. In 6 of the 36 cases, none of the skull-base fractures was visible on 5-mm sections, but these individuals had only minor associated clinical features and no therapeutic requirements. Review of HRMPRs could have been confined to patients with skull-base fractures, abnormal intracranial and extracranial air collections or opacified mastoid air cells revealed by 5-mm axial sections. This policy would have led to the detection of 79/80 (99%) of skull-base fractures and all significant anatomical features. The 5-mm axial sections demonstrated 71% of skull-base fractures and 78% of skull-base fractures with significant anatomical features, using HRMPRs as a gold standard. There were no significant clinical sequelae at short-term follow-up of those fractures only evident on HRMPRs.


Orbital metastases from neuroendocrine neoplasms: clinical implications and outcomes.
Neuroendocrine neoplasms (NENs) may rarely metastasise to the orbit. Published data on epidemiology, incidence and preferred treatment is limited. We present the largest cohort of symptomatic and asymptomatic NEN patients with orbital metastases and data on epidemiological parameters, symptoms as well as diagnostic/treatment modalities used. We identified patients from our internal NEN database of patients who had also undergone Gallium68-DOTATATE PET (Ga68-DOTA). The diagnosis of orbital metastatic NEN was made on somatostatin receptor imaging and confirmed on a dedicated MRI of orbits. We identified 27 patients of 994 patients evaluated with Ga68-DOTATATE PET imaging during their surveillance monitoring in our department; 15 female, average age at NEN diagnosis 53 years and orbital metastatic NEN diagnosis 59 years. The majority of NEN primaries originated from small bowel (18/27, 66.4%) or pancreas 4/27 (4/27, 14.8%). Hepatic with or without concomitant skeletal metastases were present in 23/27 (85%) of patients. Ocular symptoms and/or signs were evident in 11/27 (41%) of patients. 5/11 symptomatic patients underwent external beam radiotherapy (EBRT) resulting in complete symptoms resolution. The 5-year survival was estimated at 84.1%. Orbital metastases of NEN have a relatively low prevalence, more commonly associated with small bowel primary. Extraocular muscles are primarily affected, irrespectively of liver disease burden. Survival does not seem to be affected. EBRT is an efficacious treatment modality for both symptom relief and tumour growth control. Administration of peptide receptor radionuclide therapy may occasionally induce temporary ocular symptoms, which resolve following treatment with a short course of steroids.


A study of the practice of otorhinolaryngology in the United States. Initial findings.
Results of a national survey of nonfederal otorhinolaryngologist regarding their practices provide the following portrait of the typical physician who specializes in otorhinolaryngology: male, between 35 and 45 years old, engaged in solo practice in a metropolitan area in the southern part of the country. He works a 46-hour week, devoting most of his time to patient care. During a typical week, he sees 113 patients, mostly outside the hospital. Half of his patients are male; although their average age is 35, one fourth of his patients are under 15 years. Every third patient is new to him; every other patient has been referred. He spends almost 15 minutes with each patient, many of whom he is seeing on a continuous basis for a problem involving the ear. He prescribes medications in roughly half of all encounters; every tenth patient requires surgery. He rates the majority of the problems he encounters as chronic, and of minor to moderate severity and urgency--for which he provides services of limited complexity or less. He seldom refers his patients.


Gestational choriocarcinoma in a tubal ectopic pregnancy.
A case is reported of a gestational choriocarcinoma arising in a tubal ectopic pregnancy of 7 weeks' gestation. Unilateral salpingectomy and single-agent actinomycin-D chemotherapy achieved a cure. A follow-up 4 years later revealed no evidence of recurrence, with two normal births within that period. The current trend to treat ectopic pregnancy by conservative surgery necessitates monitoring of beta-HCG titres in order to avoid missing a choriocarcinoma developing in an ectopic gestation, even though this is a very rare condition.


Analysis of analgesic, antipyretic, and nonsteroidal anti-inflammatory drug use in pediatric prescriptions.
Data on clinical practice in pediatrics on the use of analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs considering the best available evidence and regulatory-agency approved use are uncertain. This study aimed to determine the frequency of prescription of these drugs according to the best scientific evidence and use approved by regulatory agencies. This was a cross-sectional study of 150 pediatric prescriptions containing analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs, followed by interview with caregivers at 18 locations (nine private drugstores and nine Basic Health Units of the Brazilian Unified Health System). The assessed outcomes included recommended use or use with no contraindication, indications with benefit evidence, and health surveillance agency-approved use. Data were analyzed in electronic databases and the variables were summarized by simple frequency. A total of 164 analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs were prescribed to 150 children aged 1-4 years (38.6%). Dipyrone was included in 82 (54.6%) and ibuprofen in 40 (26.6%) prescriptions. Non-recommended uses were identified in 15% of prescriptions and contraindicated uses were observed in 13.3%. Nimesulide (1.5%) is still prescribed to children younger than 12 years. The dose was incorrect in 74.3% of prescriptions containing dipyrone. Of the 211 reported clinical indications, 56 (26.5%) had no evidence of benefit according to the best available scientific evidence and 66 (31.3%) had indications not approved by the regulatory agencies. There are significant discrepancies between clinical practice and recommended use of analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs in pediatrics.


Eps15/Pan1p is a master regulator of the late stages of the endocytic pathway.
Endocytosis is a multistep process involving the sequential recruitment and action of numerous proteins. This process can be divided into two phases: an early phase, in which sites of endocytosis are formed, and a late phase in which clathrin-coated vesicles are formed and internalized into the cytosol, but how these phases link to each other remains unclear. In this study, we demonstrate that anchoring the yeast Eps15-like protein Pan1p to the peroxisome triggers most of the events occurring during the late phase at the peroxisome. At this ectopic location, Pan1p recruits most proteins that function in the late phases-including actin nucleation promoting factors-and then initiates actin polymerization. Pan1p also recruited Prk1 kinase and actin depolymerizing factors, thereby triggering disassembly immediately after actin assembly and inducing dissociation of endocytic proteins from the peroxisome. These observations suggest that Pan1p is a key regulator for initiating, processing, and completing the late phase of endocytosis.


Validation of a closing procedure for fourth-order RANS turbulence models with DNS data in an incompressible zero-pressure-gradient turbulent boundary layer.
Among factors affecting the accuracy of flow simulations with Reynolds-Averaged Navier-Stokes turbulence models is modeling turbulent diffusion processes. With the use of the Gram-Charlier series expansions, the turbulent diffusion in fourth-order one-point statistical closures of the Reynolds-Averaged Navier-Stokes equations can be modeled without introducing unknown model coefficients and without assuming turbulence being Gaussian. Terms representing turbulent diffusion processes in transport equations for second- and third-order velocity correlations do not require any modeling in such closures. In this regard, fourth-order closures are a more accurate alternative to lower-order closures where turbulent diffusion is modeled on semi-empirical or Gaussian turbulence assumptions. In the current paper, the accuracy of the closing procedure based on the Gram-Charlier series expansions is evaluated using data of direct numerical simulations in an incompressible zero-pressure-gradient turbulent boundary layer over a flat plate. One-point third-, fourth-, and fifth-order velocity moments were extracted for this purpose from the dataset collected by the Fluid Dynamics Group at the Universidad Politécnica de Madrid at two streamwise locations Reθ= 4101 and 5200 that correspond to channels and pipes at δ+= 1331 and 1626. Results demonstrate that the truncated Gram-Charlier series expansions are an accurate approximation of the fifth-order velocity moments in the considered flow.


Role of VPS13, a protein with similarity to ATG2, in physiology and disease.
The evolutionarily conserved VPS13 family proteins have been implicated in several cellular processes. Mutations in each of the four human VPS13s cause neurodevelopmental or neurodegenerative disorders. Until recently, the molecular function of VPS13 remained elusive. Genetic, functional and structural studies have now revealed that VPS13 acts at contact sites between intracellular organelles to transport lipids by a novel mechanism: direct transfer between bilayers via a hydrophobic channel that spans its entire rod-like N-terminal half. Predicted similarities to the autophagy protein ATG2 suggested a similar role for ATG2 that has now been confirmed by structural and functional studies. Here, after a brief review of this evidence, we discuss what is known of human VPS13 proteins in physiology and disease.


Multifaceted Roles of TIM-Family Proteins in Virus-Host Interactions.
To enhance infection, enveloped viruses exploit adhesion molecules expressed on the surface of host cells. Specifically, phosphatidylserine (PS) receptors - including members of the human T cell immunoglobulin and mucin domain (TIM)-family - have gained attention for their ability to mediate the entry of many enveloped viruses. However, recent evidence that TIM-1 can restrict viral release reveals a new role for these PS receptors. Additionally, viral factors such as the HIV-1 accessory protein Nef can antagonize this antiviral activity of TIM-1 while host restriction factors such as SERINC5 can enhance it. In this review, we examine the various roles of PS receptors, specifically TIM-family proteins, and the intricate relationship between host and viral factors. Elucidating the multifunctional roles of PS receptors in virus-host interaction is important for understanding viral pathogenesis and developing novel antiviral therapeutics.


Characterization of mouse sialyltransferase genes: their evolution and diversity.
Sialic acids are negatively charged acidic sugars, and sialylglycoconjugates often play important roles in various biological phenomena. Sialyltransferases are involved in the synthesis of sialylglycoconjugates, and 20 members of the mammalian sialyltransferase family have been identified to date. These sialyltransferases are grouped into four families according to the carbohydrate linkages they synthesize: beta-galactoside alpha2,3-sialyltransferases (ST3Gal I-VI), beta-galactoside alpha2,6-sialyltransferases (ST6Gal I and II), GalNAc alpha2,6-sialyltransferases (ST6GalNAc I-VI), and alpha2,8-sialyltransferases (ST8Sia I-VI). Analysis of the amino acid sequence similarities, substrate specificities, and gene structures of mouse sialyltransferases has revealed that they can be further divided into seven subfamilies. The genomic structural resemblance of members of the same subfamily suggests that they arose from a common ancestral gene through gene duplication events. These multiple sialyltransferase genes are needed for fine control of the expression of sialylglycoconjugates, resulting in a variety of developmental stage- and tissue-specific glycosylation patterns.


Lack of evidence for a cerebral sodium modulating mechanism in the monkey.
Experiments were carried out in seven conscious macaque monkeys undergoing a water diuresis to determine the effects of raising carotid blood sodium concentration on renal sodium excretion and free water clearance. On separate days each animal received an intracarotid infusion of hypertonic sodium chloride (90 Eq NaCl/kg.body wt./min) for 5 to 10 min, the same hypertonic infusion intravenously, and an intracarotid infusion of isotonic NaCl. None of the infusions produced a change in sodium excretion. However, the intracarotid hypertonic infusion produced a sustained decrease in free water excretion while the other infusion did not. Creatinine clearance was not affected by any of the infusions. The results of these experiments support the view that while the brain of the primate contains an osmotic sensing mechanism it does not contain a mechanism which modulates sodium excretion.


First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis.
Percutaneous aortic valve replacement is a new technology for the treatment of patients with significant aortic valve stenosis. We present the first report on a human implantation of a self-expanding aortic valve prosthesis, which is composed of three bovine pericardial leaflets inserted within a self-expanding nitinol stent. The 73-year-old woman presented with severe symptomatic aortic valve stenosis (mean transvalvular gradient of 45 mmHg; valve area of 0.7 cm2). Surgical valve replacement had been declined for the patient because of comorbidities, including previous bypass surgery. A retrograde approach via the common iliac artery was used for valve deployment. The contralateral femoral vessels were used for a temporary extracorporal circulation, unloading the left ventricle during the actual stent expansion. Clinical, hemodynamic, and echocardiographic outcomes were assessed serially during the procedure. Clinical and echocardiographic follow-up at day 1, 2, and 14 post procedure was performed to evaluate the short-term outcome. The prosthesis was successfully deployed within the native aortic valve, with accurate and stable positioning and with no impairment of the coronary artery or vein graft blood flow. 2D and doppler echo immediately after device deployment showed a significant reduction in transaortic mean pressure gradient (from 45 to 8 mmHg) without evidence of aortic or mitral valve insufficiency. The clinical status has then significantly improved. These results remained unchanged up to the day 14 follow-up. This case report demonstrates a successful percutaneous implantation of a self-expanding aortic valve prosthesis with remarkable functional and clinical improvements in the acute and short-term outcome.


A synthetic bone implant macroscopically identical to cancellous bone.
Macroporous hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) are widely used as synthetic bone replacement materials due to their high biocompatibility and osteoconductive properties. The level of porosity, pore size distribution, pore morphology, and the degree of pore interconnectivity in such grafts significantly influences the extent of bone ingrowth. It has been hypothesised that an ideal implant macrostructure may be similar in morphological characteristics to the inorganic matrix of the bone it is replacing. However, to date, clinically available synthetic materials differ structurally from cancellous bone. A method is described for the macrostructural replication of cancellous bone. Reproduction involves a multistage process requiring the manipulation of positive and negative forms of the inorganic matrix. By infiltration of a wax negative mould of cancellous bone with a ceramic slip, followed by removal of the wax, and firing, it is possible to produce a positive replica of the original cancellous macrostructure. Optimisation of slip preparation conditions (pH and percentage deflocculant addition) and sintering conditions have allowed successful replication of cancellous bone using several bioceramic compositions including HA, beta-TCP, and HA/beta-TCP.


Dynamic analysis of rabies transmission and elimination in mainland China.
Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies by 2030. In response to this goal positively, China has been dedicated to the control and elimination of rabies mainly caused by dogs, for nearly 10 years. By applying infectious disease dynamics, in this paper, we establish a dog-human rabies transmission model to forecast future epidemic trends of rabies, assess whether the goal of eliminating dog-induced human rabies cases in China can be achieved in 2030, and further evaluate and suggest the follow-up sustained preventive measures after the elimination of human rabies. By analyzing and simulating above dynamic model, it is concluded that rabies has been well controlled in China in recent years, but dog-induced human rabies cannot be eliminated by 2030 according to current situation. In addition, we propose to improve rabies control efforts by increasing the immunization coverage rate of rural domestic dogs, controlling the number of stray dogs and preventing the import of rabies virus in wild animals. Immunization coverage rate of rural domestic dogs which is currently less than 10% is far from requirement, and it needs to reach 50%-60% to meet the goal of 2030. Since it is difficult to immunize stray dogs, we suggest to control the number of stray dogs below 15.27 million to achieve the goal. If the goal of eliminating human rabies is reached in 2030, the essential immunization coverage needs to be maintained for 18 years to reduce the number of canine rabies cases to zero. Lastly, to prevent transmission of rabies virus from wild animals to dogs, the thresholds of the number of dogs and the immunization coverage rate of dogs after eliminating canine rabies cases are also discussed.


Adrenergic ligands that block oviposition in the cattle tick Rhipicephalus microplus affect ovary contraction.
The tyraminergic/octopaminergic system is central for the control of arthropod oviposition. Previous works demonstrated that the pharmacological perturbation of this system inhibits oviposition in the cattle tick Rhipicephalus microplus. In this work, we describe a physiologically active whole-mount preparation of the contractile tick ovary that allows the quantitative videometrical analysis of ovary contraction in response to different compounds. Eight adrenergic ligands known to inhibit oviposition, including octopamine and tyramine were tested. These compounds exhibited antagonistic effects; octopamine relaxes the ovary preparation while tyramine induces a very strong contraction. The other adrenergic compounds tested were classified as able to contract or relax ovary muscle tissue. Isoprotenerol has a stronger relaxative effect than octopamine. Tyramine induces the biggest contraction observed of all the compounds tested, followed, in descending amount of contraction, by salbutamol, prazosin, epinastine, clonidine and the acaricide amitraz. The effect of these adrenergic ligands on the ovary preparation, explains why these molecules inhibit tick oviposition and suggest a regulatory mechanism for ovary contraction and relaxation during oviposition. Our results also provide a physiological explanation of the egg-laying inhibition effect of amitraz when used on the cattle tick.


Effect of astaxanthin and melatonin on cell viability and DNA damage in human breast cancer cell lines.
Astaxanthin is a xanthophyll pigment found in algae and marine animals, having strong anti-oxidative, anti-tumoral, and anti-inflammatory effects. Additionally, melatonin has shown inhibitory effects on the growth of human breast cancer cells. The aim of the present study was to evaluate the effect of astaxanthin and the combined effects of astaxanthin and melatonin on breast cancer cells and the non-tumoral breast cell line. The human breast cancer cell lines, T47D and MDA-MB-231, and non-tumorigenic cell line MCF 10A were treated and compared to astaxanthin, melatonin, and co-administration of these two compounds. Cell viability, apoptosis induction, Bcl-2 protein expression, and DNA damage were measured by MTT assay, acridine orange/ethidium bromide (AO/EB) staining, immunocytochemistry, and comet assay. Astaxanthin at lower doses than melatonin reduced cell viability and Bcl2 expression, induced apoptosis and DNA damage in MDA-MB-231 and T47D. Meanwhile, the effects of astaxanthin on cell cytotoxicity, apoptosis, and DNA damage in MCF10A cells are insignificant compared to MDA-MB-231 and T47D. Moreover, the results indicated that astaxanthin in T47D cells caused more cell death compared to MDA-MB-231 cells. Astaxanthin induced cell death on breast cancer cells and without cell cytotoxicity for non-cancerous cells. Furthermore, the presence of astaxanthin increased the function of melatonin-induced cell death in breast cancer cells.


Graphene Nanoplatelets for the Development of Reinforced PLA-PCL Electrospun Fibers as the Next-Generation of Biomedical Mats.
Electrospun scaffolds made of nano- and micro-fibrous non-woven mats from biodegradable polymers have been intensely investigated in recent years. In this field, polymer-based materials are broadly used for biomedical applications since they can be managed in high scale, easily shaped, and chemically changed to tailor their specific biologic properties. Nonetheless polymeric materials can be reinforced with inorganic materials to produce a next-generation composite with improved properties. Herein, the role of graphene nanoplatelets (GNPs) on electrospun poly-l-lactide-co-poly-ε-caprolactone (PLA-PCL, 70:30 molar ratio) fibers was investigated. Microfibers of neat PLA-PCL and with different amounts of GNPs were produced by electrospinning and they were characterized for their physicochemical and biologic properties. Results showed that GNPs concentration notably affected the fibers morphology and diameters distribution, influenced PLA-PCL chain mobility in the crystallization process and tuned the mechanical and thermal properties of the electrospun matrices. GNPs were also liable of slowing down copolymer degradation rate in simulated physiological environment. However, no toxic impurities and degradation products were pointed out up to 60 d incubation. Furthermore, preliminary biologic tests proved the ability of the matrices to enhance fibroblast cells attachment and proliferation probably due to their unique 3D-interconnected structure.


[Gastrointestinal parasitic carriage in adopted children].
Intestinal parasitoses are very common infections in tropical areas. By contrast, they are rarely diagnosed in developed countries, and are mostly seen in specific populations. This analytical observational study was longitudinally performed in a French university hospital (2007-2011). It dealt with the study of gastrointestinal carriage of parasites in internationally adopted children. A standard stool examination was therefore systematically undertaken for every new immigrant. Association with risk factors was made by uni- and multivariate analysis. Overall, 69 stool samples were analyzed. The proportion of positive samples was 78 %. Protozoans, mainly Giardia duodenalis, were more prevalent than helminths. In univariate analysis, a subject's low weight and height were significantly associated with intestinal parasite carriage. Amoebae were more frequent in older children and in children from Haiti, as confirmed by the trend observed in the multivariate analysis. Flagellates were seen more often in African children. Infections with multiple parasite species were observed in half of the study population, and were inversely correlated to increasing age. According to the results of this study, gastrointestinal parasites are still very frequent in stool samples from immigrant children. Since they are easy to transmit, the majority of infections were protozoan. The best antiparasitic strategy lies in: (a) the routine screening of stool from any immigrant child coming from endemic areas and (b) the use of antiparasitic treatment.


Refugee healthcare needs and barriers to accessing healthcare services in New Zealand: a qualitative phenomenological approach.
Refuges and asylum seekers have specific healthcare needs; however there has been insufficient attention and effort to address these needs globally. Furthermore, effective communication between healthcare providers and refugees remains poor, further widening the imbalanced power dynamics. The aim of this research project was to examine refugee healthcare needs and current barriers to accessing healthcare services in New Zealand, and to propose solutions by exploring the perceptions, attitudes, beliefs, and opinions of key stakeholders regarding refugee healthcare needs within the scaffold of health and social care systems. We conducted semi-structured interviews between September and December 2018 with 18 purposively selected refugee service provider stakeholders in New Zealand using an interview guide that addressed healthcare needs, existing barriers to access healthcare services, and perceived future healthcare delivery solutions. Thematic analysis of emergent themes of this study indicated the need for a national framework of inclusion, mandating cultural safety training of frontline personnel, improving access to interpreters and cultural mediators, and establishing the role of patient navigators. Barriers to accessing health services included entrenched social health determinants such as housing scarcity and disenfranchised community environments; refugee health-seeking behaviour and poor health literacy; along with existing social support networks. We propose that healthcare delivery should focus on capacity building of existing services, including co-design processes with refugees and asylum seekers and increasing funding for refugee-specific health service via the implementation of an overarching national strategy. Based on the findings of this study, refugee organisations and their frontline personnel should seek to address the deficiencies identified in order to provide equitable, timely and culturally-accessible healthcare services for refugees in New Zealand and in comparable countries.


Ethanol-stress interaction: immediate versus delayed effects of ethanol and handling on stress responses of ethanol-consuming rats.
Rats screened for voluntary ethanol intake (high, medium, and low ethanol-preferring rats and non-ethanol-exposed controls) were given acute immobilization stress either immediately following the ethanol screening procedure, or after a 20 day period without access to ethanol. Among animals examined for stress responses immediately after ethanol screening, it was observed that water-only control rats developed significantly less frequent and less severe gastric stress ulcers than rats in all ethanol-exposed groups. This result suggests that ethanol, stress and routine handling may have contributed to ulcer formation in these animals. In contrast, among rats tested for stress responses after 20 days without ethanol, it was observed that the high ethanol-preferring animals showed less severe stress ulcers. These results indicate that among high ethanol-consuming animals, the presence of ethanol enhances ulcer severity, while prior experience with ethanol consumption does not appear to predispose rats to exacerbated stress gastric pathology.


Are fluorescein-conjugated androgens appropriate for a histochemical detection of prostatic androgen receptors?
Histochemical fluorescence techniques could be of great value in order to assay androgen receptors (AR), particularly in punch biopsies from human prostatic carcinoma (PCA). Therefore, prostatic tissue was examined for specific binding of fluorescein-labeled 5 alpha-dihydrotestosterone derivatives (FDHT) to AR. Using a 17 beta-fluoresceinated DHT derivative (17-FDHT), variable fluorescence was found in human and rat prostates at high 17-FDHT concentrations. This fluorescence could be blocked by unlabeled DHT in 11 and 73% of human and rat prostatic tissue, respectively. Control studies of receptor and organ specificity were conducted and showed that preheated slices from rat prostates displayed no decrease of fluorescent staining. No difference in fluorescence intensity could be seen between prostates from castrated and uncastrated rats. Unstained tissue slices frequently showed a considerable intensity of autofluorescence. An appreciable amount of fluorescence in both rat liver and spleen was found. From these results and various general methodical problems inherent in fluorescent receptor assays, we conclude that the fluorescence techniques described are inappropriate for demonstration of AR.


Diverticulum of the vermiform appendix is associated with chronic abdominal pain.
Diverticulum of the vermiform appendix is rarely encountered. Previous reports in the literature indicate that appendiceal diverticulum without inflammations are asymptomatic. During the past 10 years, 217 patients have been evaluated in our office for chronic lower abdominal pain. Six patients in this group were unusual in that no diagnosis could be made after a complete history, physical examination, and multiple imaging and laboratory studies. Each patient had a normal computed tomography scan of the abdomen, upper endoscopy, colonoscopy, barium enema, and small bowel enteroclysis. Each of the 6 patients underwent an exploratory laparoscopy and appendectomy. All 6 patients in this series had acquired diverticulum of the appendix with inspissated intraluminal secretions without histological evidence of inflammation. The age range was 37 to 57 years. Most patients were male, and most had a single diverticulum projecting into the mesoappendix. All 6 patients had complete resolution of their chronic abdominal pain after the laparoscopic appendectomy. An unusual cause of mild chronic abdominal pain can be the presence of appendiceal diverticulum with inspissated intraluminal secretions. The evaluation of these patients is usually normal. Exploratory laparoscopy with appendectomy should be the final evaluation for patients with mild chronic abdominal pain.


Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma.
The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM). Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies-GEN501 (N = 104) and SIRIUS (N = 124). Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54-2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population. Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM.


Effect of zinc source and picolinic acid on 65Zn uptake in an in vitro continuous-flow perfusion system for pig and poultry intestinal segments.
Twenty weanling pigs and fourteen 9-wk-old broiler chickens were used in three continuous-flow in vitro perfusion experiments using noneverted intestinal sacs to 1) determine differences in 65Zn absorption due to location within the intestinal tract, 2) evaluate 65Zn uptake from ZnCl2 and Zn-methionine (ZnMet) with or without added picolinic acid (PA) in pig intestinal sacs and 3) evaluate 65Zn uptake from ZnCl2 and ZnMet in chicken intestinal sacs. No differences in 65Zn uptake due to gut segment position were observed in the pigs. A Zn source x PA interaction was observed for 65Zn uptake into the pig gut tissue and for 65Zn uptake to the serosal side of the gut sacs. Total 65Zn absorption in the pig gut sacs from the two Zn sources was not different, but the addition of a 5 M ratio of PA to Zn depressed 65Zn absorption. No differences were observed in total 65Zn absorption or 65Zn uptake in poultry gut sac tissue. There was, however, greater uptake of 65Zn from ZnCl2 to the serosal side of the sacs than from ZnMet. The data indicate that 65Zn from ZnCl2 and ZnMet is similar in total absorption and that the addition of PA depresses Zn uptake.


Differential epitope expression of Ly-48 (mouse leukosialin).
Ly-48 is a major sialoglycoprotein expressed on the surface of a variety of mouse hematopoietic cells that exhibits many characteristic isoforms and may function in signal transduction and cell adhesion. Ly-48 is recognized by the 3E8-specific monoclonal antibody (mAb) and it has been suggested that it is the same antigen recognized by another mAb known as S7. In this report, we demonstrate definitively by transfection of a Ly-48 cDNA that S7 and two previously uncharacterized mAbs, S11 and S15, recognize the same antigen as the 3E8-specific mAb. However, 2-D gel immunoblot analyses demonstrate the complex nature of Ly-48. Although all four mAbs react similarly with lysates from the M-45 B-cell myeloma line, 2-D immunoblot analyses of the EL-4 T-cell line reveal three distinct patterns of reactivity. Further, while transfection of Ly-48 into the K562 erythroleukemic cell line conferred reactivity to all four mAbs, transfection of the Ly-48 cDNA into the nonhematopoietic cell line, Line 1, conferred reactivity only to the S11 and S15 mAbs. Thus, the Line 1 transfectants suggest the importance of posttranslational modifications in the expression of the 3E8 and S7 epitopes. Interestingly, developing fetal liver cells show the same pattern of differential Ly-48-specific mAb reactivity. The developing early fetal liver cells are reactive with S11 and S15 but are negative, to very weakly, reactive with the 3E8- and S7-specific mAbs. These results show that Ly-48 epitopes can be expressed independently on cell lines in vitro and are differentially expressed on healthy cells in vivo.


Prediction and Mapping of Intraprostatic Tumor Extent with Artificial Intelligence.
Magnetic resonance imaging (MRI) underestimation of prostate cancer extent complicates the definition of focal treatment margins. To validate focal treatment margins produced by an artificial intelligence (AI) model. Testing was conducted retrospectively in an independent dataset of 50 consecutive patients who had radical prostatectomy for intermediate-risk cancer. An AI deep learning model incorporated multimodal imaging and biopsy data to produce three-dimensional cancer estimation maps and margins. AI margins were compared with conventional MRI regions of interest (ROIs), 10-mm margins around ROIs, and hemigland margins. The AI model also furnished predictions of negative surgical margin probability, which were assessed for accuracy. Comparing AI with conventional margins, sensitivity was evaluated using Wilcoxon signed-rank tests and negative margin rates using chi-square tests. Predicted versus observed negative margin probability was assessed using linear regression. Clinically significant prostate cancer (International Society of Urological Pathology grade ≥2) delineated on whole-mount histopathology served as ground truth. The mean sensitivity for cancer-bearing voxels was higher for AI margins (97%) than for conventional ROIs (37%, p < 0.001), 10-mm ROI margins (93%, p = 0.24), and hemigland margins (94%, p < 0.001). For index lesions, AI margins were more often negative (90%) than conventional ROIs (0%, p < 0.001), 10-mm ROI margins (82%, p = 0.24), and hemigland margins (66%, p = 0.004). Predicted and observed negative margin probabilities were strongly correlated (R2 = 0.98, median error = 4%). Limitations include a validation dataset derived from a single institution's prostatectomy population. The AI model was accurate and effective in an independent test set. This approach could improve and standardize treatment margin definition, potentially reducing cancer recurrence rates. Furthermore, an accurate assessment of negative margin probability could facilitate informed decision-making for patients and physicians. Artificial intelligence was used to predict the extent of tumors in surgically removed prostate specimens. It predicted tumor margins more accurately than conventional methods.


STAT5A and STAT5B have opposite correlations with drug response gene expression.
STAT5A and STAT5B are important transcription factors that play a key role in regulation of several important physiological processes including proliferation, survival, mediation of responses to cytokines and in regulating gender differences in drug response genes such as the hepatic cytochrome P450s (CYPs) that are responsible for a large majority of drug metabolism reactions in the human body. STAT5A and STAT5b have a high degree of sequence homology and have been reported to have largely similar functions. Recent studies have, however, indicated that they can also often have distinct and unique roles in regulating gene expression. In this study, we evaluated the association of STAT5A and STAT5B mRNA expression levels with those of several key hepatic cytochrome P450s (CYPs) and hepatic transcription factors (TFs) and evaluated the potential roles of STAT5A and 5b in mediating gender differences in these CYPs and TFs. Expression profiling for major hepatic CYP isoforms and transcription factors was performed using RNA sequencing (RNA-seq) in 102 human liver samples (57 female, 45 male). Real time PCR gene expression data for selected CYPs and TFs was available on a subset of 50 human liver samples (25 female, 25 male) and was used to validate the RNA-seq findings. While STAT5A demonstrated significant negative correlation with expression levels of multiple hepatic transcription factors (including NR1I2 and HNF4A) and DMEs such as CYP3A4 and CYP2C19, STAT5B expression was observed to demonstrate positive associations with several CYPs and TFs analyzed. As STAT5A and STAT5B have been shown to be important in regulation of gender differences in CYPs, we also analyzed STAT5A and 5b associations with CYPs and TFs separately in males and females and observed gender dependent differential associations of STATs with several CYPs and TFs. Results from the real time PCR validation largely supported our RNA-seq findings. Using both RNA sequencing and real time PCR, we examined the association of STAT5A and STAT5B mRNA expression with CYP and TF gene expression. While STAT5A demonstrated significant negative correlations with expression levels of multiple hepatic TFs (including NR1I2 and HNF4α) and CYPs (eg. CYP3A4, CYP2C19), STAT5B expression was observed to demonstrate positive association with most of the CYPs/TFs analyzed suggesting that STAT5A and STAT5b have potentially different and distinct roles in regulating expression of hepatic drug response genes. Further studies are needed to elucidate the potential roles of STAT5A and 5b in regulation of CYPs/TFs and the potential implications of these findings.


Continued misinterpretation of confidence intervals: response to Miller and Ulrich.
Miller and Ulrich (2015) critique our claim (Hoekstra et al., Psychonomic Bulletin & Review, 21(5), 1157-1164, 2014), based on a survey given to researchers and students, of widespread misunderstanding of confidence intervals (CIs). They suggest that survey respondents may have interpreted the statements in the survey that we deemed incorrect in an idiosyncratic, but correct, way, thus calling into question the conclusion that the results indicate that respondents could not properly interpret CIs. Their alternative interpretations, while correct, cannot be deemed acceptable renderings of the questions in the survey due to the well-known reference class problem. Moreover, there is no support in the data for their contention that participants may have had their alternative interpretations in mind. Finally, their alternative interpretations are merely trivial restatements of the definition of a confidence interval, and have no implications for the location of a parameter.


Peanut-Shell Biochar and Biogas Slurry Improve Soil Properties in the North China Plain: A Four-Year Field Study.
Biochar and biogas slurry have been proved to improve the quality of some soil types, but the long-term effects on fluvo-aquic soil are not fully understood. This study aimed to compare the continuity effects of peanut-shell biochar and biogas slurry on the physicochemical properties, microbial population size, and enzyme activities of fluvo-aquic soil. We conducted a four-year field experiment of winter wheat-summer maize rotation in the North China Plain. Along with equal nitrogen inputs, three treatments were applied-conventional fertilizers, peanut-shell biochar, and hoggery biogas slurry-after which various soil quality indicators were compared. Compared with those of control, both biochar and biogas slurry increased the soil total nitrogen and organic matter content, and improved soil aggregation, microbial biomass, and actinomycetes. Biogas slurry decreased soil pH and improved urease and protease activities. With biochar and biogas slurry treatments, wheat yield increased by 8.46% and 23.47%, and maize yield by 18% and 15.46%, respectively. Biogas slurry increased the content of crude protein and starch in the grains. Both biogas slurry and peanut-shell biochar improved fluvo-aquic soil nutrient content, water-stable macroaggregates, and microbial population, which might be related to their high nutrient content, large specific surface area, adsorption capacity, and functional groups. Biogas slurry generally exhibited stronger effects than biochar probably because of its richness in nutrients and bioactive substances.


Analysis of herpes simplex virus low molecular-weight native proteins by polyacrylamide gel electrofocusing.
This communication has demonstrated the potential application of gel electrofocusing for the isolation and further characterization of HSV-2 native proteins. At least eight major HSV-2 specific proteins with characteristic isoelectric points could be reproducibly resolved by gel isoelectric focusing. Their isoelectric points ranged from 5.0 to 7.5 and analysis by two-dimensional electrophoresis on SDS gels indicated that their molecular weights range from 11,000 to 49,000.


Posterior Mandibular Ridge Resorption Associated with Different Retentive Systems for Overdentures: A 7-Year Retrospective Preliminary Study.
This retrospective study compared posterior mandibular residual ridge resorption with two different retentive mechanisms for overdentures after 7 years. A convenience sample of 18 edentulous men was assigned to one of two equal groups. Two implants were placed in the mandibular canine areas for each patient using the conventional two-stage surgical protocol, and the implants were splinted with a round bar 3 months later. New mandibular overdentures were then connected to the bars with clips (clip-retained overdentures, CR group) or resilient liners (resilient liner-retained overdentures, RR group). Posterior mandibular ridge resorption (PMRR) was recorded using proportional measurements and posterior area index (PAI) on panoramic radiographs taken immediately after overdenture insertion (T0) and 7 years later (T7). A linear regression model was used to verify the relationship between PAI and the following considerations: attachment type, age, initial mandibular ridge height, period of mandibular edentulism, number of previously worn dentures, and relining events. After 7 years, the RR group demonstrated a significantly (P = .014) higher change in PAI (0.11 ± 0.02) than the CR group (0.06 ± 0.04). The average PMRR for each mm of posterior mandibular ridge was 0.79 mm (0.11 mm/year) in the CR group and 1.4 mm (0.2 mm/year) in the RR group. Attachment type, initial mandibular ridge height, and relining times were significantly correlated with change in the PAI (P = .004, P = .035, and P = .045, respectively). Within the limitations of this preliminary study's design, it was observed that following a 7-year period of use, resilient liner attachments for bar/implant-retained overdentures appear to be associated with greater posterior mandibular ridge resorption when compared to clip attachments.


A systematic review of opioid use and multimodal strategies in solid organ transplant recipients and living donors.
The opioid epidemic has impacted analgesia in the postoperative period for solid organ transplant (SOT) donors and recipients. However, optimal pain management and opioid stewardship strategies have not been identified across this unique population. The purpose of this systematic review was to evaluate the impact of perioperative opioid use and to describe multimodal analgesic strategies to reduce opiate use in SOT recipients and living donors. A systematic review was conducted. Electronic searches were performed in Medline, Embase, Google Scholar, and Web of Science through December 31, 2021. Title and abstracts were screened. Relevant articles underwent full-text review. Literature was separated into effects of opioid exposure on post-transplant outcomes, recipient pain management strategies, and living donor pain management strategies. Search yielded 25,190 records, and 63 were ultimately included. The impact of opioid use on post-transplant outcomes was assessed in 19 publications. The risk of graft loss in pretransplant opioid users was assessed in six reports and was found to be higher in the majority (66%) of publications. Opioid minimization strategies were reported in 20 studies in transplant recipients. Twenty-four studies evaluated pain management strategies in living donors. Both populations used a combination of multimodal strategies to minimize opioid use throughout the hospitalization and on discharge. Opioids are associated with select negative outcomes in post-transplant recipients. To minimize their use while also maintaining appropriate analgesia, multimodal pain regimens should be considered in SOT recipients and donors.


High frequency current effects during transurethral resection.
Transurethral resection has been simulated electrically to detect the current pathways and locations of heat production inside the patient. Different electrical behavior was noted with instruments using electrically insulated or metal sheaths. Conductive lubricating jelly should be used with the metal sheath and non-conducting jelly should be used with the insulated sheath.


Association of the single nucleotide polymorphism in chromosome 9p21 and chromosome 9q33 with coronary artery disease in Chinese population.
Our study aims to explore the association of rs7025486 single-nucleotide polymorphisms (SNP) in DAB2IP and rs1333049 on chromosome 9p21.3 with the coronary artery disease in Chinese population. All patients came from the east China area and underwent coronary angiography. Rs7025486 and rs1333049 polymorphism were genotyped in 555 patients with CAD and in 480 healthy controls that underwent coronary angiography. In Chinese population, the rs7025486 genotype in the case group was no significant different than the control group (P = 0.531).Meanwhile, the rs1333049 SNP has statistically significant (P = 0.006), which was the independent risk factors for CAD (OR1.252, P = 0.039), and consistent with the past studies conclusion. Genotype of rs1333049 on chromosome 9p21, but not rs7025486 on chromosome 9q33, is an independent determinant of the incidence of CAD in Chinese population.


Blood component utilization in COVID-19 patients in New York City: Transfusions do not follow the curve.
Blood suppliers and transfusion services have worked diligently to maintain an adequate blood supply during the COVID-19 pandemic. Our experience has shown that some COVID-19 inpatients require transfusion support; understanding this need is critical to blood product inventory management. Hospital-wide and COVID-19 specific inpatient blood product utilization data were collected retrospectively for our network's two tertiary academic medical centers over a 9-week period (March 1, 2020-May 2, 2020), when most inpatients had COVID-19. Utilization data were merged with a COVID-19 patient database to investigate clinical demographic characteristics of transfused COVID-19 inpatients relative to non-transfused ones. Overall, 11 041 COVID-19 patients were admitted and 364 received blood product transfusions for an overall transfusion rate of 3.3%. COVID-19 patients received 1746 blood components in total, the majority of which were red blood cells. COVID-19 patients' weekly transfusion rate increased as the pandemic progressed, possibly reflecting their increased severity of illness. Transfusion was significantly associated with several indicators of severe disease, including mortality, intubation, thrombosis, longer hospital admission, lower hemoglobin and platelet nadirs, and longer prothrombin and activated partial thromboplastin times. As the pandemic progressed, institutional adherence to transfusion guidelines improved for RBC transfusions compared to prior year trends but did not improve for platelets or plasma. There is a need to closely monitor the blood product inventory and demand throughout the COVID-19 pandemic as patients' transfusion needs may increase over time. Daily or weekly trending of patients' clinical status and laboratory values may assist blood banks in inventory management.


Managing menstruation in the workplace: an overlooked issue in low- and middle-income countries.
The potential menstrual hygiene management barriers faced by adolescent girls and women in workplace environments in low- and middle-income countries has been under addressed in research, programming and policy. Despite global efforts to reduce poverty among women in such contexts, there has been insufficient attention to the water and sanitation related barriers, specifically in relation to managing monthly menstruation, that may hinder girls' and women's contributions to the workplace, and their health and wellbeing. There is an urgent need to document the specific social and environmental barriers they may be facing in relation to menstrual management, to conduct a costing of the implications of inadequate supportive workplace environments for menstrual hygiene management, and to understand the implications for girls' and women's health and wellbeing. This will provide essential evidence for guiding national policy makers, the private sector, donors and activists focused on advancing girls' and women's rights.


Effects of G2 treatments with inhibitors of DNA synthesis and repair on chromosome damage induced by X-rays and chemical clastogens in root tips of Vicia faba. Comparison with corresponding effects in cultured human lymphocytes.
The frequencies of chromatid aberrations produced in roots of Vicia faba by clastogenic (chromosome-damaging) agents were strongly enhanced by exposing the root-tip cells to inhibitors of DNA synthesis during the G2 phase. Chromosome damage produced by both S-dependent (maleic hydrazide, methyl methanesulfonate, thio-TEPA) and S-independent (X-rays, streptonigrin) mechanisms was enhanced by the inhibitor treatments. The types of aberrations affected by the inhibitors were mainly chromatid gaps and breaks and isochromatid breaks of the non-union type. Most effective among the inhibitors tested were hydroxyurea (HU) and 5-fluorodeoxyuridine (FdUrd). Post-treatments with caffeine were effective in enhancing clastogen-induced chromosome damage when given during the S phase. All types of aberrations, exchanges as well as breaks, were enhanced by the post-treatments. When given during the G2 phase, caffeine enhanced only the frequency of chromatid aberrations produced by X-rays. The enhancement was slight and obtained only when the cells were irradiated in the G2 phase and immediately post-treated with caffeine. Clastogen-treated cultures of human lymphocytes responded to post-treatments with inhibitors of DNA synthesis in very much the same way as clastogen-treated root-tip cells of Vicia faba. Thus, the frequencies of chromatid gaps and breaks and isochromatid breaks of the non-union type were strongly enhanced by exposing clastogen-treated lymphocytes to inhibitors of DNA synthesis during the G2 phase. The efficiency of the inhibitors, however, varied considerably in the two materials. On the whole, the number of inhibitors capable of enhancing induced chromosome damage was much larger in lymphocytes than in bean root tips. Only HU was equally effective in both materials. The most striking difference between the two materials was found when caffeine was given as a post-treatment. Thus, in human lymphocytes the frequencies of chromatid aberrations induced by most clastogenic agents were strongly enhanced when caffeine was given during the G2 phase, but little affected by post-treatments with caffeine during the S phase.


Loop-Mediated Isothermal Amplification-Based Microfluidic Platforms for the Detection of Viral Infections.
Easy-to-use, fast, and accurate virus detection method is essential for patient management and epidemic surveillance, especially during severe pandemics. Loop-mediated isothermal amplification (LAMP) on a microfluidic platform is suitable for detecting infectious viruses, regardless of the availability of medical resources. The purpose of this review is to introduce LAMP-based microfluidic devices for virus detection, including their detection principles, methods, and application. Facing the uncontrolled spread of viruses, the large-scale deployment of LAMP-based microfluidic platforms at the grassroots level can help expand the coverage of nucleic acid testing and shorten the time to obtain test reports. Microfluidic chip technology is highly integrated and miniaturized, enabling precise fluid control for effective virus detection. Performing LAMP on miniaturized systems can reduce analysis time, reagent consumption and risk of sample contamination, and improve analytical performance. Compared to traditional benchtop protocols, LAMP-based microfluidic devices reduce the testing time, reagent consumption, and the risk of sample contamination. In addition to simultaneous detection of multiple target genes by special channel design, microfluidic chips can also integrate digital LAMP to achieve absolute quantification of target genes.


Nanocompartment-confined polymerization in living systems.
Polymerization in living systems has become an effective strategy to regulate cell functions and behavior. However, the requirement of high concentrations of monomers, the existence of complicated intracorporal interferences, and the demand for extra external stimulations hinder their further biological applications. Herein, a nanocompartment-confined strategy that provides a confined and secluded environment for monomer enrichment and isolation is developed to achieve high polymerization efficiency, reduce the interference from external environment, and realize broad-spectrum polymerizations in living systems. For exogenous photopolymerization, the light-mediated free-radical polymerization of sodium 4-styrenesulfonate induces a 2.7-fold increase in the reaction rate with the protection of a confined environment. For endogenous hydrogen peroxide-responsive polymerization, p‑aminodiphenylamine hydrochloride embedded in a nanocompartment not only performs a 6.4-fold higher reaction rate than that of free monomers, but also activates an effective second near-infrared photoacoustic imaging-guided photothermal immunotherapy at tumor sites. This nanocompartment-confined strategy breaks the shackles of conventional polymerization, providing a universal platform for in vivo synthesis of polymers with diverse structures and functions.


Follow-up of 30 pregnancies after embryo cryopreservation.
In an observational follow-up study, the pregnancy outcome of the first 30 women who conceived after transfer of cryopreserved embryos was evaluated. The main outcome measures were duration and complications of pregnancy, mode of delivery, complications during and after childbirth, birthweight, Apgar score, and congenital anomalies. Twenty-six pregnancies ended in birth of one (n = 22) or more (n = 4) infants with a cesarean section rate of 23%. Of the singleton pregnancies 77% were uncomplicated, but there was a high incidence of breech presentation (14%). Infant birthweight tended to be above average with 45% of singletons weighing more than the 75th centile of weight for gestation. There were no major congenital deformations. The results of our embryo cryopreservation program are encouraging, but sustained follow-up of such pregnancies and infants is needed.