Undue inducement: a case study in CAPRISA 008.
: Participant safety and data integrity, critical in trials of new investigational drugs, are achieved through honest participant report and precision in the conduct of procedures. HIV prevention post-trial access studies in middle-income countries potentially offer participants many benefits including access to proven efficacious but unlicensed technologies, ancillary care that often exceeds local standards-of-care, financial reimbursement for participation and possibly unintended benefits if participants choose to share or sell investigational drugs. This case study examines the possibility that this combination of benefits may constitute an undue inducement for some participants in middle-income countries, where economic challenges are prevalent. A case study is presented of a single participant in a cohort of 382 participants who used concealment, fabrication and deception to ensure eligibility for a post-trial access study of an unlicensed HIV prevention technology at potential risk to her health and that of her fetus. A root cause analysis revealed her desire to access HIV prevention during an unplanned pregnancy with a partner whose faithfulness was in question. Researchers should consider implementation of systems to efficiently identify similar cases without inconveniencing the majority of participants TRIAL REGISTRATION NUMBER: NCT01691768.


The Mycobacterium tuberculosis high-affinity iron importer, IrtA, contains an FAD-binding domain.
Iron is an essential nutrient not freely available to microorganisms infecting mammals. To overcome iron deficiency, bacteria have evolved various strategies including the synthesis and secretion of high-affinity iron chelators known as siderophores. The siderophores produced and secreted by Mycobacterium tuberculosis, exomycobactins, compete for iron with host iron-binding proteins and, together with the iron-regulated ABC transporter IrtAB, are required for the survival of M. tuberculosis in iron deficient conditions and for normal replication in macrophages and in mice. This study further characterizes the role of IrtAB in M. tuberculosis iron acquisition. Our results demonstrate a role for IrtAB in iron import and show that the amino terminus domain of IrtA is a flavin-adenine dinucleotide-binding domain essential for iron acquisition. These results suggest a model in which the amino terminus of IrtA functions to couple iron transport and assimilation.


Special health care needs among children in the child welfare system.
The aim of this study was to determine levels of special health care need among children in the child welfare system and how these needs may affect children's functioning. Data were from the National Survey of Child and Adolescent Well-being, a national probability study of children investigated for child maltreatment. The sample consisted of 5496 children aged 0 to 15 years at baseline. For analysis, we used descriptive statistics to determine special health care needs and children's functioning from baseline to 3-year follow-up. Logistic regression was used to examine correlates of special health care needs. At any point in the study period, approximately one third of the children were identified as having special health care needs. Overall, across 3 years of follow-up data, 50.3% of the children were identified as having special health care needs. Boys were significantly more likely than girls to have had special health care needs, and children aged 0 to 2 years at baseline were significantly less likely to have had special health care needs than older children. Adopted and foster children were significantly more likely to have had special health care needs than children never placed out of the home. The most commonly reported type of chronic health condition was asthma. The most commonly reported type of special need was a learning disability. Special health care needs are prevalent among children in the child welfare system. Many children with special health care needs have cognitive, language, adaptive, social, or behavioral functional impairments. Mechanisms are needed to ensure that this vulnerable population has access to and receives coordinated health and related social services.


Mapping of insertion mutations in gnd of Escherichia coli with deletions defining the ends of the gene.
A genetic map was prepared for gnd, the gene of Escherichia coli which encodes the metabolically regulated 6-phosphogluconate dehydrogenase. Direct selection methods were used for the isolation of mutants with deletions that define the respective ends of gnd. These selections depended on the availability of a defective lysogen in which gnd was present on a lambda h80 dgnd his prophage located at the att phi 80 region of the chromosome. Mutants with deletions entering gnd from the his-distal end were selected as Gnd- TonB- mutants. Mutants with his-proximal gnd deletions were selected as Gnd-, temperature-resistant mutants of a specially prepared stable lysogen. Gnd- mutants were also isolated after mutagenesis with bacteriophage Mu cts61, and genetic tests were used to determine which mutants carry a Mu cts61 prophage in gnd. The deletion mutations were mapped against each other and against the insertion mutations through the use of F' merodiploid strains. The insertion mutations mapped at seven distinct sites in gnd; three mapped under the deletions defining the his-proximal portion of the gene and three mapped with the his-distal deletions.


Ethinyl estradiol and conjugated estrogens as postcoital contraceptives.
Five study centers enrolled 1,311 women seeking postcoital contraception methods. Ethinyl estradiol was administered at 5 mg/day and conjugated estrogens at 30 mg/day for five consecutive days starting within 72 hours of unprotected coitus. Eleven pregnancies occurred in the 976 women who had a single unprotected coitus at midcycle. Based on published information, 69 pregnancies would have been expected if no contraceptives were used. Although both treatments were effective in preventing pregnancy, ethinyl estradiol seemed to be more effective. At the two centers alternately prescribing both drugs, none of 137 women treated with ethinyl estradiol became pregnant, while six of the 132 given conjugated estrogens became pregnant. Women whose treatment commenced on the first postcoital day seemed to have lower pregnancy rates than those whose medication was delayed to the second or third postcoital day regardless of which drug was used. Side effects were mainly limited to nausea that occurred in 70% and vomiting that was experienced by 33% of all women treated.


Comparison of the effects of CORM-2, CORM-3 and CORM-A1 on coagulation in human plasma.
Carbon monoxide derived from the catalytic action of heme oxygenase-1 or carbon monoxide-releasing molecules (CORMs) has been found to potentially be an anticoagulant or procoagulant agent. Of interest, two water-soluble CORMs, CORM-3 and CORM-A1, recently became commercially available. Thus, the purpose of the present study was to assess and compare the effects of the previously well studied CORM-2 to the effects of CORM-3 and CORM-A1 on coagulation in citrated human plasma with thrombelastography. Plasma exposed to CORMs was incubated at 37°C for at least one carbon monoxide release half-time, and then tissue factor-activated coagulation was commenced with calcium addition. CORM-2 and CORM-3 enhanced the velocity of clot formation and thrombus strength in a similar manner, whereas CORM-A1 did not affect coagulation. However, CORM-A1 did diminish tissue-type plasminogen activator initiated fibrinolysis. The similarity in effect on coagulation by CORM-2 and CORM-3 was likely secondary to the relatively inert effect of their ruthenium-containing carrier molecule, whereas the boron-containing CORM-A1 may have had no effect secondary to boron binding to fibrinogen, preventing carbon monoxide-mediated changes in fibrinogen protein structure via attached heme group(s). Future investigations with CORMs should have special attention to confounding effects of the carrier molecule.


Effects of dietary camelina, flaxseed, and canola oil supplementation on plasma fatty acid concentrations and health parameters in horses.
Camelina (Camelina sativa) is a hardy, low-input oilseed crop that provides a rich source of the n-3 fatty acid, α-linolenic acid (ALA). The primary purpose of the present study was to assess the effects of dietary camelina oil (CAM) consumption on various health parameters, as compared to horses fed canola oil (OLA) or flax oil (FLX). Secondly, to determine how dietary CAM, FLX, and OLA alter circulating plasma total lipids across time. Thirty horses, from three separate herds, were used for this study [14.9 years ± 5.3 years; 544 ± 66 kg calculated BW (mean ± SD)]. After a 4-week gradual acclimation period using sunflower oil mixed with soaked hay cubes, horses were balanced by location, age, sex, weight, and breed and randomly allocated to one of three treatment oils (CAM, OLA, or FLX) at an inclusion of 370 mg of oil/kg BW/day. Horses had ad libitum access to hay and/or pasture for the duration of the study. Body condition score (BCS), BW, oil intake, complete blood counts, plasma biochemical profiles, and plasma total lipids were measured on weeks 0, 2, 4, 8, and 16 throughout the 16-week treatment period. BW, BCS, and oil intake were analyzed using an ANOVA using PROC GLIMMIX in SAS Studio. Complete blood counts and biochemical profiles were analyzed using an ANCOVA, and fatty acids were analyzed using an ANOVA in PROC MIXED in SAS Studio. No differences were observed among treatment groups for BW, BCS, oil intake, complete blood counts, and biochemical parameters. Individual fatty acids that differed among treatments and/or across time were largely reflective of the different FA profiles of the oils provided. Most notably, plasma ALA was greater for FLX than OLA, but neither differed from CAM (P = 0.01). Linoleic acid did not differ among treatments or over time (P > 0.05). The n-6:n-3 ratio decreased over time for both CAM and FLX, and ratios were lower for FLX than OLA at week 16, but not different from CAM (P = 0.02). These results suggest that dietary CAM had no adverse effects on health parameters and that daily supplementation of CAM and FLX at 370 mg of oil/kg BW/day induces positive changes (a decrease) in the n-6:n-3 status of the horse. Consequently, CAM may be considered as an alternative oil to FLX in equine diets.


An Online Intervention for Co-Occurring Depression and Problematic Alcohol Use in Young People: Primary Outcomes From a Randomized Controlled Trial.
Depression and problematic alcohol use represent two of the major causes of disease burden in young adults. These conditions frequently co-occur and this is associated with increased harm and poorer outcomes than either disorder in isolation. Integrated treatments have been shown to be effective; however, there remains a significant gap between those in need of treatment and those receiving it. The increased availability of eHealth programs presents a unique opportunity to treat these conditions. This study aimed to evaluate the feasibility and preliminary efficacy of an automated Web-based self-help intervention (DEAL Project) in treating co-occurring depressive symptoms and problematic alcohol use in young people. Young people (aged 18 to 25 years) with moderate depression symptoms and drinking at hazardous levels (recruited largely via social media) were randomly allocated to the DEAL Project (n=60) or a Web-based attention-control condition (HealthWatch; n=44). The trial consisted of a 4-week intervention phase with follow-up assessment at posttreatment and at 3 and 6 months postbaseline. The primary outcomes were change in depression severity according to the Patient Health Questionnaire-9 as well as quantity and frequency of alcohol use (TOT-AL). The DEAL Project was associated with statistically significant improvement in depression symptom severity (d=0.71) and reductions in alcohol use quantity (d=0.99) and frequency (d=0.76) in the short term compared to the control group. At 6-month follow-up, the improvements in the intervention group were maintained; however, the differences between the intervention and control groups were no longer statistically significant, such that between-group effects were in the small to moderate range at 6 months (depression symptoms: d=0.39; alcohol quantity: d=-0.09; alcohol frequency: d=0.24). Overall, the DEAL Project was associated with more rapid improvement in both depression symptoms and alcohol use outcomes in young people with these co-occurring conditions relative to an attention-control condition. However, long-term outcomes are less clear. Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000033741; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363461 (Archived by WebCite at http://www.webcitation.org/6fpsLEGOy).


Nanoscale structural response of biomimetic cell membranes to controlled dehydration.
Although cell membranes exist in excess of water under physiological conditions, there are a number of biochemical processes, such as adsorption of biomacromolecules or membrane fusion events, that require partial or even complete transient dehydration of lipid membranes. Even though the dehydration process is crucial for understanding all fusion events, still little is known about the structural adaptation of lipid membranes when their interfacial hydration layer is perturbed. Here, we present the study of the nanoscale structural reorganization of phase-separated, supported lipid bilayers (SLBs) under a wide range of hydration conditions. Model lipid membranes were characterised using a combination of fluorescence microscopy and atomic force microscopy and, crucially, without applying any chemical or physical modifications that have previously been considered essential for maintaining the membrane integrity upon dehydration. We revealed that decreasing the hydration state of the membrane leads to an enhanced mixing of lipids characteristic of the liquid-disordered (Ld) phase with those forming the liquid-ordered (Lo) phase. This is associated with a 2-fold decrease in the hydrophobic mismatch between the Ld and Lo lipid phases and a 3-fold decrease in the line tension for the fully desiccated membrane. Importantly, the observed changes in the hydrophobic mismatch, line tension, and lipid miscibility are fully reversible upon subsequent rehydration of the membrane. These findings provide a deeper insight into the fundamental processes, such as cell-cell fusion, that require partial dehydration at the interface of two membranes.


[Psychosomatic aspects in otorhinolaryngology exemplified by the "globus" sensation].
The term "psychosomatic" is defined by means of the "globe" sign in its clinical use. Psychosomatic anamnesis is introduced as a mode to establish the somatic and psychic status. In this diagnostic therapeutic process the psychosomatically oriented ENT specialist assesses the pattern of these frequent psychophysical disturbances. The therapy of psychosomatic disorders is based on the multiplex aetiology of these diseases; therefore, psychosocial factors of distress must be considered with the same attention as the somatic signs and symptoms. To meet this challenge the specialist has to consider the therapeutic dialogue, psychodynamics and distress coping, effective relaxation techniques and the use of psychotropic drugs.


Reprogramming cooperative monotone dynamical systems.
Multistable dynamical systems are ubiquitous in nature, especially in the context of regulatory networks controlling cell fate decisions, wherein stable steady states correspond to different cell phenotypes. In the past decade, it has become experimentally possible to "reprogram" the fate of a cell by suitable externally imposed input stimulations. In several of these reprogramming instances, the underlying regulatory network has a known structure and often it falls in the class of cooperative monotone dynamical systems. In this paper, we therefore leverage this structure to provide concrete guidance on the choice of inputs that reprogram a cooperative dynamical system to a desired target steady state. Our results are parameter-independent and therefore can serve as a practical guidance to cell-fate reprogramming experiments.


Epidemiological evidence relating snus to health--an updated review based on recent publications.
An earlier review summarized evidence relating use of snus (Swedish-type moist snuff) to health and to initiation and cessation of smoking. This update considers the effect recent publications on snus use and health have on the overall evidence. The additional evidence extends the list of neoplastic conditions unassociated with snus use (oropharynx, oesophagus, stomach, lung) to include colorectal cancer and acoustic neuroma, and further undermines the weakly-based argument that snus use increases the risk of pancreatic cancer, although there is a report of poorer cancer survival in users. It remains undemonstrated that "snuff-dipper's lesion" increases risk of oral cancer, and recent publications add to the evidence that snus use has no effect on periodontitis or dental caries. Although onset of acute myocardial infarction is not adversely associated with snus use, there is some evidence of an association with reduced survival. Whether this is a direct effect of snus use or a result of confounding by socioeconomic status or other factors requires further investigation, as does a report of an increased risk of heart failure in snus users. Even if some adverse health effects of snus use do exist, it remains clear that they are far less than those of smoking.


Development and survival of immature Aedes albopictus and Aedes triseriatus (Diptera: Culicidae) in the laboratory: effects of density, food, and competition on response to temperature.
Effects of food, density, and heterospecific interactions on temperature-dependent development of Aedes albopictus (Skuse) and Aedes triseriatus (Say) larvae and pupae were described using a degree-day model. Under all conditions, the predicted number of degree-days (DD(T0)) to complete larval development was less, and the threshold temperature (T0) for initiation of larval development was higher for Ae. albopictus than for Ae. triseriatus. The DD(T0) for both species was food and density dependent. However, the per capita food ration appeared to exert a greater influence on the developmental times of Ae. triseriatus immatures, whereas for Ae. albopictus effects of density were not completely eliminated by an increase in the per capita food ration. The presence of heterospecific larvae did not prolong the DD(T0) of either species. At the low food ration, DD(T0) for both species were significantly greater under conspecific conditions. The DD(T0) for Ae. triseriatus increased directly as the proportion of conspecific larvae increased. However, when a higher per capita food ration was provided, conspecific effects on DD(T0) were mitigated. For Ae. albopictus, estimated DD(T0) values for larvae reared in pure culture were significantly higher than when heterospecific larvae were present, regardless of the per capita amount of food provided. Survivorship of immatures was density and food-dependent for both species. Ae. albopictus exhibited higher immature survivorship under all conditions relative to Ae. triseriatus. For both species, survival probabilities were lowest under conditions of high density and low food. Addition of food improved survival for both species. The presence of heterospecific larvae exerted a differential effect on the survivorship response of Ae. albopictus immatures to temperature. Lowest probability of survival for Ae. albopictus was occurred at low temperature when the proportion of heterospecific larvae in containers was the highest. In contrast, at high temperatures, survivorship of immatures improved, but was lowest for pure species cultures. For Ae. triseriatus, survivorship of immatures was consistently lower for pure species cultures regardless of the temperature. Standing crop production of adults of both species was primarily food rather that density-dependent. Under field conditions, Ae. triseriatus were predicted to initiate development sooner and exhibit faster population growth early in the season than Ae. albopictus. However, because of the shorter DD(T0), Ae. albopictus population growth was predicted to surpass that of Ae. triseriatus populations later in the season. Based on optimal DD(T0) values from laboratory experiments, spring emergence dates of Ae. triseriatus females in western North Carolina for 1989 and 1990 were predicted from accumulated degree-days calculated from local air temperature records. Predicted emergence dates were congruent with results of a previous survey for the same locality, indicating that accumulated degree-days can be used to accurately predict the seasonal occurrence of Ae. triseriatus. The utility of the degree-day approach in predicting the phenology of Ae. albopictus remains to be established.


Negative Affect-Associated USV Acoustic Characteristics Predict Future Excessive Alcohol Drinking and Alcohol Avoidance in Male P and NP Rats.
Negative emotional status and adverse emotional events increase vulnerability to alcohol abuse. Ultrasonic vocalizations (USVs) emitted by rats are a well-established model of emotional status that can reflect positive or negative affective responses in real time. Most USV studies assess counts, yet each USV is a multidimensional data point characterized by several acoustic characteristics that may provide insight into the neurocircuitry underlying emotional response. USVs emitted from selectively bred alcohol-naïve and alcohol-experienced alcohol-preferring and nonpreferring rats (P and NP rats) were recorded during 4-hour sessions on alternating days over 4 weeks. Linear mixed modeling (LMM) and linear discriminant analysis (LDA) were applied to USV acoustic characteristics (e.g., frequency, duration, power, and bandwidth) of negative affect (22 to 28 kilohertz [kHz])- and positive (50 to 55 kHz) affect-related USVs. Hundred percent separation between alcohol-naïve P and NP rats was achieved through a linear combination (produced by LDA) of USV acoustic characteristics of 22- to 28-kHz USVs, whereas poor separation (36.5%) was observed for 50- to 55-kHz USVs. 22- to 28-kHz LDA separation was high (87%) between alcohol-experienced P and NP rats, but was poor for 50- to 55-kHz USVs (57.3%). USV mean frequency and duration were the highest weighted characteristics in both the naïve and experienced 22- to 28-kHz LDA representations suggesting that alcohol experience does not alter the representations. LMM analyses of 22- to 28-kHz USV acoustic characteristics matched the LDA results. Poor LDA separation was observed between alcohol-naïve and alcohol-experienced P rats for both 22- to 28-kHz and 50- to 55-kHz USVs. Advanced statistical analysis of negative affect-associated USV data predicts future behaviors of excessive alcohol drinking and alcohol avoidance in selectively bred rats. USV characteristics across rat lines reveal affect-related motivation to consume alcohol and may predict neural pathways mediating emotional response. Further characterization of these differences could delineate particular neurocircuitry and methods to ameliorate dysregulated emotional states often observed in human alcohol abusers.


False economies in home-based parenteral antibiotic treatment: a health-economic case study of management of lower-limb cellulitis in Australia.
The majority of healthcare costs accrued managing cellulitis can be attributed to the small proportion of patients treated with parenteral antibiotics. Hospital in the home (HITH) instead of or following initial inpatient treatment is a safe and effective alternative, but there are few data evaluating its cost-effectiveness for cellulitis. Our retrospective cohort study included all treatment episodes (by either HITH or an inpatient service for >24 h) with an ICD-10 primary diagnosis code of lower-leg cellulitis at a tertiary-level health service in Melbourne, Australia over 12 months (2012-13). Data included demography, social factors and ICD-10 codes mapped to major comorbidities constituting the Charlson comorbidity index (CCI). Differences in length of stay (LOS) and individual clinical costing (ICC) between HITH- and non-HITH-treated patients were tested with univariable and multivariable (generalized linear model) analyses. For 328 admissions in 294 patients, the average per-day costs were AU$431 for HITH and AU$761 for inpatient care. For 124 patients (38%) treated in HITH, both LOS [mean (95% CI) 7.48 days (6.76-8.20 days) versus 5.82 days (3.45-8.18 days)] and ICC [mean (95% CI) AU$5873 (AU$5212-AU$6534) versus AU$5196 (AU$4567- AU$5824)] were higher than those for patients with solely inpatient care. In multivariable analysis controlling for age, comorbidity, carer support and language, HITH remained associated with significantly longer LOS [1.63-fold (95% CI: 1.24- to 2.13-fold): P < 0.001] and non-significantly with higher cost [1.14-fold (95% CI: 0.97- to 1.34-fold): P = 0.11]. Management of cellulitis represents a substantial cost burden for hospital services. Modest per-day cost savings from HITH can be offset by much longer HITH LOS.


Current status of hepatocyte transplantation.
Hepatocyte transplantation (HT) has been performed in patients with liver-based metabolic disease and acute liver failure as a potential alternative to liver transplantation. The results are encouraging in genetic liver conditions where HT can replace the missing enzyme or protein. However, there are limitations to the technique, which need to be overcome. Unused donor livers to isolate hepatocytes are in short supply and are often steatotic, although addition of N-acetylcysteine improves the quality of the cells obtained. Hepatocytes are cryopreserved for later use and this is detrimental to metabolic function on thawing. There are improved cryopreservation protocols, but these need further refinement. Hepatocytes are usually infused into the hepatic portal vein with many cells rapidly cleared by the innate immune system, which needs to be prevented. It is difficult to detect engraftment of donor cells in the liver, and methods to track cells labeled with iron oxide magnetic resonance imaging contrast agents are being developed. Methods to increase cell engraftment based on portal embolization or irradiation of the liver are being assessed for clinical application. Encapsulation of hepatocytes allows cells to be transplanted intraperitoneally in acute liver failure with the advantage of avoiding immunosuppression. Alternative sources of hepatocytes, which could be derived from stem cells, are needed. Mesenchymal stem cells are currently being investigated particularly for their hepatotropic effects. Other sources of cells may be better if the potential for tumor formation can be avoided. With a greater supply of hepatocytes, wider use of HT and evaluation in different liver conditions should be possible.


Magnetic resonance enterography in Crohn's disease: Standard and advanced techniques.
Crohn's disease (CD) is a chronic autoimmune disorder that affects mainly young people. The clinical management is based on the Crohn's Disease Activity Index and especially on biologic parameters with or without additional endoscopic and imaging procedures, such as barium and computed tomography examinations. Recently, magnetic resonance (MR) imaging has been a promising diagnostic radiologic technique with lack of ionizing radiation, enabling superior tissue contrast resolution due to new pulse-sequence developments. Therefore, MR enterography has the potential to become the modality of choice for imaging the small bowel in CD patients.


An integrated multipurpose lesion-making electrode.
Although excellent results are reported from centers using microelectrode mapping during stereotactic pallidotomy, the recording methods used are time-consuming and technically cumbersome. We sought to develop a new electrode concept that may, when eventually applied in clinical practice, improve the efficiency and safety of microelectrode-guided functional neurosurgical procedures. The scout electrode uses a recently developed research technique for simultaneously obtaining multiple microelectrode recordings along the shaft of a macroelectrode. By positioning recording sites on either side of a lesion-making contact, it is possible to functionally "scout" the brain tissue surrounding the proposed lesion site, thus eliminating the need for serial movements and electrode interchanges. The feasibility of the scout electrode concept was tested using prototypes placed into cat medial geniculate nucleus. High-quality unit recordings were simultaneously obtained from different regions within the medial geniculate nucleus. This ability to physiologically map sites above and below the lesion-making contact facilitated precise placement of radiofrequency lesions in the center of the medial geniculate nucleus. These results suggest that it may be possible to develop clinically useful devices based on this novel concept.


Lymphocele Containing Staphylococcus lugdunensis.
Staphylococcus species are a leading cause of community-acquired bacteremia. Of them, the most serious cause of mortality is from methicillin-resistant Staphylococcus aureus, with mortality rates as high as 40%. Another Staphylococcus species that has been noted to cause equal levels of infection and mortality is Staphylococcus lugdunensis (S. lugdunensis). It can cause harmless skin infections to life-threatening endocardial complications. We would like to report a rare presentation of S. lugdunensis bacteremia from a lymphocele that developed post surgery. An 80-year-old male presented to the emergency department with complaints of abdominal pain and fevers. Cultures of lymphocele fluid grew S. lugdunensis. A computed tomography of the abdomen and pelvis with contrast showed the presence of a large lymphocele. S. lugdunensis is a coagulase-negative staphylococci normally known to be a skin colonizer. Over the years, it has shown to cause a wide variety of infections especially involving prosthetic joints and heart valves. S. lugdunensis has been noted to be highly susceptible to penicillins, such as oxacillin, erythromycin, linezolid and a wide a variety of other antibiotics. S. lugdunensis produces a biofilm that makes treatment challenging even with susceptible antibiotics. However, the data on S. lugdunensis is growing as more case reports are being published in regards to source and susceptibilities.


Antibacterial activity of soil-isolated Bacillus altitudinis/pumilus complex against methicillin-resistant Staphylococcus aureus from Mwanza, Tanzania.
Antimicrobial resistance in methicillin-resistant Staphylococcus aureus and beta-lactamase-producing Gram-negative bacteria is a global health concern necessitating research and the development of effective antimicrobial agents. This study, conducted in May 2020 in Mwanza, Tanzania, aimed to determine the antibacterial activity of metabolites from soil-isolated Bacillus species against clinical bacterial pathogens. One soil-isolated Bacillus species, identified as Bacillus altitudinis/pumilus complex, showed antibacterial activity against Gram-positive cocci, including a methicillin-resistant S. aureus strain with inducible clindamycin resistance, previously isolated from a patient with osteomyelitis. Bacillus altitudinis/pumilus complex metabolites may be a potential source of antimicrobial agents against multidrug-resistant bacteria. The study supports existing research on the discovery and development of new antimicrobial agents against multi-drug-resistant bacteria. We report the antimicrobial activity of metabolites extracted from soil-isolated Bacillus altitudinis/pumilus complex strains against Gram-positive bacteria, including a methicillin-resistant Staphylococcus aureus strain with inducible clindamycin resistance.


Variation in CT use for paediatric head injuries across different types of emergency departments in Australia and New Zealand.
CT of the brain (CTB) for paediatric head injury is used less frequently at tertiary paediatric emergency departments (EDs) in Australia and New Zealand than in North America. In preparation for release of a national head injury guideline and given the high variation in CTB use found in North America, we aimed to assess variation in CTB use for paediatric head injury across hospitals types. Multicentre retrospective review of presentations to tertiary, urban/suburban and regional/rural EDs in Australia and New Zealand in 2016. Children aged <16 years, with a primary ED diagnosis of head injury were included and data extracted from 100 eligible cases per site. Primary outcome was CTB use adjusted for severity (Glasgow Coma Scale) with 95% CIs; secondary outcomes included hospital length of stay and admission rate. There were 3072 head injury presentations at 31 EDs: 9 tertiary (n=900), 11 urban/suburban (n=1072) and 11 regional/rural EDs (n=1100). The proportion of children with Glasgow Coma Score ≤13 was 1.3% in each type of hospital. Among all presentations, CTB was performed for 8.2% (95% CI 6.4 to 10.0) in tertiary hospitals, 6.6% (95% CI 5.1 to 8.1) in urban/suburban hospitals and 6.1% (95% CI 4.7 to 7.5) in regional/rural. Intragroup variation of CTB use ranged from 0% to 14%. The regional/rural hospitals admitted fewer patients (14.6%, 95% CI 12.6% to 16.9%, p<0.001) than tertiary and urban/suburban hospitals (28.1%, 95% CI 25.2% to 31.2%; 27.3%, 95% CI 24.7% to 30.1%). In Australia and New Zealand, there was no difference in CTB use for paediatric patients with head injuries across tertiary, urban/suburban and regional/rural EDs with similar intragroup variation. This information can inform a binational head injury guideline.


Paediatric cerebral sinovenous thrombosis: findings of the International Paediatric Stroke Study.
We evaluated clinical features, treatment practices and early outcome in a multicentre cohort of children with cerebral sinovenous thrombosis (CSVT). Children with CSVT from 10 countries were enrolled from January 2003 to July 2007 in the International Paediatric Stroke Study. We analysed clinical symptoms, underlying conditions, antithrombotic treatment and neurological outcome at hospital discharge in 170 children. Of 170 children enrolled, 60% were male; median age 7.2 years (IQR 2.9-12.4). Headache, altered consciousness, focal deficits and seizures were common presenting clinical features. Infarction affected 37% and intracranial haemorrhage 31%. Risk factors included chronic disease in 50%; acute systemic illness or head/neck disorders 41%; prothrombotic state 20% and other haematological abnormality 19%. Discharge neurological status was normal in 48%, abnormal in 43% and unknown in 5%. Antithrombotic therapy was common, most often low molecular weight heparin was common, with significant regional variation in treatment practices. Mortality was low (4%) and was associated with no anticoagulation but not underlying chronic disease, anatomic extent of thrombosis or intracranial haemorrhage. Abnormal neurological status at discharge or death was associated with decreased level of consciousness at presentation and the presence of an identified prothrombotic state. Our study extends the observations of previously published smaller studies in children with CSVT that this is a morbid disease with diverse underlying causes and risk factors. Divergent treatment practices among highly specialised centres as well as limited data on treatment efficacy and safety suggest that further study of this condition is warranted.


Antagonism of lidocaine inhibition by open-channel blockers that generate resurgent Na current.
Na channels that generate resurgent current express an intracellular endogenous open-channel blocking protein, whose rapid binding upon depolarization and unbinding upon repolarization minimizes fast and slow inactivation. Na channels also bind exogenous compounds, such as lidocaine, which functionally stabilize inactivation. Like the endogenous blocking protein, these use-dependent inhibitors bind most effectively at depolarized potentials, raising the question of how lidocaine-like compounds affect neurons with resurgent Na current. We therefore recorded lidocaine inhibition of voltage-clamped, tetrodotoxin-sensitive Na currents in mouse Purkinje neurons, which express a native blocking protein, and in mouse hippocampal CA3 pyramidal neurons with and without a peptide from the cytoplasmic tail of NaVβ4 (the β4 peptide), which mimics endogenous open-channel block. To control channel states during drug exposure, lidocaine was applied with rapid-solution exchange techniques during steps to specific voltages. Inhibition of Na currents by lidocaine was diminished by either the β4 peptide or the native blocking protein. In peptide-free CA3 cells, prolonging channel opening with a site-3 toxin, anemone toxin II, reduced lidocaine inhibition; this effect was largely occluded by open-channel blockers, suggesting that lidocaine binding is favored by inactivation but prevented by open-channel block. In constant 100 μm lidocaine, current-clamped Purkinje cells continued to fire spontaneously. Similarly, the β4 peptide reduced lidocaine-dependent suppression of spiking in CA3 neurons in slices. Thus, the open-channel blocking protein responsible for resurgent current acts as a natural antagonist of lidocaine. Neurons with resurgent current may therefore be less susceptible to use-dependent Na channel inhibitors used as local anesthetic, antiarrhythmic, and anticonvulsant drugs.


Types of alcohol use experience from childhood through adolescence.
There have been few reports of the development of alcohol involvement from childhood through adolescence. We examined the ages at which children first sipped or tasted alcohol, drank, had three or more drinks in a row, had five or more drinks in a row, were drunk, or had alcohol problems, to describe the types of drinking experience exhibited at each age from 8.5 through 18.0 years. Sipping and three or more drinks per occasion have been understudied to date. We collected 14 waves of longitudinal data from 452 children aged 8 or 10 years, randomly sampled from Allegheny County, Pennsylvania. Ages of initiating each alcohol use behavior were determined, and the data were coded to reflect the child's status on each behavior at each age. We determined types of alcohol use experience using latent class analyses. From age 8.5 to 12.5 years, there were two latent classes: abstainers and sippers. The percentage of sippers increased to 67% by age 12.5 years. From ages 13.0 to 18.0, we identified three latent classes: abstainers, sippers/light drinkers, and drinkers with drunkenness. At ages 13.5-15.5 years, drinkers in the latter class reported drunkenness with just three to four drinks per occasion. By age 18 years, sippers/light drinkers comprised 55% of the sample and drinkers with drunkenness comprised 38%. Childhood experience with alcohol was surprisingly widespread. Sipping or tasting alcohol was common by age 12 years. A quarter of the sample drank before age 15 years. Experience of intoxication increased throughout adolescence, even among those who had ever consumed just three to four drinks on an occasion.


Near-Infrared Emission CuInS/ZnS Quantum Dots: All-in-One Theranostic Nanomedicines with Intrinsic Fluorescence/Photoacoustic Imaging for Tumor Phototherapy.
Many theranostic nanomedicines (NMs) have been fabricated by packaging imaging and therapeutic moieties together. However, concerns about their potential architecture instability and pharmacokinetic complexity remain major obstacles to their clinical translation. Herein, we demonstrated the use of CuInS/ZnS quantum dots (ZCIS QDs) as "all-in-one" theranostic nanomedicines that possess intrinsic imaging and therapeutic capabilities within a well-defined nanostructure. ZCIS QDs were exploited for multispectral optical tomography (MSOT) imaging and synergistic PTT/PDT therapy. Due to the intrinsic fluorescence/MSOT imaging ability of the ZCIS QDs, their size-dependent distribution profiles were successfully visualized at tumor sites in vivo. Our results showed that the smaller nanomedicines (ZCIS NMs-25) have longer tumor retention times, higher tumor uptake, and deeper tumor penetration than the larger nanomedicines (ZCIS NMs-80). The ability of ZCIS QDs to mediate photoinduced tumor ablation was also explored. Our results verified that under a single 660 nm laser irradiation, the ZCIS NMs had simultaneous inherent photothermal and photodynamic effects, resulting in high therapy efficacy against tumors. In summary, the ZCIS QDs as "all-in-one" versatile nanomedicines allow high therapeutic efficacy as well as noninvasively monitoring tumor site localization profiles by imaging techniques and thus hold great potential as precision theranostic nanomedicines.


Interrogating genomes with combinatorial artificial transcription factor libraries: asking zinc finger questions.
Artificial transcription factors (ATFs) are proteins designed to specifically bind and regulate genes. Because of their DNA-binding selectivity and modular organization, arrays of zinc finger (ZF) domains have traditionally been used to build the ATF's DNA-binding domains. ATFs have been designed and constructed to regulate a variety of therapeutic targets. Recently, novel combinatorial technologies have been developed to induce expression of any gene of interest or to modify cellular phenotypes. Large repertoires of ATFs have been generated by recombination of all available sequence-specific ZF lexicons. These libraries comprise millions of ATFs with unique DNA-binding specificities. The ATFs are produced by combinatorial assembly of three- and six-ZF building blocks and are linked to activator or repressor domains. Upon delivery into a cell population, any gene in the human genome can potentially be regulated. ATF library members generate genome-wide, experimental perturbations of gene expression, resulting in a phenotypically diverse population, or cellular library. A variety of phenotypic screenings can be applied to select for cells exhibiting a phenotype of interest. The ATFs are then used as genetic probes to identify the targeted genes responsible for the phenotypic switch. In this review we will summarize several applications of ATF library screenings in gene discovery, biotechnology, and disease therapeutics.


Proof-of-concept recall-by-genotype study of extremely low and high Alzheimer's polygenic risk reveals autobiographical deficits and cingulate cortex correlates.
Genome-wide association studies demonstrate that Alzheimer's disease (AD) has a highly polygenic architecture, where thousands of independent genetic variants explain risk with high classification accuracy. This AD polygenic risk score (AD-PRS) has been previously linked to preclinical cognitive and neuroimaging features observed in asymptomatic individuals. However, shared variance between AD-PRS and neurocognitive features are small, suggesting limited preclinical utility. Here, we recruited sixteen clinically asymptomatic individuals (mean age 67; range 58-76) with either extremely low / high AD-PRS (defined as at least 2 standard deviations from the wider sample mean (N = 4504; N EFFECTIVE = 90)) with comparable age sex and education level. We assessed group differences in autobiographical memory and T1-weighted structural neuroimaging features. We observed marked reductions in autobiographical recollection (Cohen's d = - 1.66; P FDR = 0.014) and midline structure (cingulate) thickness (Cohen's d = - 1.55, P FDR = 0.05), with no difference in hippocampal volume (P > 0.3). We further confirm the negative association between AD-PRS and cingulate thickness in a larger study with a comparable age (N = 31,966, β = - 0.002, P = 0.011), supporting the validity of our approach. These observations conform with multiple streams of prior evidence suggesting alterations in cingulate structures may occur in individuals with higher AD genetic risk. We were able to use a genetically informed research design strategy that significantly improved the efficiency and power of the study. Thus, we further demonstrate that the recall-by-genotype of AD-PRS from wider samples is a promising approach for the detection, assessment, and intervention in specific individuals with increased AD genetic risk.


Fast and Robust Iterative Closest Point.
The iterative closest point (ICP) algorithm and its variants are a fundamental technique for rigid registration between two point sets, with wide applications in different areas from robotics to 3D reconstruction. The main drawbacks for ICP are its slow convergence, as well as its sensitivity to outliers, missing data, and partial overlaps. Recent work such as Sparse ICP achieves robustness via sparsity optimization at the cost of computational speed. In this paper, we propose a new method for robust registration with fast convergence. First, we show that the classical point-to-point ICP can be treated as a majorization-minimization (MM) algorithm, and propose an Anderson acceleration approach to speed up its convergence. In addition, we introduce a robust error metric based on the Welsch's function, which is minimized efficiently using the MM algorithm with Anderson acceleration. On challenging datasets with noises and partial overlaps, we achieve similar or better accuracy than Sparse ICP while being at least an order of magnitude faster. Finally, we extend the robust formulation to point-to-plane ICP, and solve the resulting problem using a similar Anderson-accelerated MM strategy. Our robust ICP methods improve the registration accuracy on benchmark datasets while being competitive in computational time.


Experience with the live Oka-strain varicella vaccine in children with solid tumours.
A comparative evaluation of radioimmunoassay (RIA), indirect immunofluorescence, fluorescent antibody to membrane antigen, competitive inhibition RIA, and complement fixation methods for determining the immune status to varicella-zoster virus (VZV) showed that RIA was the most sensitive test. However, this test is still not regarded as being entirely satisfactory and possible reasons are discussed. To date, 28 children, mainly with solid tumours, have been inoculated with the Oka-strain live varicella vaccine. Two of these vaccinees developed minor reactions, but only 62% developed a RIA-detectable humoral response. Approximately 46% of the responders had lost induced antibody within 12 months of vaccination. None of the 6 vaccinees that have subsequently been in contact with varicella developed any illness suggesting that they had been protected.


CRD-BP/IMP1 expression characterizes cord blood CD34+ stem cells and affects c-myc and IGF-II expression in MCF-7 cancer cells.
The coding region determinant-binding protein/insulin-like growth factor II mRNA-binding protein (CRD-BP/IMP1) is an RNA-binding protein specifically recognizing c-myc, leader 3' IGF-II and tau mRNAs, and the H19 RNA. CRD-BP/IMP1 is predominantly expressed in embryonal tissues but is de novo activated and/or overexpressed in various human neoplasias. To address the question of whether CRD-BP/IMP1 expression characterizes certain cell types displaying distinct proliferation and/or differentiation properties (i.e. stem cells), we isolated cell subpopulations from human bone marrow, mobilized peripheral blood, and cord blood, all sources known to contain stem cells, and monitored for its expression. CRD-BP/IMP1 was detected only in cord blood-derived CD34(+) stem cells and not in any other cell type of either adult or cord blood origin. Adult BM CD34(+) cells cultured in the presence of 5'-azacytidine expressed de novo CRD-BP/IMP1, suggesting that epigenetic modifications may be responsible for its silencing in adult non-expressing cells. Furthermore, by applying the short interfering RNA methodology in MCF-7 cells, we observed, subsequent to knocking down CRD-BP/IMP1, decreased c-myc expression, increased IGF-II mRNA levels, and reduced cell proliferation rates. These data 1) suggest a normal role for CRD-BP/IMP1 in pluripotent stem cells with high renewal capacity, like the CB CD34(+) cells, 2) indicate that altered methylation may directly or indirectly affect its expression in adult cells, 3) imply that its de novo activation in cancer cells may affect the expression of c-Myc and insulin-like growth factor II, and 4) indicate that the inhibition of CRD-BP/IMP1 expression might affect cancer cell proliferation.


Protoplasmic organization of hyphal tips among fungi: vesicles and Spitzenkörper.
Hyphal tips of fungi representing Oömycetes, Zygomycetes, Ascomycetes, Basidiomycetes, and Deuteromycetes were examined by light and electron microscopy and compared with respect to their protoplasmic organization. In all fungi studied, there is a zone at the hyphal apex which is rich in cytoplasmic vesicles but nearly devoid of other cell components. Some vesicle profiles are continuous with the plasma membrane at the apices of these tip-growing cells. The subapical zones of hyphae contain an endomembrane system which includes smooth-surfaced cisternae associated with small clusters of vesicles. The findings are consistent with the hypothesis that vesicles produced by the endomembrane system in the subapical region become concentrated in the apex where they are incorporated at the expanding surface. Septate fungi (Ascomycetes, Basidiomycetes, and Deuteromycetes) have an apical body (Spitzenkörper) which is associated with growing hyphal tips. In electron micrographs of these fungi, an additional specialized region within the accumulation of apical vesicles is shown for the first time. This region corresponds on the bases of distribution among fungi, location in hyphae, size, shape and boundary characteristics to the Spitzenkörper seen by light microscopy. This structure is not universally associated with tip growth, whereas apical vesicles are widespread among tip-growing systems.


Oocyte-specific inactivation of Omcg1 leads to DNA damage and c-Abl/TAp63-dependent oocyte death associated with dramatic remodeling of ovarian somatic cells.
Aberrant loss of oocytes following cancer treatments or genetic mutations leads to premature ovarian insufficiency (POI) associated with endocrine-related disorders in 1% of women. Therefore, understanding the mechanisms governing oocyte death is crucial for the preservation of female fertility. Here, we report the striking reproductive features of a novel mouse model of POI obtained through oocyte-specific inactivation (ocKO) of Omcg1/Zfp830 encoding a nuclear zinc finger protein involved in pre-mRNA processing. Genetic ablation of OMCG1 in early growing oocytes leads to reduced transcription, accumulation of DNA double-strand breaks and subsequent c-Abl/TAp63-dependent oocyte death, thus uncovering the key role of OMCG1 for oocyte genomic integrity. All adult Omcg1(ocKO) females displayed complete elimination of early growing oocytes and sterility. Unexpectedly, mutant females exhibited a normal onset of puberty and sexual receptivity. Detailed studies of Omcg1(ocKO) ovaries revealed that the ovarian somatic compartment underwent a dramatic structural and functional remodeling. This allowed the cooperation between oocyte-depleted follicles and interstitial tissue to produce estradiol. Moreover, despite early folliculogenesis arrest, mutant mice exhibited sexual cyclicity as shown by cyclical changes in estrogen secretion, vaginal epithelium cytology and genital tract weight. Collectively, our findings demonstrate the key role of Omcg1 for oocyte survival and highlight the contribution of p63 pathway in damaged oocyte elimination in adulthood. Moreover, our findings challenge the prevailing view that sexual cyclicity is tightly dependent upon the pace of folliculogenesis and luteal differentiation.


Investigation of the magnetosome biomineralization in magnetotactic bacteria using graphene liquid cell - transmission electron microscopy.
Understanding the biomineralization pathways in living biological species is a grand challenge owing to the difficulties in monitoring the mineralization process at sub-nanometer scales. Here, we monitored the nucleation and growth of magnetosome nanoparticles in bacteria and in real time using a transmission electron microscope (TEM). To enable biomineralization within the bacteria, we subcultured magnetotactic bacteria grown in iron-depleted medium and then mixed them with iron-rich medium within graphene liquid cells (GLCs) right before imaging the bacteria under the microscope. Using in situ electron energy loss spectroscopy (EELS), the oxidation state of iron in the biomineralized magnetosome was analysed to be magnetite with trace amount of hematite. The increase of mass density of biomineralized magnetosomes as a function of incubation time indicated that the bacteria maintained their functionality during the in situ TEM imaging. Our results underpin that GLCs enables a new platform to observe biomineralization events in living biological species at unprecedented spatial resolution. Understanding the biomineralization processes in living organisms facilitates the design of biomimetic materials, and will enable a paradigm shift in understanding the evolution of biological species.


Vaccinated Healthcare Workers' Adherence to COVID-19 Prevention Measures and Associated Factors in Northwest Ethiopia: A Facility-Based Cross-Sectional Study.
The initial response to coronavirus disease 2019 (COVID-19) was non-pharmaceutical interventions (NPIs). Long-term protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection does not appear to be possible by either infection or vaccination. Thus, traditional herd immunity seems impossible. In addition to increasing vaccination rates, NPIs may be needed. A facility-based cross-sectional study was conducted among vaccinated healthcare workers. The study took place from July 15 to August 15, 2022. A self-administered questionnaire was used for data collection. In a multivariable logistic regression model, a p-value of less than 0.05 was considered statistically significant. Four hundred eleven healthcare workers were included in the study. Sixty percent of participants were fully vaccinated. After vaccination, 10.2% of respondents reported infection with SARS-CoV-2. The study showed that 49.4% of participants had a good knowledge of the efficacy and safety of vaccines against SARS-CoV-2. In this study, 36% of individuals adhered well to the COVID-19 prevention strategies. Good knowledge of the efficacy and safety of SARS-CoV-2 vaccines (AOR = 1.69, 95% CI: 1.03-2.78) increased the odds of implementing preventive measures. Healthcare workers who perceived a low and medium risk of SARS-CoV-2 infection after vaccination and who were knowledgeable about SARS-CoV-2 breakthrough infections were less likely to follow preventive measures. The knowledge of healthcare workers regarding the efficacy and safety of vaccines against SARS-CoV-2 was comparable. However, a large proportion of healthcare workers poorly adhered to prevention practices. Therefore, to reduce the risk of SARS-CoV-2 infection among healthcare professionals, prevention strategies must be continuously evaluated and awareness of the need for preventive measures must be raised even after vaccination.


Concurrent psychotherapy and behavior therapy. Treatment of psychoneurotic outpatients.
The feasibility and effects of treating psychoneurotic outpatients with concomitant but separate treatment programs of psychoanalytically oriented psychotherapy and behavior therapy was investigated in three cases, utilizing detailed clinical observations and questionnaire responses. The two treatment regimens appeared to have synergistic effects, and anticipated difficulties, such as a split therapeutic alliance, symptom substitution, or preciptious withdrawal from psychotherapy after symptom removal, did not occur. Although there was no evidence of symptom substitution after the behavioral removal of the "target symptom," both clinical observations and questionnaire responses indicated that successful behavior therapy had many unanticipated effects on the patient's nontarget behaviors and cognitions.


Barriers to cervical cancer screening: a qualitative study with women in Serbia.
Serbia employs opportunistic approaches to cervical cancer screening, leading to inequitable health care access. To better understand the health care needs of women, we investigated their knowledge of and perceived barriers to cervical cancer screening. Data reported in the paper arise from nine focus group discussions with 62 women from diverse socio-economic backgrounds. They were recruited in two cities with contrasting social settings, Belgrade, the Serbian capital, and a regional town, Smederevo. Thematic analysis identified that the interplay of social and personal barriers influenced women's poor presentation for screening. Inadequate public health education, lack of patient-friendly health services, socio-cultural health beliefs, gender roles, and personal difficulties were the most salient barriers to screening. We suggest how within the context of opportunistic screening patient education may be employed. The introduction of compulsory cervical cancer screening, suggested by some participants, is also discussed.


Chemical and nutritional characteristics of United States soybeans and soybean meals.
Two experiments were conducted to determine U.S. soybean meal (SBM) variation. In experiment 1, SBM from 55 U.S. processors was evaluated. Significant (P < 0.05) but numerically small differences were detected in dry matter (DM) and organic matter (OM) concentrations. Crude protein (CP) concentrations (51.6-54.6%) were higher (P < 0.05) in SBM produced in the southern U.S. Lipid and total dietary fiber concentrations also differed (P < 0.05). The protein dispersibility index was affected (P < 0.05) by the source of SBM. In experiment 2, soybeans and resultant SBMs were obtained from 10 U.S. processing plants. Soybean DM, OM, and CP concentrations differed (P < 0.05). Soybean meal varied (P < 0.05) in CP (48.2-56.2%), acid-hydrolyzed fat (3.3-9.2%), total dietary fiber (17.0-20.7%), and lysine concentrations. Soybean meal carbohydrate composition was also affected by processing conditions. These results indicate a significant variation in chemical and nutritional characteristics of U.S. SBM from different sources.


Chromosome-level genome assembly and population genomic analysis provide novel insights into the immunity and evolution of Sogatella furcifera.
Sogatella furcifera is a destructive agricultural pest causing large threats to rice production in China and Southeast Asian countries. Despite recent breakthroughs in long-read sequencing, high quality genomic data are very limited in S. furcifera. In present study, a chromosome-level assembly of the S. furcifera genome was completed (0.64 GB), comprising 15 chromosomes covered 95.04% of the estimated genome size, along with other 624 small scaffolds making up the remaining 4.96% of the genome of S. furcifera. A total of 24,669 protein-coding genes, 1211 long noncoding RNA and 7595 circular RNA transcripts were predicted in this study. Comparative genomic analysis revealed rapidly evolved genes were associated with multiple immune-related pathways in S. furcifera. Genome resequencing of 44 individuals from 12 geographic populations revealed frequent gene flow among populations. The systemic genomic analysis will provide more insights into the understanding of the immunity and evolutionary adaptation of S. furcifera.


Experimental Study on Shear Performance of Cast-In-Place Ultra-High Performance Concrete Structures.
In order to study the direct shear properties of ultra-high performance concrete (UHPC) structures, 15 Z-shaped monolithic placement specimens (MPSs) and 12 Z-shaped waterjet treated specimens (WJTSs) were tested to study the shear behavior and failure modes. The effects of steel fiber shape, steel fiber volume fraction and interface treatment on the direct shear properties of UHPC were investigated. The test results demonstrate that the MPSs were reinforced with steel fibers and underwent ductile failure. The ultimate load of the MPS is about 166.9% of the initial cracking load. However, the WJTSs failed in a typical brittle mode. Increasing the fiber volume fraction significantly improves the shear strength, which can reach 24.72 MPa. The steel fiber type has little effect on the shear strength and ductility, while increasing the length of steel fibers improves its ductility and slightly reduces the shear strength. The direct shear strength of the WJTSs made from 16 mm hooked-type steel fibers can reach 9.15 MPa, which is 2.47 times the direct shear strength of the specimens without fibers. Finally, an interaction formula for the shear and compressive strength was proposed on the basis of the experimental results, to predict the shear load-carrying capacity of the cast-in-place UHPC structures.


Predicting the pKa of small molecule.
The biopharmaceutical profile of a compound depends directly on the dissociation constants of its acidic and basic groups, commonly expressed as the negative decadic logarithm pKa of the acid dissociation constant (Ka). We survey the literature on computational methods to predict the pKa of small molecules. In this, we address data availability (used data sets, data quality, proprietary versus public data), molecular representations (quantum mechanics, descriptors, structured representations), prediction methods (approaches, implementations), as well as pKa-specific issues such as mono- and multiprotic compounds. We discuss advantages, problems, recent progress, and challenges in the field.


[Clinico-morphological characteristics of the methods of connection of the postoperative wound edges].
The decision for the method of connection of the skin wound edges should be based on specific reconstruction of the injured tissues depending on the suture material and kind of the skin suture. An alternative of the classical suturing of the postoperative wound is a sutureless fixation of the skin edges--a method of using adhesive plaster. The work includes a clinico-morphological comparison of the course of the process of regeneration when using the intracutaneous suture and the adhesive plaster. The macroscopic and pathologic-histological estimation of the healing of the postoperative wound of the skin has shown that a smoother course of the postoperative period is noted in the groups where the adhesive plaster was used.


NGAL promotes recruitment of tumor infiltrating leukocytes.
We have previously shown that Neutrophil Gelatinase-Associated Lipocalin (NGAL) is strongly expressed in thyroid carcinomas, especially of anaplastic type, where it protects neoplastic cells from serum deprivation-induced apoptosis and enhances tumor invasivity by regulating MMP-9 activity. Here we demonstrate that NGAL-containing conditioned medium from human anaplastic thyroid carcinoma (ATC) cells is able to induce monocyte migration via up-regulation of a number of different chemokines. The enhanced chemokines transcription is due to the NGAL-mediated intracellular iron uptake. Very importantly, mice tumor allografts raised from subcutaneous injection of syngeneic colon carcinoma cell lines, expressing high levels of NGAL, show a dense leukocyte infiltrate which strongly decreases in tumor allografts from NGAL-depleted cell injected mice. Our results indicate that the NGAL promotes leukocytes recruitment in tumor microenvironment through iron-mediated chemokines production.


Novel measure of lung function for assessing disease activity in asthma.
In asthma, lung function measures are often discordant with clinical features such as disease activity or control. We investigated a novel technique that provides a measure (σCL) of unevenness (inhomogeneity) in lung inflation/deflation. In particular, we compared σCL with FEV1% predicted (FEV1%pred) as measures of disease activity in the asthmatic lung. σCL correlated modestly with FEV1%pred. However, σCL is not simply a proxy for FEV1%pred as the effects of salbutamol on the two parameters were unrelated. Importantly, σCL reflected disease control better than FEV1. We conclude that σCL shows promise as an objective measure of disease activity in asthma.


Blood-nourishing and hard-softening capsule costs less in the management of osteoarthritic knee pain: a randomized controlled trial.
The blood-nourishing and hard-softening (BNHS) capsule is a traditional Chinese formula used in the symptomatic treatment of inflammation and pain. We conducted this randomized controlled trial to compare the efficacy of BNHS with other commonly prescribed drugs. We recruited 120 patients from two teaching hospitals; 30 patients in each hospital were randomly assigned to receive BNHS. In one hospital, the 30 controls were given another traditional Chinese drug; whereas a Western medicine (chondroprotection drug/Viartril-s) was used as the control in the other hospital. Intervention was carried out over a period of 4 weeks. Primary outcome measures included self-reported pain level, and changes in stiffness and functional ability as measured by the Western Ontario McMaster Universities Osteoarthritis (WOMAC) index. Mixed models were used for statistical analysis. Substantial improvements in disease-specific symptoms were observed, after 4 weeks of treatment, in patients taking BNHS capsules. As assessed by the WOMAC index, pain level of the BNHS group decreased by 57% [95% confidence interval (CI) = 50, 63], stiffness by 63% (95% CI = 55, 71) and functional ability increased by 56% (95% CI = 50, 63). No significant differences were found in any of the outcome measures between the BNHS group and either of the comparison groups. No severe adverse effects were reported. However, this study lacked a placebo group; therefore, we conclude that BNHS appears to be as effective as commonly prescribed medicines for the relief of pain and dysfunction in knee osteoarthritis patients, but costs a lot less than other Western and herbal drugs in the study.


Identifying and managing infectious disease syndemics in patients with HIV.
We will present recent articles focusing on HIV synergistic interactions with other sexually transmitted infections, tuberculosis, and hepatitis, as well as recent advances in the study of social and behavioral determinants that facilitate this clustering of infectious disease. For each synergistic interaction, we highlight evidence-based interventions that clinicians and policymakers should consider to tackle HIV and infectious disease syndemics. Significant advances in understanding the behavioral and structural determinants of HIV and other infectious disease synergisms have been made in the past years. Intervention strategies based on these new models have also been developed. It is now well understood that treating infectious disease syndemics will require a multidisciplinary and multipronged approach. HIV is synergistic with multiple other infectious diseases because the risk behaviors that lead to HIV acquisition may be similar to the other infections. The influence of HIV on the other infection may be due to immunosuppression associated with disease progression resulting in increased susceptibility (e.g., HIV and tuberculosis), especially when patients are not virologically suppressed using antiretroviral therapy. In reverse, another infectious disease may, when not treated, influence HIV disease progression. Social/structural determinants like homelessness, mass incarceration, and structural discrimination precipitate psychiatric comorbidity, substance use, and risky sex behavior which lead to the spread and co-occurrence of infectious disease.


Development of low cost all glass recirculation systems for environmental applications.
Some simple glassware has been developed for recirculation of liquid medium. These glassware have wider applications and have been tested in experiments involving leaching, biodegradation, and desulfurization. The fabrication cost is minimum and can be developed in a small glassware workshop. Such a development has certain advantages as no separate mechanical devices are needed, the flow can be easily monitored due to transparency of the apparatus, acidic or alkaline medium can also be circulated. The paper discusses the development, design and fabrication of some specialized glass recirculation systems and its environmental applications.


Regulation of glycogen synthase and protein phosphatase-1 by hexosamines.
The hexosamine biosynthesis pathway has been hypothesized to be involved in mediating some of the adverse effects of high glucose. We have previously shown that glucose downregulates basal glycogen synthase (GS) activity in Rat-1 cells and that overexpressing the rate-limiting enzyme in the hexosamine biosynthesis pathway (glutamine:fructose-6-phosphate amidotransferase [GFA]) makes the cells more sensitive to these effects of glucose. GFA overexpression also leads to a reduction in insulin sensitivity of GS. Here we examine the effects of glucose and glucosamine on insulin-stimulated GS activity and on protein phosphatase-1 (PP1) activity. These activities were assayed in cytoplasmic extracts from Rat-1 fibroblasts overexpressing human GFA and cultured in varying glucose concentrations. Both maximal insulin-stimulated GS activity and insulin sensitivity decreased with increasing glucose. Overexpression of GFA leads to a further reduction in insulin sensitivity but not in maximal insulin-stimulated GS activity. Because there were no differences in total (glucose-6-phosphate-dependent) GS activity between cell lines or as a function of glucose concentration, these results most likely reflect a change in the phosphorylation state of the synthase. Activity of PP1, a potential mediator of these effects, was responsive to glucose and hexosamines. Control cells showed a 9.3 +/- 4.3% decrease in PP1 activity with increasing glucose. GFA cells showed a greater response to glucose, with PP1 activity decreasing 34.2 +/- 5.5% with increasing glucose. Glucosamine was more potent than glucose in decreasing PP1 activity in control cells. Cells overexpressing the normal human insulin receptor (HIRc-B) were used to facilitate analysis of insulin-stimulated PP1 activity. Stimulation with 1.7 mmol/l insulin led to a 37.6 +/- 9.9% increase in PP1 activity in HIRc-B cells cultured in 1 mmol/l glucose, while cells cultured in 5 mmol/l glucosamine or 20 mmol/l glucose demonstrated only 3.79 +/- 0.60 or 1.6 +/- 0.75% increases, respectively. We conclude that both basal and insulin- stimulable GS and PP1 activity are downregulated by high glucose in fibroblasts and this regulation is mediated by products of the hexosamine biosynthesis pathway.


A Logical Model of Homology for Comparative Biology.
There is a growing body of research on the evolution of anatomy in a wide variety of organisms. Discoveries in this field could be greatly accelerated by computational methods and resources that enable these findings to be compared across different studies and different organisms and linked with the genes responsible for anatomical modifications. Homology is a key concept in comparative anatomy; two important types are historical homology (the similarity of organisms due to common ancestry) and serial homology (the similarity of repeated structures within an organism). We explored how to most effectively represent historical and serial homology across anatomical structures to facilitate computational reasoning. We assembled a collection of homology assertions from the literature with a set of taxon phenotypes for the skeletal elements of vertebrate fins and limbs from the Phenoscape Knowledgebase. Using seven competency questions, we evaluated the reasoning ramifications of two logical models: the Reciprocal Existential Axioms (REA) homology model and the Ancestral Value Axioms (AVA) homology model. The AVA model returned all user-expected results in addition to the search term and any of its subclasses. The AVA model also returns any superclass of the query term in which a homology relationship has been asserted. The REA model returned the user-expected results for five out of seven queries. We identify some challenges of implementing complete homology queries due to limitations of OWL reasoning. This work lays the foundation for homology reasoning to be incorporated into other ontology-based tools, such as those that enable synthetic supermatrix construction and candidate gene discovery. [Homology; ontology; anatomy; morphology; evolution; knowledgebase; phenoscape.].


Morphine blood levels, dependence, and regulation of hippocampal subgranular zone proliferation rely on administration paradigm.
Chronic morphine, administered via s.c. pellet, decreases the number of proliferating cells in the dentate gyrus subgranular zone (SGZ) in both rats and mice. This robust morphine-induced decrease could be used to better understand mechanisms regulating adult hippocampal neurogenesis, as well as to explore the relationship between neurogenesis and drug dependence, withdrawal, and relapse behaviors. Such research would benefit enormously from identifying a route of morphine administration that produces addiction-relevant blood levels of morphine, results in a high degree of dependence, translates to both rat and mouse, and is free of the behavioral confounds of s.c. pellets. Therefore, we examined a classic chronic morphine pellet paradigm (two s.c. pellets over 5 days) versus three chronic morphine injection paradigms (escalating dose i.p. injections over 2, 5, or 10 days) for their effect in adult male C57BL/6J mice. We assessed blood morphine levels, SGZ proliferation, and drug dependence as assessed by tolerance to locomotion sensitization and naloxone-precipitated withdrawal. The pellet paradigm produced high and relatively stable blood levels of morphine, a high degree of dependence, and a significant decrease in SGZ proliferation. In contrast, the three injection paradigms produced transient spikes in morphine blood levels, significantly less dependence than the pellet paradigm, and no significant decrease in SGZ proliferation. These data show that regulation of mouse SGZ proliferation requires high and relatively stable blood levels of morphine, and provide critical knowledge for the design of future studies to probe the relationship between addiction and neurogenesis.


Does conformational free energy distinguish loop conformations in proteins?
Limitations in protein homology modeling often arise from the inability to adequately model loops. In this paper we focus on the selection of loop conformations. We present a complete computational treatment that allows the screening of loop conformations to identify those that best fit a molecular model. The stability of a loop in a protein is evaluated via computations of conformational free energies in solution, i.e., the free energy difference between the reference structure and the modeled one. A thermodynamic cycle is used for calculation of the conformational free energy, in which the total free energy of the reference state (i.e., gas phase) is the CHARMm potential energy. The electrostatic contribution of the solvation free energy is obtained from solving the finite-difference Poisson-Boltzmann equation. The nonpolar contribution is based on a surface area-based expression. We applied this computational scheme to a simple but well-characterized system, the antibody hypervariable loop (complementarity-determining region, CDR). Instead of creating loop conformations, we generated a database of loops extracted from high-resolution crystal structures of proteins, which display geometrical similarities with antibody CDRs. We inserted loops from our database into a framework of an antibody; then we calculated the conformational free energies of each loop. Results show that we successfully identified loops with a "reference-like" CDR geometry, with the lowest conformational free energy in gas phase only. Surprisingly, the solvation energy term plays a confusing role, sometimes discriminating "reference-like" CDR geometry and many times allowing "non-reference-like" conformations to have the lowest conformational free energies (for short loops). Most "reference-like" loop conformations are separated from others by a gap in the gas phase conformational free energy scale. Naturally, loops from antibody molecules are found to be the best models for long CDRs (> or = 6 residues), mainly because of a better packing of backbone atoms into the framework of the antibody model.


The Association of COVID-19 Incidence with Sport and Face Mask Use in United States High School Athletes.
The relationships between different sports, face mask use and COVID-19 risk among high school athletes remains unknown. The purpose of this study was to evaluate the influence of sport characteristics and face mask use on COVID-19 incidence among high school athletes. Descriptive Epidemiology Study Setting: United States High School Athletic Departments Participants: Athletic Directors Interventions: None Main Outcome Measures: Surveys were completed regarding sport re-initiation, COVID-19 cases, and risk reduction procedures in fall 2020. Separate mixed effects Poisson regression models were developed to evaluate the associations between reported COVID-19 incidence and 1) sport characteristics (contact/non-contact, individual/team, indoor/outdoor) and 2) face mask use while playing (yes/no). 991 schools had restarted fall sports, representing 152,484 athletes on 5,854 teams. 2,565 cases of COVID-19 were reported, representing a case rate of 1,682 cases per 100,000 athletes and an incidence rate of 24.6 cases per 100,000 player-days. COVID-19 incidence was lower among outdoor versus indoor sports (incidence rate ratio [IRR]=0.54, 95% CI=0.49-0.60, p<0.001) and non-contact versus contact sports (IRR=0.78 [0.70-0.87], p<0.001), but not team versus individual sports (IRR=0.96 [0.84-1.1], p=0.49). Face mask use was associated with a decreased incidence in girls' volleyball (IRR=0.53 [0.37-0.73], p<0.001), boys' basketball (IRR=0.53 [0.33-0.83], p=0.008) and girls' basketball (IRR=0.36 [0.19-0.63], p<0.001), and approached statistical significance in football (IRR=0.79 [0.59-1.04], p=0.10) and cheer/dance (IRR=0.75 [0.53-1.03], p=0.081). In this nationwide survey of high school athletes, lower COVID-19 incidence was independently associated with participation in outdoor versus indoor and non-contact versus contact sports, but not team versus individual sports. Face mask use was associated with decreased COVID-19 incidence among indoor sports, and may be protective among outdoor sports with prolonged close contact between participants.


Refinement of polyclonal antibody production by combining oral immunization of chickens with harvest of antibodies from the egg yolk.
Polyclonal antibody production in mammals is generally associated with multiple injections of antigens and adjuvants and repeated blood sampling procedures. During the past 20 yr, the use of chickens instead of mammals for this purpose has increased. A major advantage of using birds is that the antibodies can be harvested from the egg yolk instead of serum, thus making blood sampling obsolete. In addition, the antibody productivity of an egg-laying hen is much greater than that of a similar sized mammal. This article focuses on the developments in oral immunization strategies for chickens that combined with the antibodies from the egg yolk, have great potential for active implementation of the three Rs (replacing, reducing, and refining the use of laboratory animals to the extent possible) in polyclonal antibody production schemes.


Electrical stimulation as a therapeutic option to improve eyelid function in chronic facial nerve disorders.
To establish whether it is possible to improve orbicularis oculi muscle function in the eyelids of patients with a chronic seventh cranial nerve palsy by using transcutaneous electrical stimulation to the point at which electrical stimulation induces a functional blink. Ten subjects (one woman, nine men) aged 36 to 76 with chronic, moderate to severe facial nerve palsy were recruited into the study. Voluntary and spontaneous eyelid movements were assessed, using an optical measuring system, before, during, and after a 3-month treatment period. Voluntary and spontaneous lid velocities were also measured and compared with eyelid kinematic data in normal subjects (12 women, 18 men; age range, 22-56 years). Therapeutic electrical stimulation applied over 3 months produced improvement in eyelid movement (>2 mm) in 8 of 10 patients during voluntary eyelid closure. However, there was no significant improvement recorded in spontaneous blink amplitudes or peak downward-phase velocity of the upper eyelid. This regimen of stimulation failed to recover function well enough that a functional blink could be induced in the paretic eyelid by electrical stimulation. Electrical stimulation using transcutaneous electrical nerve stimulators units can improve voluntary eye closure, apparently because of a reduction in stiffness of eyelid mechanics, rather than an improvement of muscle function. Investigation of alternative stimulation regimens is warranted.


Atmospheric pressure ion source development: experimental validation of simulated ion trajectories within complex flow and electrical fields.
Three-dimensionally (3D) resolved ion trajectory calculations within the complex viscous flow field of an atmospheric pressure ion source are presented. The model calculations are validated with spatially resolved measurements of the relative sensitivity distribution within the source enclosure, referred to as the distribution of ion acceptance (DIA) of the mass analyzer. In previous work, we have shown that the DIA shapes as well as the maximum signal strengths strongly depend on ion source operational parameters such as gas flows and temperatures, as well as electrical field gradients established by various source electrode potentials (e.g., capillary inlet port potential and spray shield potential). In all cases studied, distinct, reproducible, and, to some extent, surprising DIA patterns were observed. We have thus attempted to model selected experimental operational source modes (called operational points) using a validated computational flow dynamics derived 3D-velocity field as an input parameter set for SIMION/SDS, along with a suite of custom software for data analysis and parameter set processing. Despite the complexity of the system, the modeling results reproduce the experimentally derived DIA unexpectedly well. It is concluded that SIMION/SDS in combination with accurate computational fluid dynamics (CFD) input data and adequate analysis software is capable of successfully modeling operational points of an atmospheric pressure ion (API) source. This approach should be very useful in the computer-aided design of future API sources.


Soy isoflavones improve endothelial function in spontaneously hypertensive rats in an estrogen-independent manner: role of nitric-oxide synthase, superoxide, and cyclooxygenase metabolites.
The aim of this study was to analyze the effects of the isoflavones genistein and daidzein, and the mammalian estrogen 17beta-estradiol on endothelial function in isolated aortic rings from male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Relaxation to acetylcholine on precontracted rings was impaired and endothelium-dependent contraction to acetylcholine in aortic rings was increased in SHR compared with WKY. Aortic NADPH-stimulated O(2)(-) release and prostaglandin (PG)H(2) production evoked by acetylcholine were increased, whereas nitric-oxide synthase activity was reduced in SHR versus WKY. Genistein, daidzein, or 17beta-estradiol enhanced the relaxant response to acetylcholine and decreased the endothelium-dependent vasoconstrictor responses to acetylcholine in SHR, but not in WKY, and these effects were not modified by the estrogen receptor antagonist ICI 182,780 (7alpha,17beta-[9[(4,4,5,5,5-pentafluoropentyl)-sulfinyl]nonyl]estra-1,3,5(10)-triene-3,17-diol). Moreover, isoflavones enhanced nitric-oxide (NO) synthase activity and inhibited NADPH-stimulated O(2)(-) roduction and endothelial release of PGH(2). The contractions induced by the TP receptor agonist U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha)) in denuded aortic rings were inhibited by genistein, daidzein, and 17beta-estradiol in both strains. In conclusion, the isoflavones genistein and daidzein and 17beta-estradiol restore endothelial function in male SHR through estrogen receptor-independent mechanisms. Increased NO production and protection of NO from O(2)(-)-driven inactivation might be involved in the improvement of vascular relaxation to acetylcholine in aortic rings from SHR. Moreover, isoflavones and 17beta-estradiol inhibited aortic endothelium-dependent contraction to acetylcholine in SHR by reducing the endothelial PGH(2) release and its vasoconstrictor response.


A new macrocycle demonstrates ditopic recognition properties.
The synthesis and binding properties of a new macrocycle is reported. The host, comprised of three basic pyridines, four hydrogen bond accepting carbonyls, and two hydrogen bond donating amide groups, binds mono-alkyl ammonium salts in a manner that is dependent on the counter-ion of the ammonium guest.


On wave-breaking free fiber lasers mode-locked with two saturable absorber mechanisms.
We propose a hybrid mode-locking scheme for wave-breaking free fiber lasers based on a saturable Bragg reflector and the nonlinear polarization evolution in the fiber section. With this scheme, the self-starting operation is ensured by the saturable Bragg reflector while the nonlinear polarization evolution acts as an additional pulse shaper in the steady state. Owing to the sensitivity of the pulse dynamics to filtering effects, a tuning range of more than 10nm as well as the suppression of undesired modes of operation became possible. The impact of the modulation depth and the non-saturated losses is discussed via comparative measurements with different saturable Bragg reflectors.


Complete Genome Sequence of Salmonella enterica Serovar Enteritidis NCM 61, with High Potential for Biofilm Formation, Isolated from Meat-Related Sources.
Here, we report the complete genome sequence of strain NMC 61 of Salmonella enterica serovar Enteritidis, which was previously isolated from conveyor belts during chicken slaughter and has the potential to form biofilms on several surfaces. The genome is predicted to contain 110 noncoding small RNAs on the chromosome.


Psychometric Properties of the Pediatric Patient-Reported Outcomes Measurement Information System Item Banks in a Dutch Clinical Sample of Children With Juvenile Idiopathic Arthritis.
To assess the psychometric properties of 8 pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) item banks in a clinical sample of children with juvenile idiopathic arthritis (JIA). A total of 154 Dutch children (mean ± SD age 14.4 ± 3.0 years; range 8-18 years) with JIA completed 8 pediatric version 1.0 PROMIS item banks (anger, anxiety, depressive symptoms, fatigue, pain interference, peer relationships, physical function mobility, physical function upper extremity) twice and the Pediatric Quality of Life Inventory (PedsQL) and the Childhood Health Assessment Questionnaire (C-HAQ) once. Structural validity of the item banks was assessed by fitting a graded response model (GRM) and inspecting GRM fit (comparative fit index [CFI], Tucker-Lewis index [TLI], and root mean square error of approximation [RMSEA]) and item fit (S-X2 statistic). Convergent validity (with PedsQL/C-HAQ subdomains) and discriminative validity (active/inactive disease) were assessed. Reliability of the item banks, short forms, and computerized adaptive testing (CAT) was expressed as the SE of theta (SE[θ]). Test-retest reliability was assessed using intraclass correlation coefficients (ICCs) and smallest detectable change. All item banks had sufficient overall GRM fit (CFI >0.95, TLI >0.95, RMSEA <0.08) and no item misfit (all S-X2 P > 0.001). High correlations (>0.70) were found between most PROMIS T scores and hypothesized PedsQL/C-HAQ (sub)domains. Mobility, pain interference, and upper extremity item banks were able to discriminate between patients with active and inactive disease. Regarding reliability, PROMIS item banks outperformed legacy instruments. Post hoc CAT simulations outperformed short forms. Test-retest reliability was strong (ICC >0.70) for all full-length item banks and short forms, except for the peer relationships item bank. The pediatric PROMIS item banks displayed sufficient psychometric properties for Dutch children with JIA. PROMIS item banks are ready for use in clinical research and practice for children with JIA.


Liver function tests and metabolic-associated fatty liver disease: Changes in upper normal limits, does it really matter?
Metabolic-associated fatty liver disease (MAFLD) is the commonest cause of abnormal liver function tests (LFTs). Current upper normal of limit (UNL) of LFTs was derived from a "healthy" population, where undiagnosed MAFLD and viral hepatitis might be suspected. To evaluated potential implications of changes in UNL of alanine aminotransferase (ALT) in MAFLD. We retrospectively assessed consecutive first referrals with a diagnosis of MAFLD from 2010 to 2017. The conventional UNL of ALT was 45 IU/L for men and 34 IU/L for women, while a low UNL of ALT was 30 IU/L for men and 19 IU/L for women. The UNL of aspartate aminotransferase (AST) was 40 IU/L. Total 436 patients were enrolled; of these, 288 underwent liver biopsy. Setting a lower UNL reduced the percentage of those with significant disease despite normal ALT; specifically, patients with advanced fibrosis (F ≥ F3) or definite "metabolic-associated steato-hepatitis (MASH)" (NAS ≥ 5) within normal ALT decreased from 10% to 1% and from 28% to 4% respectively. However, the proportion of those with elevated ALT and no evidence of advanced fibrosis or "definite MASH" increased from 39% to 47% and from 3% to 19%. Overall, LFTs performed poorly in distinguishing "definite MASH" from simple steatosis (receiver operating characteristic areas under the curves 0.59 for ALT and 0.55 for AST). Liver function tests might both under- and overestimate MASH-related liver disease. Reducing the UNL might not be beneficial and imply an increase in healthcare burden. Risk stratification in MAFLD should rely on a combination of risk factors, not on LFTs alone.


Analysis of afferent responses from isolated semicircular canal of the guitarfish using rotational acceleration white-noise inputs. II. Estimation of linear system parameters and gain and phase spectra.
Quantitative estimates were computed for exponential coefficients and rate constants contributing to afferent unit impulse responses obtained from bundles innervating specific regions of the semicircular canal. The grouping of these estimates into specific response classes provided quantitative correlations with specific anatomical regions of innervation of the crista. Linear system gain and phase spectra were computed also, by applying Fourier transformations to unit impulse responses, for purposes of comparison with previous studies employing frequency domain analyses. Responses fitted by third-order linear system equations were specific to afferents innervating the crest and transition regions of the crista; whereas those fitted by overdamped, second-order equations were specific to afferents innervating the slopes and transition crista regions. It was concluded that strictly mechanical models of the transduction process are inadequate to account for the diverse and spatially distributed classes of observed responses and, moreover, structural features such as different hair cell types or efferent innervation effects could be excluded as inoperative in this preparation. The alternative hypothesis was suggested that certain of the observed subcomponents could be direct reflections of the initial mechanical stimulus, but that other subcomponents were reflections of more complex filtering mechanisms operating at the cellular or synaptic levels.


pH-controlled delivery of curcumin from a compartmentalized solid lipid nanoparticle@mesostructured silica matrix.
Silicalization of curcumin-loaded solid lipid nanoparticle (SLN)/micelle dispersions afforded a compartmentalized nanovector, with both macro- and mesostructured domains. SLNs act as reservoirs of curcumin (CU), while mesopores act as pathways to control drug release. Moreover, the release sustainability depends on the nature of the solid lipid (cetyl palmitate vs. stearic acid) and on the pH of the receiving phase. The meso-macrostructured silica matrix templated by SLNs appears thus as a promising drug delivery system for pH-responsive controlled release.


The monopulsed nature of sperm whale clicks.
Traditionally, sperm whale clicks have been described as multipulsed, long duration, nondirectional signals of moderate intensity and with a spectrum peaking below 10 kHz. Such properties are counterindicative of a sonar function, and quite different from the properties of dolphin sonar clicks. Here, data are presented suggesting that the traditional view of sperm whale clicks is incomplete and derived from off-axis recordings of a highly directional source. A limited number of assumed on-axis clicks were recorded and found to be essentially monopulsed clicks, with durations of 100 micros, with a composite directionality index of 27 dB, with source levels up to 236 dB re: 1 microPa (rms), and with centroid frequencies of 15 kHz. Such clicks meet the requirements for long-range biosonar purposes. Data were obtained with a large-aperture, GPS-synchronized array in July 2000 in the Bleik Canyon off Vesterålen, Norway (69 degrees 28' N, 15 degrees 40' E). A total of 14 h of sound recordings was collected from five to ten independent, simultaneously operating recording units. The sound levels measured make sperm whale clicks by far the loudest of sounds recorded from any biological source. On-axis click properties support previous work proposing the nose of sperm whales to operate as a generator of sound.


Zika virus and assisted reproduction.
Due to the fact that the Zika virus can be sexually transmitted, there is a potential risk for disease transmission at several stages of assisted reproduction. Such a possibility poses a serious challenge to couples pursing fertility with reproductive technologies. Here, we discuss what is known regarding Zika virus infection with respect to sexual transmission and correlate this knowledge with recent recommendations in the realm of infertility treatment. Zika virus can be transmitted from infected men and women through vaginal, oral or anal intercourse. Zika virus RNA has been detected in blood, semen, cervical mucus and vaginal fluid. Currently, the Centers for Disease Control recommends that infected men wait 6 months, and infected women 8 weeks, prior to attempting pregnancy. Reproductive tissue donors should wait 6 months before giving a specimen. Further study of Zika virus transmission in different reproductive tissues and establishment of validated testing methods for viral disease transmissibility are urgently needed. Reproductive technologists need to establish screening, testing and laboratory protocols aimed to reduce the risk of Zika virus transmission during assisted reproduction.


Isolation and characterization of the mating type locus of Mycosphaerella fijiensis, the causal agent of black leaf streak disease of banana.
SUMMARY Idiomorphs mat1-1 and mat1-2 from Mycosphaerella fijiensis, the causal agent of black leaf streak disease of banana, were isolated. Degenerate oligos were used to amplify the HMG box of the mat1-2 idiomorph from M. fijiensis, showing homology with the HMG box of Mycosphaerella graminicola. Using a DNA walking strategy, anchored on the DNA lyase gene towards the HMG box, a 9-kb-long region of mat1-2 was obtained. A 5-kb fragment from the mat1-1 region was obtained by long-range PCR using primers on the flanking regions, which have close to 100% identity between both idiomorphs. High-identity (77-89%), inverted regions within both idiomorphs were found, which suggest unique inversion events, which have not been found before, and that could have been significant in the evolution of this species. The predicted genes showed the conserved introns in both idiomorphs as well as an additional intron within the alpha box. The implications for the evolution of species in the Mycosphaerella complex on banana are discussed.


Low levels of awareness, treatment, and control of hypertension in Andean communities of Ecuador.
The major burden of hypertension (HTN) occurs in low-middle-income countries (LMIC) and it is the main modifiable risk factor for cardiovascular diseases (CVD). Few population studies on HTN prevalence have been carried out in Ecuador where there is limited information regarding its prevalence, awareness, treatment, and control. Thus, the aim of the present study was to determine the prevalence, awareness, treatment, and control of HTN and its association with socio-economic, nutritional, and lifestyle habits in urban and rural Andean communities of Pichincha province in Ecuador. The authors studied 2020 individuals aged 35-70 years (mean age 50.8 years, 72% women), included in the Ecuadorian cohort of the Prospective Urban and Rural Epidemiology (PURE) study, from February to December 2018. The hypertension prevalence (>140/90 mmHg) was 27% and was greater in urban than in rural communities, more common in men, in individuals older than 50 years of age, in people with low monthly income and low level of education. Higher prevalence was also observed in subjects with obesity, and among former smokers and those who consumed alcohol. Only 49% of those with HTN were aware of their condition, 40% were using antihypertensive medications, and 19% had their blood pressure under control (<140/90 mmHg). These results showed low levels of awareness, treatment, and control of HTN in the Andean region of Ecuador, suggesting the urgent necessity of implementing programs to improve the diagnosis and management of HTN.