[Occurrence of suspicious changes in cervix cytology in women after liver transplantation].
After transplantation the necessary immunosuppressive therapy predisposes to the development of de novo cancers. From January 1989 to April 1994 we collected PAR smears of 98 women before and repeatedly after liver transplantation. After surgery all women received as immunosuppressive agents either Cyclosporin A or FK 506 as long-term medication. In seven patients (8.5%) who had a normal cervical cytology before transplantation a suspicious PAP smear was found on average 11 months after transplantation. In five cases a histological verification (exploratory excision, coning of the cervix) was made. In two cases we found a CIN III. Possible causes for the higher incidence of dysplasia of the cervix observed in the transplant patients are discussed. Similar to kidney transplant recipients female liver transplant recipients are at higher risk of developing cervical dysplasias and neoplasias. Accelerated development of malignancy seems likely. The influence on the cervical cells of both immunosuppressive drugs Cyclosporin A and FK 506 seems to be of a similar nature. Recommendations for the gynaecological care of female liver transplant recipients treated with immunosuppressive therapy are given.


Sensing the invisible world.
The human eye has a very limited spectral response and is completely insensitive to ir radiation. Objects at or near earth ambient temperatures of 300 K emit ir radiation. In order to sense this long wavelength ir radiation, a variety of image translation devices have been developed. This introductory article describes the important characteristics of some of these image translation devices. It also briefly mentions a few of their very many applications in the field of nondestructive examination and testing. Further details of the image translation scanners and of related instruments and techniques, as well as of their multifold applications, are given in the following papers that constitute the feature of the September 1968 issue of APPLIED OPTICS.


The Aurora kinase Ipl1 maintains the centromeric localization of PP2A to protect cohesin during meiosis.
Homologue segregation during the first meiotic division requires the proper spatial regulation of sister chromatid cohesion and its dissolution along chromosome arms, but its protection at centromeric regions. This protection requires the conserved MEI-S332/Sgo1 proteins that localize to centromeric regions and also recruit the PP2A phosphatase by binding its regulatory subunit, Rts1. Centromeric Rts1/PP2A then locally prevents cohesion dissolution possibly by dephosphorylating the protein complex cohesin. We show that Aurora B kinase in Saccharomyces cerevisiae (Ipl1) is also essential for the protection of meiotic centromeric cohesion. Coupled with a previous study in Drosophila melanogaster, this meiotic function of Aurora B kinase appears to be conserved among eukaryotes. Furthermore, we show that Sgo1 recruits Ipl1 to centromeric regions. In the absence of Ipl1, Rts1 can initially bind to centromeric regions but disappears from these regions after anaphase I onset. We suggest that centromeric Ipl1 ensures the continued centromeric presence of active Rts1/PP2A, which in turn locally protects cohesin and cohesion.


Energy transportation in a subwavelength waveguide composed of a pair of comb-shape nanorod chains.
A subwavelength plasmonic waveguide composed of a pair of comb-shape nanorod chains is proposed. The electromagnetic energy can be transported in the waveguide via the interaction strength of magnetoinductive coupling as well as conduction current exchange. Finite Element Method simulation results reveal that for such a waveguide composed of 50 pairs of 400 nm-long-nanorods, a passband ranging from zero to cutoff frequency 156.2 THz, and an effective propagation length of 20.87 μm can be achieved simultaneously. The proposed mechanism of energy transport in the nanoscale has potential applications in subwavelength transmission lines for a wide range of integrated optical devices.


Assessment of the evolution of cancer treatment therapies.
Cancer therapy has been characterized throughout history by ups and downs, not only due to the ineffectiveness of treatments and side effects, but also by hope and the reality of complete remission and cure in many cases. Within the therapeutic arsenal, alongside surgery in the case of solid tumors, are the antitumor drugs and radiation that have been the treatment of choice in some instances. In recent years, immunotherapy has become an important therapeutic alternative, and is now the first choice in many cases. Nanotechnology has recently arrived on the scene, offering nanostructures as new therapeutic alternatives for controlled drug delivery, for combining imaging and treatment, applying hyperthermia, and providing directed target therapy, among others. These therapies can be applied either alone or in combination with other components (antibodies, peptides, folic acid, etc.). In addition, gene therapy is also offering promising new methods for treatment. Here, we present a review of the evolution of cancer treatments, starting with chemotherapy, surgery, radiation and immunotherapy, and moving on to the most promising cutting-edge therapies (gene therapy and nanomedicine). We offer an historical point of view that covers the arrival of these therapies to clinical practice and the market, and the promises and challenges they present.


Surgical management of complete ureteric duplication abnormalities in children.
A variety of clinical problems due to complete ureteric duplication (CUD) in children may be encountered. Surgical management of CUD varies and is controversial. Therefore, we reviewed the cases of 15 children with CUD operated on at our hospital in an effort to evaluate the various facets of this disorder that influenced our surgical management. Fifteen children with abnormalities associated with CUD underwent surgery from 1987 to 1998. There were 14 girls and one boy. Their age at surgery ranged from 15 days to 3.5 years (average, 9.5 months). All children underwent ultrasonography, including 10 intravenous urograms and five prenatal examinations. The anatomic abnormalities of all children were noted according to the Weigert-Meyer rule. Six of 15 ultrasonograms were misinterpreted as hydronephrosis only, while the 10 intravenous urograms were interpreted correctly as CUD. Four patients had recurrent urinary tract infections after surgery. Two of them underwent further surgery, one for stone formation in the residual ureter stump and the other for persistent ureterocele. There was one surgical complication after an upper pole nephroureterectomy. It involved ureteric necrosis with urine leakage. This patient underwent ipsilateral lower pole nephrectomy 28 days after the first operation. All children remained symptom-free during follow-up. Accurate diagnosis of duplex kidney requires careful imaging studies, especially for fetal renal abnormalities. Management of CUD should be individualized. Usually, upper pole nephroureterectomy is performed for a nonfunctioning moiety. For functioning segments, ureteropyelostomy or ureteric reimplantation can be considered. The results are satisfactory, but long-term follow-up is necessary.


THE ELECTROPHORETIC MOBILITY OF RABBIT ERYTHROCYTES AND GHOSTS.
Measurements of the electrical mobility of washed rabbit red cells and of ghosts produced by hypotonic solutions, freezing-and-thawing, chloroform, and saponin were made in the Abramson horizontal microelectrophoresis cell. These different forms of lysis, which corresponds to a variety of degrees of injury to the red cell, are unaccompanied by any change in electrical mobility. These observations are discussed from the standpoint of the possible structure of the cell membrane and the action of lysins upon it.


What Would an HIV Cure Mean to You? Qualitative Analysis from a Crowdsourcing Contest in Guangzhou, China.
Much HIV cure social science research has focused on high-income countries. Local key population perspectives, especially from people living with HIV (PLHIV), are needed in low- and middle-income countries. We organized an open contest soliciting responses from key populations, including PLHIV, about what a cure would mean in their lives. Tailored in-person events and social media were used to engage PLHIV, men who have sex with men (MSM), people who inject drugs, and local residents. We received 471 contributions over 4 months. Our thematic analysis showed that many people perceived that a cure would sterilize HIV and bring about new life for PLHIV. Many individuals believed a cure would decrease PLHIV discrimination and many MSM perceived a cure would decrease MSM discrimination. Some participants noted that a cure could help improve interpersonal relations, particularly with families and partners. Many individuals envisioned HIV cure as a panacea to bring about social stability. Some participants also anticipated changes in attitudes toward sex that may result in increased condomless sex. Our findings suggest a continued need for careful management of patient expectations and community engagement.


Role of Aurora-A in Ovarian Cancer: A Meta-Analysis.
Recently, several studies have examined associations between Aurora-A expression and clinical outcome in patients with ovarian cancer, but yielded conflicting results with respect to survival. Therefore, the aim of this study was to evaluate the prognostic significance of Aurora-A in ovarian cancer by performing a meta-analysis. PubMed, Cochrane library, Web of Science, Embase, Medline and Chinese BioMed Database (CBM) databases were searched systematically and only articles in which Aurora-A expression was detected by immunohistochemical staining were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted and pooled for overall survival (OS) and disease-free survival (DFS). Our results show that the pooled HR for OS was 1.40 (95% CI 0.82-1.98, p < 0.01) by univariate analysis in 7 articles (1,028) and 0.32 (95% CI 0.04-0.615, p = 0.23) by multivariate analysis in 3 studies (155). The association between Aurora-A expression and DFS was also statistically significant in 5 studies (HR = 1.14, 95% CI 0.50-1.78, p < 0.01). This present meta-analysis suggests that the Aurora-A expression may be associated with poor prognosis in patients with ovarian cancer. Furthermore, studies of larger scale and well-matched regimes are warranted to confirm the findings in the future.


[Development of modern medical doctors in Japan from late Edo to early Meiji].
Western medicine began to be introduced to Japan since late 16th century. Japanese encounter with Western medicine centered on Dejima in Nagasaki in the seventeenth and eighteenth century and the initial process of introduction was gradual and slow. In the mid-nineteenth century, facing threats from Western countries, Tokugawa bakufu asked Dutch naval surgeon, J. L. C. Pompe van Meerdervoort to teach western medicine at the Kaigun Denshujo naval academy in Nagasaki. The government also supported the western medical school in Edo. This paper deals with how modern western medical doctors were developed in Japan from late Edo to early Meiji. The publication of the New Text on Anatomy in 1774 translated by Sugita Genpaku and his colleagues stimulated Japanese doctors and scholars to study western medicine, called Rangaku. During the Edo period, western medicine spread into major cities and countryside in Japan through Rangaku doctors. In 1838, for example, Dr. Ogata Koan established the Rangaku school named Tekijuku and educated many people with western medicine. When smallpox vaccination was introduced in Japan in 1849, Rangaku doctors played an important role in practiving the vaccination in cities and in countryside. After the Edo bakufu and the feudal lords of han(han) actively pursued to introduce western medicine to their hans by sending their Samurai to Edo or Nagasaki or abroad and by establishing medical schools and hospitals until their abolition in 1871. In late Edo and early Meiii military doctors were the main focus of training to meet the urgent need of military doctors in the battle fields of civil wars. The new Meiji government initiated a series of top-down reformations concerning army recruitment, national school system, public health and medical system. In 1874, the government introduced a law on medicine to adopt western medicine only and to launch a national licence system for medical doctors. Issuing supplementary regulations in the following years, the Meiji government settled down a dual-track medical licensing system: one for the graduates from medical schools with certain quality and the other for the graduate from less qualified schools who should take the licensing examination.


Analysis of calcium binding protein immunoreactivity in the claustrum and the endopiriform nucleus of the rabbit.
The present paper describes parvalbumin, calbindin-D28k and calretinin immunoreactivity in the claustrum and endopiriform nucleus of adult rabbits. Studied neuronal populations are characterized by morphological heterogeneity. Four types were identified in each subpopulation of cells containing calcium binding proteins on the basis of the number of processes and their branching pattern. There were no spatial differences in the distribution of cells containing either parvalbumin or calbindin-D28k in the claustrum and endopiriform nucleus. Well documented presence of the various projective zones in the rabbit claustrum did not reflect the specific distribution of neurons containing calcium binding proteins, except those containing calretinin. Their localization may correspond with the limbic zone. We have found that the rabbit claustrum and endopiriform nucleus have different pattern of parvalbumin and calretinin immunoreactivity. The former was more intense in the claustrum and the distribution of cell types was significantly different from that in the endopiriform nucleus. Calretinin-positive cells were observed in the claustrum, while in the endopiriform nucleus they were scarce. The distribution of neither calbindin-D28k-ir neurons nor fibers allowed differentiation of claustrum and endopiriform nucleus. Significant differences between the claustrum and endopiriform nucleus observed in the rabbit might be related with ontogenetic as well as other (functional) factors.


The emerging medical/industrial complex. The industrialization of medicine.
Until recently, the traditional practice of medicine has been thought of as a cottage industry practiced by individuals or small partnership groups. The transition of practice settings to large groups, multi-specialty groups, and corporations has paved the way to industrialization, with even larger health care organizations primarily managed by non-physicians. The similarities of these events to the industrial revolution and its impact on crafts guilds are striking. In order to understand this point of view, this article explores the function and influence of crafts guilds during stages of industrial development and the dynamics of the changes of employment needs and employability in an industrial environment as a comparison to what is happening in the health care field.


Design of Children's Motor Skills Training Management System Based on Human Movement Recognition Algorithm of Depth Information.
With the deepening of the concept of all-round development, the training of children's motor skills is becoming more and more popular. Children's motor skills training management system is based on the product of children's motor skills training combined with modern technology. This article aims to design a management system for children's motor skills training based on human motion recognition methods. This article proposes a human motion recognition algorithm based on depth information. The traditional human motion recognition algorithm is more biased towards children's motor skills. For the design of the system, this article also pays great attention to children's experience. After analyzing the performance of the system in this study, it is found that the system is not ideal for multitarget human motion recognition. Therefore, this article optimizes the recognition. After the optimization, the recognition rate of the head, upper body, and lower body of the multiobjective human motion recognition is more than 80%.


Assemblases and coupling proteins in thick filament assembly.
Thick filaments are stable assemblies of myosin that are characteristic of specific muscle types from both vertebrates and invertebrates. In general, their structure and assembly require remarkably precise determination of lengths and diameters, structural differentiation and nonequivalence of myosins, a high degree of inelasticity and rigidity, and dynamic regulation of assembly and disassembly in response to both extracellular and intracellular signals. Directed assembly of myosin in which additional proteins function in key roles, therefore, is more likely to be significant than the simple self assembly of myosin into thick filaments. The nematode Caenorhabditis elegans permits a wide spectrum of biochemical, genetic, molecular and structural approaches to be applied to the experimental testing of this hypothesis. Biochemical analysis of C. elegans thick filaments reveals that paramyosin, a homologue of the myosin rod that is the unique product of a single genetic locus, exists as two populations which differ by post-translational modification. The major paramyosin species interacts with the two genetically specified myosin heavy chain isoforms. The minor paramyosin species is organized within the cores of the thick filaments, where it is associated stoichiometrically with three recently identified proteins P20, P28 and P30. These proteins have now been characterized molecularly and contain unique, novel amino acid sequences. Structural analysis of the core shows that seven paramyosin subfilaments are crosslinked by additional internal proteins into a highly rigid tubule. P20, P28 and P30 are proposed to couple the paramyosin subfilaments together into the core tubule during filament assembly. Mutants that affect paramyosin assembly are being characterized for alterations in the core proteins. A fourth protein has been identified recently as the product of the unc-45 gene. Computational analysis of this gene's DNA suggests that the predicted protein may exhibit protein phosphatase and chaperone activities. Genetic analysis shows that three classes of specific unc-45 mutant proteins differentially interact with the two myosins during thick filament assembly. The unc-45 protein is proposed to be a myosin assemblase, a protein catalyst of thick filament assembly.


GC-MS method validation and levels of methyl eugenol in a diverse range of tea tree (Melaleuca alternifolia) oils.
Tea tree oil distilled from Melaleuca alternifolia has widespread use in the cosmetic industry as an antimicrobial as well as for other functions in topical products. Concerns were first raised by the European Commission's Scientific Committee on Consumer Products in 2004 about the level of the potentially carcinogenic phenylpropanoid compound methyl eugenol in tea tree oil. Limits on oil content in different types of cosmetic products were set based on a reported upper level of 0.9% methyl eugenol in the oil. A previous publication indicated that these levels were based on oil from a Melaleuca species not used in the commercial production of oil. Even the highest recorded levels in Melaleuca alternifolia, the overwhelmingly most common species used, were ∼15 times less than this, meaning that more oil could be safely used in the products. The current study, including details on methodology and reproducibility, extends that work across a suite of 57 plantation-sourced oils from a range of geographical locations and production years, as well as many Australian and international commercial oils. Lower levels of methyl eugenol in oils of known provenance were confirmed, with a recorded range of 160-552 ppm and a mean of 337 ppm. Analysis of variance showed methyl eugenol levels in Australian plantation oils to be correlated to the geographical region but not to the year of production. Average methyl eugenol levels in commercial oils were significantly lower, and these samples were divided into an authentic group and a group that were suspected of being adulterated based on an independent test. Authentic commercial oils had similar levels of methyl eugenol to Australian provenance material, whilst the oils classed as suspect had significantly lower levels.


[Identification of implicated factors in angiogenesis for the study of vascular anomalies].
Angiogenesis, the development of the vascular network, and lymphangiogenesis, the development of the lymphatic system, are two processes that are tightly linked and pivotal for the development and growth of a human being. Therefore, it is not surprising that lymph/angiogenesis plays a important role for health and is implicated in many diseases such as arteriosclerosis, arthritis, diabetes and cancer, both in children and in adults. To better understand lymph/angiogenesis and the factors that are implied in man, I became interested in the etiopathogenesis of vascular and lymphatic anomalies. These lesions are often congenital, very diversified, and occur with variable frequency, but in general affect about 0,3% of the population. Most frequently, they are well demarcated and localized, and histologically constituted of enlarged, tortuous vessels. By using a genetic approach on the familial forms, we have been able to identify several genes and causative mutations. These discoveries serve as a starting point for more precise clinical diagnosis and identification of the precise underlying pathophysiological mechanisms. These genes are also important for the search of novel therapies for these anomalies, as well as for all other disorders in which lymph/angiogenesis is implicated.


A strategy for human factors/ergonomics: developing the discipline and profession.
Human factors/ergonomics (HFE) has great potential to contribute to the design of all kinds of systems with people (work systems, product/service systems), but faces challenges in the readiness of its market and in the supply of high-quality applications. HFE has a unique combination of three fundamental characteristics: (1) it takes a systems approach (2) it is design driven and (3) it focuses on two closely related outcomes: performance and well-being. In order to contribute to future system design, HFE must demonstrate its value more successfully to the main stakeholders of system design. HFE already has a strong value proposition (mainly well-being) and interactivity with the stakeholder group of 'system actors' (employees and product/service users). However, the value proposition (mainly performance) and relationships with the stakeholder groups of 'system experts' (experts fromtechnical and social sciences involved in system design), and 'system decision makers' (managers and other decision makers involved in system design, purchase, implementation and use), who have a strong power to influence system design, need to be developed. Therefore, the first main strategic direction is to strengthen the demand for high-quality HFE by increasing awareness among powerful stakeholders of the value of high-quality HFE by communicating with stakeholders, by building partnerships and by educating stakeholders. The second main strategic direction is to strengthen the application of high-quality HFE by promoting the education of HFE specialists, by ensuring high-quality standards of HFE applications and HFE specialists, and by promoting HFE research excellence at universities and other organisations. This strategy requires cooperation between the HFE community at large, consisting of the International Ergonomics Association (IEA), local (national and regional) HFE societies, and HFE specialists. We propose a joint world-wide HFE development plan, in which the IEA takes a leadership role. Human factors/ergonomics (HFE) has much to offer by addressing major business and societal challenges regarding work and product/service systems. HFE potential, however, is underexploited. This paper presents a strategy for the HFE community to strengthen demand and application of high-quality HFE, emphasising its key elements: systems approach, design driven, and performance and well-being goals.


A new class of DNA photolyases present in various organisms including aplacental mammals.
DNA photolyase specifically repairs UV light-induced cyclobutane-type pyrimidine dimers in DNA through a light-dependent reaction mechanism. We have obtained photolyase genes from Drosophila melanogaster (fruit fly), Oryzias latipes (killifish) and the marsupial Potorous tridactylis (rat kangaroo), the first photolyase gene cloned from a mammalian species. The deduced amino acid sequences of these higher eukaryote genes show only limited homology with microbial photolyase genes. Together with the previously cloned Carassius auratus (goldfish) gene they form a separate group of photolyase genes. A new classification for photolyases comprising two distantly related groups is proposed. For functional analysis P.tridactylis photolyase was expressed and purified as glutathione S-transferase fusion protein from Escherichia coli cells. The biologically active protein contained FAD as light-absorbing cofactor, a property in common with the microbial class photolyases. Furthermore, we found in the archaebacterium Methanobacterium thermoautotrophicum a gene similar to the higher eukaryote photolyase genes, but we could not obtain evidence for the presence of a homologous gene in the human genome. Our results suggest a divergence of photolyase genes in early evolution.


The role of antibiotics and probiotics in pouchitis.
Pouchitis is a non-specific inflammation of the ileal reservoir and the most common complication of proctocolectomy with ileal pouch-anal anastomosis (IPAA) in patients with ulcerative colitis. Its frequency is related to the duration of the follow up, occurring in up to 50% of patients 10 years after IPAA in large series from major referral centers. Treatment of pouchitis is largely empirical and only small placebo-controlled trials have been conducted. The rationale for using probiotics and antibiotics in pouchitis is based on convincing evidence that implicates intestinal bacteria in the pathogenesis of this disease. Probiotics are living organisms, which, upon ingestion in certain numbers, exert health benefits beyond inherent basic nutrition. VSL#3, a highly concentrated cocktail of probiotics has been shown to be effective in the prevention of pouchitis onset and relapses. Antibiotics are the mainstay of treatment of pouchitis, and metronidazole and ciprofloxacin are the most common initial approaches, often with a rapid response. The use of antibiotics in pouchitis is largely justified although proper controlled trials have not been conducted.


Value of an immunofluorescence assay for the detection of Pneumocystis carinii in Bronchoalveolar lavage.
An indirect immunofluorescence monoclonal antibody assay was found to have higher sensitivity than usual stains for the detection of Pneumocystis carinii, particularly in bronchoalveolar lavage fluids in which there are only a few parasites, as in HIV-patients or in HIV+ patients with prophylaxis or treatment. For patients without any therapy, when different stains give conflicting results, decisions on therapeutic approaches to be used should consider the patient's clinical and biological status. Prospective studies are necessary to evaluate the predictive value of low parasitism in asymptomatic immunosuppressed patients.


[Proliferative vitreoretinopathy: relation to the extent of retinal detachment, size of retinal tears and coagulation surface].
Preretinal dispersion of stimulated RPE cells has been suggested as a possible cause of the development of proliferative vitreoretinopathy (PVR). Retinal detachment (RD) and retinal breaks are associated with an exposure of corresponding areas of retinal pigment epithelium (RPE) which has been mechanically stimulated by coagulation. In a prospective, controlled study of 141 patients between 20 and 75 years of age, PVR grades were determined before and RD surgery and within six months following it PVR grades were correlated with the extent of RD, size of breaks, and area of coagulation. The severity of the PVR correlated significantly with both the extent of RD as well as the total number of coagulation exposures. There was a tendency toward higher grades of PVR with larger retinal breaks. The results are compatible with the hypothesis that at least certain variations of PVR are caused by preretinal dispersion of stimulated RPE cells.


The transfer of trichloroethylene (TCE) from a shower to indoor air: experimental measurements and their implications.
Experiments were performed to measure the transfer of trichloroethylene (TCE), a volatile organic compound (VOC), from tap water in showers to indoor air. In these experiments, the loss of TCE from tap water in the shower is based on the difference between influent and effluent concentrations. We have developed and previously published a three-compartment model, which we use to simulate the 24-h concentration history of VOCs in the shower, bathroom, and remaining household volumes resulting from the use of contaminated tap water. An important input to this model is the transfer efficiency of the VOC from water to air. The experiments reveal that the transfer efficiency of TCE from shower water to air has an arithmetic mean value of 61 percent and an arithmetic standard deviation of 9 percent. Analysis of the results shows that there is no statistically significant difference between the transfer efficiency measured with hot (37 degrees C) or cold (22 degrees C) shower water and that there is no statistically significant change in transfer efficiency with time during a 20-min shower. The implications for exposure assessment are considered.


Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy.
B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.


Oxytocin use in grand-multiparous patients: safety and complications.
To determine whether the use of oxytocin for the augmentation of labor in grandmultiparous women increases the risk of peripartum complications. During the years 1989-97, 11 075 grand-multiparous women delivered at our institution. In 424 grand-multiparous women, intravenous oxytocin was used for augmentation of labor. The control group consisted of the other 10 651 grand-multiparous women. All women were monitored for fetal heart rate and uterine contractions. We compared the rates of maternal and perinatal complications in these two groups by using chi(2) analysis and Fisher's exact test when appropriate. No significant differences were found between the oxytocin and the control groups in the rates of placental abruption, intrapartum fetal death, postpartum hemorrhage, uterine rupture, fetal distress, meconium-stained amniotic fluid, an Apgar score of less than 7 at 5 min, Cesarean section, retained placenta and vaginal and cervical lacerations. In contrast, a significant increase in the rate of vacuum deliveries was observed in patients given oxytocin as compared to controls (3.5% vs. 1.4%, respectively; p = 0.001). The use of oxytocin in the grand-multiparous parturient was a safe procedure with no significant increase in peripartum complications. However, a higher rate of vacuum deliveries was found.


Double-blind placebo-controlled trial of etanercept in the prevention of work disability in ankylosing spondylitis.
Etanercept has been shown to be rapidly effective in suppressing disease activity in ankylosing spondylitis (AS). The aim of this study was to determine whether etanercept improves work instability as measured by the Ankylosing Spondylitis Work Instability Scale (AS-WIS). Forty patients with active AS who were in work but were work unstable were recruited. Patients were randomised to receive 25 mg etanercept or placebo twice weekly for 12 weeks. The primary outcome was change in AS-WIS at week 12. The AS-WIS is a patient-derived outcome measure which allows stratification of the risk of job loss. Secondary outcomes included clinical outcomes and gait parameters. The mean improvement in AS-WIS score at week 12 was 2.75 in the etanercept group and 0.68 in the placebo group (p=0.125). The risk of job loss decreased for 11 (55%) of the etanercept group compared with 7 (35%) in the placebo group. Conversely, the risk of job loss increased in 3 (15%) of the placebo group compared with 1 (5%) in the etanercept group. There was no statistically significant difference between treatment groups in change in WIS categories (Mann-Whitney U test=0.153, p=0.160). Significant improvement with etanercept was seen at week 12 in clinical outcomes and gait parameters. Etanercept was well tolerated, with no dropouts due to adverse events. This small study confirms the efficacy of etanercept on clinical outcome measures in patients with AS and suggests an effect on work instability which needs to be replicated in a larger controlled study.


Vibration white finger: a follow up study.
To study the course of vibration white finger (VWF) 55 men were re-examined three and a half to six years after the first examination. The patients were interviewed and finger systolic pressure after general body and local finger cooling was measured. The test results at the two examinations were compared. At the follow up examination some patients experienced a subjective improvement of VWF symptoms but not until more than three years had passed after they had stopped working with vibrating tools. To study the effect of diminished cold exposure on subjective symptoms, vibration exposed outdoor workers who changed to unexposed indoor work were studied separately. In this subgroup also improvement was reported only when more than three years has passed after the change of work, indicating that diminished cold exposure is not the primary explanation for the improvement. The cold provocation test, however, showed no tendency towards a diminished reaction of the vessels to cooling. Patients who continue to work with vibrating tools report a subjective increase in symptoms. This subjective impairment was reflected in an increased reaction to cold as measured in the cold provocation test.


Learning sparse log-ratios for high-throughput sequencing data.
The automatic discovery of sparse biomarkers that are associated with an outcome of interest is a central goal of bioinformatics. In the context of high-throughput sequencing (HTS) data, and compositional data (CoDa) more generally, an important class of biomarkers are the log-ratios between the input variables. However, identifying predictive log-ratio biomarkers from HTS data is a combinatorial optimization problem, which is computationally challenging. Existing methods are slow to run and scale poorly with the dimension of the input, which has limited their application to low- and moderate-dimensional metagenomic datasets. Building on recent advances from the field of deep learning, we present CoDaCoRe, a novel learning algorithm that identifies sparse, interpretable and predictive log-ratio biomarkers. Our algorithm exploits a continuous relaxation to approximate the underlying combinatorial optimization problem. This relaxation can then be optimized efficiently using the modern ML toolbox, in particular, gradient descent. As a result, CoDaCoRe runs several orders of magnitude faster than competing methods, all while achieving state-of-the-art performance in terms of predictive accuracy and sparsity. We verify the outperformance of CoDaCoRe across a wide range of microbiome, metabolite and microRNA benchmark datasets, as well as a particularly high-dimensional dataset that is outright computationally intractable for existing sparse log-ratio selection methods. The CoDaCoRe package is available at https://github.com/egr95/R-codacore. Code and instructions for reproducing our results are available at https://github.com/cunningham-lab/codacore. Supplementary data are available at Bioinformatics online.


A new dimension of the PACU: the dilemma of the ICU overflow patient.
With the increase in the number of critically ill patients needing extended periods of time in the ICU and the subsequent shortage of ICU beds, hospitals have examined ways to use the PACU as an alternative for the short-term critically ill patient. This article identifies common problems encountered by the PACU staff, and the author suggests criteria for establishing and implementing guidelines for successful integration of these short-term critically ill patients without losing sight of the PACU's goals and compromising patient care. The criteria for establishing guidelines were based on the personal experience of the author in developing a program for ICU overflow patients, as well as from experiences of other PACU nurses working in PACUs where successful guidelines currently are used.


Comparison of Cervicovaginal Cytopathological Samples Collected in Basic Health Units and in Private Clinics in the Midwest of Santa Catarina.
To compare the quality of cervicovaginal samples obtained from basic health units (BHUs) of the Unified Health System (SUS) and those obtained from private clinics to screen precursor lesions of cervical cancer. It was an intervention study whose investigated variables were: adequacy of the samples; presence of epithelia in the samples, and cytopathological results. A total of 940 forms containing the analysis of the biological samples were examined: 470 forms of women attended at BHUs of the SUS and 470 forms of women examined in private clinics in January and February of 2016. All the unsatisfactory samples were collected at BHUs and corresponded to 4% of the total in this sector (p < 0.0001). There was a higher percentage of samples containing only squamous cells in the SUS (43.9%). There was squamocolumnar junction (SJC) representativeness in 82.1% of the samples from the private clinics (p < 0.0001). Regarding negative results for intraepithelial lesions and/or malignancies, the percentages obtained were 95.9% and 99.1% (p < 0.0049) in the exams collected in the private system and SUS, respectively. Less serious lesions corresponded to 0.89% of the samples from the SUS and 2.56% of the tests from the private sector; more serious lesions were not represented in the samples obtained from BHUs, whereas the percentage was 1.49% in private institutions. Unsatisfactory cervical samples were observed only in exams performed at the SUS. There is a need for guidance and training of professionals who perform this procedure to achieve higher reliability in the results and more safety for women who undergo this preventive test.


The PARP inhibitor, olaparib, depletes the ovarian reserve in mice: implications for fertility preservation.
What is the impact of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, alone or in combination with chemotherapy on the ovary in mice? Olaparib treatment, when administered alone, depletes primordial follicle oocytes, but olaparib does not exacerbate chemotherapy-mediated ovarian follicle loss in mice. The ovary contains a finite number of oocytes stored within primordial follicles, which give rise to all mature ovulatory oocytes. Unfortunately, they are highly sensitive to exogenous DNA damaging insults, such as cytotoxic cancer treatments. Members of the PARP family of enzymes are central to the repair of single-strand DNA breaks. PARP inhibitors have shown promising clinical efficacy in reducing tumour burden, by blocking DNA repair capacity. Olaparib is a PARP1/2 inhibitor recently FDA-approved for treatment of BRCA1 and BRCA2 mutation carriers with metastatic breast cancer. It is currently being investigated as an adjunct to standard treatment at an earlier stage, potentially curable, BRCA1- and BRCA2-associated breast cancer which affects reproductive age women. Despite this, there is no preclinical or clinical information regarding the potential impacts of olaparib on the ovary or on female fertility. Unfortunately, it may be many years before clinical data on fertility outcomes for women treated with PARP inhibitors becomes available, highlighting the importance of rigorous preclinical research using animal models to establish the potential for new cancer therapies to affect the ovary in humans. We aimed to comprehensively determine the impact of olaparib alone, or following chemotherapy, on the ovary in mice. On Day 0, mice (n = 5/treatment group) were administered a single intraperitoneal dose of cyclophosphamide (75 mg/kg/body weight), doxorubicin (10 mg/kg), carboplatin (80 mg/kg), paclitaxel (7.5 mg/kg) or vehicle control. From Days 1 to 28, mice were administered subcutaneous olaparib (50 mg/kg) or vehicle control. This regimen is proven to reduce tumour burden in preclinical mouse studies and is also physiologically relevant for women. Adult female wild-type C57BL6/J mice at peak fertility (8 weeks) were administered a single intraperitoneal dose of chemotherapy, or vehicle, then either subcutaneous olaparib or vehicle for 28 days. Vaginal smears were performed on each animal for 14 consecutive days from Days 15 to 28 to monitor oestrous cycling. At 24 h after final treatment, ovaries were harvested for follicle enumeration and immunohistochemical analysis of primordial follicle remnants (FOXL2 expressing granulosa cells), DNA damage (γH2AX) and analysis of apoptosis by TUNEL assay. Serum was collected to measure circulating anti-Müllerian hormone (AMH) concentrations by ELISA. Olaparib significantly depleted primordial follicles by 36% compared to the control (P < 0.05) but had no impact on other follicle classes, serum AMH, corpora lutea number (indicative of ovulation) or oestrous cycling. Primordial follicle remnants were rarely detected in control ovaries but were significantly elevated in ovaries from mice treated with olaparib alone (P < 0.05). Similarly, DNA damage denoted by γH2AX foci was completely undetectable in primordial follicles of control animals but was observed in ∼10% of surviving primordial follicle oocytes in mice treated with olaparib alone. These observations suggest that functional PARPs are essential for primordial follicle oocyte maintenance and survival. Olaparib did not exacerbate chemotherapy-mediated follicle depletion in the wild-type mouse ovary. N/A. This study was performed in mice, so the findings may not translate to women and further studies utilizing human ovarian tissue and sera samples should be performed in the future. Only one long-term time point was analysed, therefore olaparib-mediated follicle damage should be assessed at more immediate time points in the future to support our mechanistic findings. Olaparib dramatically depleted primordial follicles and this could be attributed to loss of intrinsic PARP-mediated DNA repair mechanisms. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility. Notably, the extent of follicle depletion might be enhanced in BRCA1 and BRCA2 mutation carriers, and this is the subject of current investigations. Together, our data suggest that fertility preservation options should be considered for young women prior to olaparib treatment, and that human studies of this issue should be prioritized. This work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. This work was supported by funding from the National Health and Medical Research Council (NHMRC); (K.J.H. #1050130) (A.L.W. #1120300). K.A.P. is a National Breast Cancer Foundation Fellow (Australia-PRAC-17-004). K.A.P. is the Breast Cancer Trials (Australia) Study Chair for the OlympiA clinical trial sponsored by AstraZeneca, the manufacturer of olaparib. All other authors declare no competing financial or other interests.


Accuracy and cost-effectiveness of cervical cancer screening by high-risk human papillomavirus DNA testing of self-collected vaginal samples.
Estimate the accuracy and cost-effectiveness of cervical cancer screening strategies based on high-risk human papillomavirus (HPV) DNA testing of self-collected vaginal samples. A subset of 1,665 women (age range, 18-50 y) participating in a cervical cancer screening study were screened by liquid-based cytology and by high-risk HPV DNA testing of both self-collected vaginal swab samples and clinician-collected cervical samples. Women with positive/abnormal screening test results and a subset of women with negative screening test results were triaged to colposcopy. On the basis of individual and combined test results, 5 screening strategies were defined. Estimates of sensitivity and specificity for cervical intraepithelial neoplasia grade 2 or worse were calculated, and a Markov model was used to estimate the incremental cost-effectiveness ratios for each strategy. Compared with cytology-based screening, high-risk HPV DNA testing of self-collected vaginal samples was more sensitive (68%, 95% CI = 58%-78% vs 85%, 95% CI = 76%-94%) but less specific (89%, 95% CI = 86%-91% vs 73%, 95% CI = 67%-79%). A strategy of high-risk HPV DNA testing of self-collected vaginal samples followed by cytology triage of HPV-positive women was comparably sensitive (75%, 95% CI = 64%-86%) and specific (88%, 95% CI = 85%-92%) to cytology-based screening. In-home self-collection for high-risk HPV DNA detection followed by in-clinic cytology triage had a slightly lower lifetime cost and a slightly higher quality-adjusted life year (QALY) expectancy than did cytology-based screening (incremental cost-effectiveness ratio of triennial screening compared with no screening was $9,871/QALY and $12,878/QALY, respectively). Triennial screening by high-risk HPV DNA testing of in-home, self-collected vaginal samples followed by in-clinic cytology triage was cost-effective.


Optimal two-stage strategy for detecting interacting genes in complex diseases.
The mapping of complex diseases is one of the most important problems in human genetics today. The rapid development of technology for genetic research has led to the discovery of millions of polymorphisms across the human genome, making it possible to conduct genome-wide association studies with hundreds of thousands of markers. Given the large number of markers to be tested in such studies, a two-stage strategy may be a reasonable and powerful approach: in the first stage, a small subset of promising loci is identified using single-locus testing, and, in the second stage, multi-locus methods are used while taking into account the loci selected in the first stage. In this report, we investigate and compare two possible two-stage strategies for genome-wide association studies: a conditional approach and a simultaneous approach. We investigate the power of both the conditional and the simultaneous approach to detect the disease loci for a range of two-locus disease models in a case-control study design. Our results suggest that, overall, the conditional approach is more robust and more powerful than the simultaneous approach; the conditional approach can greatly outperform the simultaneous approach when one of the two disease loci has weak marginal effect, but interacts strongly with the other, stronger locus (easily detectable using single-locus methods in the first stage). Genome-wide association studies hold the promise of finding new genes implicated in complex diseases. Two-stage strategies are likely to be employed in these large-scale studies. Therefore we compared two natural two-stage approaches: the conditional approach and the simultaneous approach. Our power studies suggest that, when doing genome-wide association studies, a two-stage conditional approach is likely to be more powerful than a two-stage simultaneous approach.


Biosynthesis of von Willebrand protein by human megakaryocytes.
Immunofluorescence staining of buffy coat smears from a patient with chronic myelogenous leukemia in accelerated phase showed that approximately 13% of all nucleated cells contained von Willebrand protein and, therefore, appeared to be of megakaryocytic origin. This was confirmed by positive staining with antisera against platelet factor 4 and platelet glycoproteins. Short-term cultures of the buffy coat, which lacked endothelial cells, were metabolically labeled with [35S]methionine, and von Willebrand protein was immunopurified from cell lysates and culture medium. Cultures from this patient synthesized and secreted von Willebrand protein, in contrast with cultures from other patients with leukemia, who lacked circulating megakaryocytes, and from normal volunteers. The subunit composition of the megakaryocytic von Willebrand protein was very similar to that of human umbilical vein endothelial cells. The size of the processed subunit (220 kD) and of the cellular (260 kD) and secreted (275 kD) precursors from the two cell types were indistinguishable by gel electrophoresis. Furthermore, the ratio of precursor to processed subunit and the pattern of cellular and secreted nonreduced multimers were very similar. It appears, therefore, that the processing steps in biosynthesis of von Willebrand protein used by the megakaryocytes are very similar to those of umbilical vein endothelial cells.


The effect on the stratum-specific odds ratios of nondifferential misclassification of a dichotomous covariate.
Precise measurement of confounding or effect modifying variables is seldom possible. Nondifferential misclassification of such a variable can introduce bias in the odds ratios within the strata of the confounding variable. For two strata, the effect on the odds ratios is dependent on separate measures of the degree of nondifferential misclassification of the confounding variable. The authors investigate the bias in the stratum-specific odds ratios from nondifferential misclassification of a confounder in a case-control study, and show how estimates of the true stratum-specific odds ratios can be derived. For one stratum, the degree of bias introduced in the odds ratio is dependent only on the sensitivity of the measure of the confounding variable while only the specificity of this measure determines the bias introduced in the other stratum-specific odds ratio. The results are applied to a case-control study of fenoterol prescription and asthma death.


Knowledge, attitude, motivation and planning of breastfeeding: a cross-sectional study among Jordanian women.
In Jordan, the rate of exclusive breastfeeding is declining. The trend variation in breastfeeding practice is determined by different factors including antenatal women's attitude and planning which are affected by their awareness and the support they receive. This study aims to assess knowledge, attitude, support, and planning of breastfeeding among Jordanian women. A face-to-face cross-sectional semi-structured questionnaire survey was conducted among healthy women in the antenatal clinic and postpartum ward at three hospitals in Northern Jordan during the period August 2019 to December 2019. Data were collected about demographic characteristics, women's knowledge and attitude towards breastfeeding, antenatal and postnatal support and counseling, and feeding planning. Customized scales were utilized to assess knowledge and attitude. Factors associated with planning to breastfeed were reported. 660 women completed the survey questionnaire. The majority were 20 to 35 years of age, 10% were primiparous, and 30% were employed. 78% were knowledgeable about breastfeeding benefits and aware of WHO recommendations. 72% had a positive attitude towards breastfeeding. More than half received support from their husbands to breastfeed their infants, while less than 20% received any counseling from their obstetric providers. 97% reported their intention to breastfeed, and more than half indicated their willingness to breastfeed exclusively. With multivariable logistic regression modelling, predictors of EBF planning include: primiparity (AOR 1.79; 95% CI 1.1, 3.25), positive attitude (AOR 1.80; 95% CI 1.05, 3.1) and positive husband's support (AOR 1.92; 95% CI 1.18, 3.15). Barriers include women's employment (AOR 0.43; 95% CI 0.26, 0.70) and low birthweight (AOR 0.46; 95% CI 0.25, 0.84). Jordanian women are highly knowledgeable about breastfeeding benefits, and they exhibit a positive attitude towards breastfeeding resulting in a very high percentage intending to breastfeed their infants. Limited counseling about breastfeeding is a major gap in antenatal care. As intentions might not reflect the actual practice after delivery, gaps and barriers affecting the determinants of successful breastfeeding should be identified, and corrective tools should be implemented accordingly. Allocating a specific time for antenatal or postnatal counseling and support is expected to promote breastfeeding practice in our population.


An assessment of Qatar's coral communities in a regional context.
Qatar's once extensive coral communities have undergone considerable change in recent decades. We quantitatively surveyed three coral assemblages in Qatar to assess current status, and compared these against 14 sites in Bahrain and the United Arab Emirates to evaluate Qatar in a larger biogeographic context. Umm Al-Arshan had the highest species richness of 17 sites examined in the southern Arabian Gulf, as well as the highest coral cover and the only Acropora observed on sites in Qatar. Coral cover and richness were more modest at Fuwayrit and Al-Ashat, reflecting greater impacts from earlier stress events. Two distinct communities were identified across the southern Gulf, with Umm Al-Arshan clustering with high-cover, mixed merulinid/poritid assemblages that were less impacted by earlier bleaching and long-term stress, while Fuwayrit and Al-Ashat grouped with a lower-cover, stress-tolerant community characteristic of more extreme environments in the southern Gulf. We recommend implementation of a nation-wide baseline assessment of coral communities to guide development of an MPA network and long-term coral monitoring program for Qatar.


Casein phosphopeptide calcium chelation: preparation optimization, in vitro gastrointestinal simulated digestion, and peptide fragment exploration.
Calcium is important in the formation of bones and teeth, cell metabolism, and other physiological activities. In this work, casein phosphopeptide-calcium chelate (CPP-Ca) was synthesized and the optimal process parameters for the chelation reaction were obtained. The bioavailability of calcium in CPP-Ca was investigated by in vitro gastrointestinal simulated digestion. The existence of phytic acid and oxalic acid in the digestion system was evaluated to clarify the calcium holding ability of casein phosphopeptide (CPP). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify oligopeptides from CPP-Ca. The optimal process parameters for the chelation reaction were: peptide concentration 7.76 mgmL-1 , pH 8.54, and reaction temperature 43.3 °C. The digestion in vitro results indicated that the calcium release rate of CPP-Ca in the stomach for 2 h reached 85%, and about 50% of the ionized calcium was re-chelated with CPP in the intestine. Phytic acid and oxalic acid could lead to a sharp decrease in soluble calcium but around 50% of the calcium was still retained in the form of chelates in the presence of CPP. The LC-MS/MS identified 19 casein-derived oligopeptides after digestion, and calcium modifications were found on eight peptides derived from β-casein and αs2 -casein. This study clarified the excellent calcium holding capacity of CPP in the presence of phytic acid and oxalic acid. Liquid chromatography-tandem mass spectrometry also revealed peptide changes, and identified peptides that chelate with calcium. These findings provided significant insights that could be relevant to the further utilization and product development of peptide-calcium chelate in the food industry. © 2023 Society of Chemical Industry.


Anharmonicity and Disorder in the Black Phases of Cesium Lead Iodide Used for Stable Inorganic Perovskite Solar Cells.
Hybrid organic-inorganic perovskites emerged as a new generation of absorber materials for high-efficiency low-cost solar cells in 2009. Very recently, fully inorganic perovskite quantum dots also led to promising efficiencies, making them a potentially stable and efficient alternative to their hybrid cousins. Currently, the record efficiency is obtained with CsPbI3, whose crystallographical characterization is still limited. Here, we show through high-resolution in situ synchrotron XRD measurements that CsPbI3 can be undercooled below its transition temperature and temporarily maintained in its perovskite structure down to room temperature, stabilizing a metastable perovskite polytype (black γ-phase) crucial for photovoltaic applications. Our analysis of the structural phase transitions reveals a highly anisotropic evolution of the individual lattice parameters versus temperature. Structural, vibrational, and electronic properties of all the experimentally observed black phases are further inspected based on several theoretical approaches. Whereas the black γ-phase is shown to behave harmonically around equilibrium, for the tetragonal phase, density functional theory reveals the same anharmonic behavior, with a Brillouin zone-centered double-well instability, as for the cubic phase. Using total energy and vibrational entropy calculations, we highlight the competition between all the low-temperature phases of CsPbI3 (γ, δ, β) and show that avoiding the order-disorder entropy term arising from double-well instabilities is key to preventing the formation of the yellow perovskitoid phase. A symmetry-based tight-binding model, validated by self-consistent GW calculations including spin-orbit coupling, affords further insight into their electronic properties, with evidence of Rashba effect for both cubic and tetragonal phases when using the symmetry-breaking structures obtained through frozen phonon calculations.


Face Mask Wearing Behaviors, Depressive Symptoms, and Health Beliefs Among Older People During the COVID-19 Pandemic.
The COVID-19 pandemic has affected more than 100 countries. Despite the global shortage of face masks, the public has adopted universal mask wearing as a preventive measure in many Asian countries. The COVID-19 mortality rate is higher among older people, who may find that wearing a face mask protects their physical health but jeopardizes their mental health. This study aimed to explore the associations between depressive symptoms, health beliefs, and face mask wearing behaviors among older people. By means of an online survey conducted between March and April 2020, we assessed depressive symptoms, health beliefs regarding COVID-19, and face mask use and reuse among community-dwelling older people. General linear models were employed to explore the associations among these variables. Of the 355 valid participants, 25.6% experienced depressive symptoms. Health beliefs regarding the perceived severity of disease (p = 0.001) and perceived efficacy of practicing preventive measures (p = 0.005) were positively associated with face mask use. Those who reused face masks (p = 0.008) had a stronger belief in disease severity (p < 0.001), had poorer cues to preventive measures (p = 0.002), and were more likely to experience depressive symptoms. Mask reuse was significantly associated with depression only among those who perceived the disease as serious (p = 0.025) and those who had poorer cues to preventive measures (p = 0.004). In conclusion, health beliefs regarding perceived severity and efficacy contributed to more frequent face mask use, which was unrelated to depressive symptoms. Older people who had a stronger belief in disease severity had less adequate cues to preventive measures and reused face masks experienced greater depressive symptoms. A moderation effect of health beliefs (i.e., disease severity and cues to preventive measures) on face mask reuse and depression was observed.


Ectopic overexpression of wild-type and mutant hipA genes in Escherichia coli: effects on macromolecular synthesis and persister formation.
Persistence is an epigenetic trait that allows a small fraction of bacteria, approximately one in a million, to survive prolonged exposure to antibiotics. In Escherichia coli an increased frequency of persisters, called "high persistence," is conferred by mutations in the hipA gene, which encodes the toxin entity of the toxin-antitoxin module hipBA. The high-persistence allele hipA7 was originally identified because of its ability to confer high persistence, but little is known about the physiological role of the wild-type hipA gene. We report here that the expression of wild-type hipA in excess of hipB inhibits protein, RNA, and DNA synthesis in vivo. However, unlike the RelE and MazF toxins, HipA had no effect on protein synthesis in an in vitro translation system. Moreover, the expression of wild-type hipA conferred a transient dormant state (persistence) to a sizable fraction of cells, whereas the rest of the cells remained in a prolonged dormant state that, under appropriate conditions, could be fully reversed by expression of the cognate antitoxin gene hipB. In contrast, expression of the mutant hipA7 gene in excess of hipB did not markedly inhibit protein synthesis as did wild-type hipA and yet still conferred persistence to ca. 10% of cells. We propose that wild-type HipA, upon release from HipB, is able to inhibit macromolecular synthesis and induces a bacteriostatic state that can be reversed by expression of the hipB gene. However, the ability of the wild-type hipA gene to generate a high frequency of persisters, equal to that conferred by the hipA7 allele, may be distinct from the ability to block macromolecular synthesis.


Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials.
Although randomized controlled trials (RCTs) have suggested a non-significant increased risk of stroke among proton pump inhibitor (PPI) users, the association has not been confirmed. We evaluated the association between regular use of PPIs and incident stroke and identified population groups at high net risk. This is a prospective analysis of 492,479 participants free of stroke from the UK biobank. Incident stroke was identified through linkage to hospital admission and death registries using the International Classification of Diseases (ICD)-10 codes (I60, I61, I63, and I64). We evaluated hazard ratios (HRs) adjusting for demographic factors, lifestyle habits, prevalent comorbidities, concomitant use of medications, and indications of PPIs. We assessed the risk differences (RDs) according to the baseline Framingham Stroke Risk Score. In the meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (from 1988 to 1 June 2020) for randomized trials comparing PPIs with other interventions, placebo, or no treatment on stroke risk. Results were combined using a fix-effect meta-analysis (Mantel-Haenszel method). We documented 5182 incident strokes over 3,935,030 person-years of follow-up. Regular PPI users had a 16% higher risk of stroke than non-users (HR 1.16, 95% CI 1.06 to 1.27). The estimated effect was similar to our meta-analysis of nine RCTs (case/participants 371/26,642; RR 1.22, 95% CI 1.00 to 1.50; quality of evidence: moderate). The absolute effect of PPI use on stroke increased with the baseline Framingham Stroke Risk Score, with an RD of 1.34‰, 3.32‰, 4.83‰, and 6.28‰ over 5 years for the lowest, quartile 2, quartile 3, and the highest quartile, respectively. Regular use of PPIs was associated with an increased risk of stroke, with a higher absolute risk observed in individuals with high baseline stroke risk. Physicians should therefore exercise caution when prescribing PPIs. An assessment of the underlying stoke risk is recommended for individualized use of PPIs.


Cancer disparities in Appalachian Kentucky.
Cancer is the second leading cause of death in the United States, and the disease burden is elevated in Appalachian Kentucky, due in part to health behaviors and inequities in social determinants of health. This study's goal was to evaluate Appalachian Kentucky's cancer burden compared to non-Appalachian Kentucky, and Kentucky compared to the United States (excluding Kentucky). The following data were analyzed: annual all-cause and all-site cancer mortality rates from 1968 to 2018; 5-year all-site and site-specific cancer incidence and mortality rates from 2014 to 2018; aggregated screening and risk factor data from 2016 to 2018 for the United States (excluding Kentucky), Kentucky, non-Appalachian Kentucky, and Appalachian Kentucky; and human papilloma virus vaccination prevalence by sex from 2018 for the United States and Kentucky. Since 1968, the United States has experienced a large decrease in all-cause and cancer mortality, but the reduction in Kentucky has been smaller and slower, driven by even smaller and slower reductions within Appalachian Kentucky. Appalachian Kentucky has higher overall cancer incidence and mortality rates and higher rates for several site-specific cancers compared to non-Appalachian Kentucky. Contributing factors include screening rate disparities and increased rates of obesity and smoking. Appalachian Kentucky has experienced persistent cancer disparities, including elevated all-cause and cancer mortality rates for 50+ years, widening the gap between this region and the rest of the country. In addition to addressing social determinants of health, increased efforts aimed at improving health behaviors and increased access to health care resources could help reduce this disparity.


Hydroxyl PAMAM dendrimer-based gene vectors for transgene delivery to human retinal pigment epithelial cells.
Ocular gene therapy holds promise for the treatment of numerous blinding disorders. Despite the significant progress in the field of viral and non-viral gene delivery to the eye, significant obstacles remain in the way of achieving high-level transgene expression without adverse effects. The retinal pigment epithelium (RPE) is involved in the pathogenesis of retinal diseases and is a key target for a number of gene-based therapeutics. In this study, we addressed the inherent drawbacks of non-viral gene vectors and combined different approaches to design an efficient and safe dendrimer-based gene-delivery platform for delivery to human RPE cells. We used hydroxyl-terminated polyamidoamine (PAMAM) dendrimers functionalized with various amounts of amine groups to achieve effective plasmid compaction. We further used triamcinolone acetonide (TA) as a nuclear localization enhancer for the dendrimer-gene complex and achieved significant improvement in cell uptake and transfection of hard-to-transfect human RPE cells. To improve colloidal stability, we further shielded the gene vector surface through incorporation of PEGylated dendrimer along with dendrimer-TA for DNA complexation. The resultant complexes showed improved stability while minimally affecting transgene delivery, thus improving the translational relevance of this platform.


Approaching In Vivo Models of Pneumococcus-Host Interaction: Insights into Surface Proteins, Capsule Production, and Extracellular Vesicles.
Infections caused by the Gram-positive bacterium Streptococcus pneumoniae have become a major health problem worldwide because of their high morbidity and mortality rates, especially in developing countries. This microorganism colonizes the human upper respiratory tract and becomes pathogenic under certain circumstances, which are not well known. In the interaction with the host, bacterial surface structures and proteins play major roles. To gain knowledge into gradual changes and adaptive mechanisms that this pathogen undergoes from when it enters the host, we mimicked several in vivo situations representing interaction with epithelial and macrophage cells, as well as a condition of presence in blood. Then, we analyzed, in four pneumococcal strains, two major surface structures, the capsule and extracellular vesicles produced by the pneumococci, as well as surface proteins by proteomics, using the "shaving" approach, followed by LC-MS/MS. We found important differences in both surface ultrastructures and proteins among the culture conditions and strains used. Thus, this work provides insights into physiological adaptations of the pneumococcus when it interacts with the host, which may be useful for the design of strategies to combat infections caused by this pathogen.


A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability.
Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.


Cognitive control is quickly adapted to actual task requirements despite misleading context cues-Evidence from the N2, CRN, and ERN.
Cognitive control is flexibly adapted to task requirements in healthy individuals. Medio-frontal negativities in the event-related potential of the electroencephalogram can serve as indicators of cognitive control. With increasing conflict frequency, stimulus-locked control, as indexed by the N2, is increased and response-locked control, as indexed by the correct-related negativity, is reduced. On the behavioral level, this shift is associated with improved conflict resolution as evident in reduced response times and error rates in incompatible trials and a reduced response time congruency effect. Cognitive control adaptation might be implemented through experience-based task sets specifying advantageous processing strategies. Here, we investigated whether the cognitive control task set will be sustained when coupled with a contextual cue, even when the initial task requirements are no longer present. A flanker task with two conflict frequency conditions (25% incompatible and 75% incompatible trials) was presented. In the training phase, the conflict frequency conditions were paired with a distinct context cue (i.e., background color). In the test phase, the previously associated cues were again presented, but conflict frequency was identical in both conditions (50% incompatible trials). Although typical cognitive control adaptation was observed in the training phase on the behavioral and event-related potentials level, this pattern was not sustained in the test phase. Thus, the present study provides further evidence that cognitive control is flexibly adapted to task requirements even in the presence of misleading cues.


Study of the cell biology and biochemistry of cherubism.
To establish whether the multinucleate cells in lesions of patients with cherubism are also osteoclasts and if this is the case whether they were responsive to calcitonin; to carry out cytogenetic studies on two members of the same family affected by cherubism in an attempt to identify any major chromosomal defects; and to perform an in-depth modern biochemical study of four children in the same family. Four related children with cherubism were studied. Tissue taken from one of the children at elective decompression of an optic nerve was submitted to in vitro bone resorption studies. Cytogenetic studies were done on two of the children and biochemical studies on all four. The multinucleate cells in the cherubic lesions were shown to be osteoclasts since they synthesised tartrate resistant acid phosphatase, expressed the vitronectin receptor, and resorbed bone. Bone resorption by the cultured multinucleate cells was significantly inhibited by calcitonin. High resolution cytogenetic studies failed to detect any chromosomal abnormalities in two children with cherubism. The biochemistry profile of all four children with cherubism showed that serum calcium, parathyroid hormone, parathyroid related hormone, calcitonin, and alkaline phosphatase were within normal levels. Urine analysis of pyridinium and deoxypyridinium cross links, hydroxyproline, and calcium in relation to urine creatinine were measured to assess bone resorption in these children, and the values were at the upper end of the normal range in all four. Further studies are required to determine whether calcitonin treatment will control this grossly deforming disease until the time when the physiological changes that occur at puberty rectify the pathology. It is not recommended that biochemical markers of bone resorption are used in isolation to monitor the activity of cherubism in individuals because the results are based on a small number of children and because of reports of marked interindividual variation in the levels of these markers, particularly in children.


Risk factors of Omicron variant associated acute encephalitis/encephalopathy in children.
Outbreak of Omicron BA.2 in Taiwan led to an increased number of acute encephalitis/encephalopathy cases in children and several fatal cases drew public attention. In pre-Omicron period, pediatric cases of COVID-19-associated acute encephalitis have been reported and during Omicron epidemic, febrile convulsions, encephalitis were mentioned more frequently. The outcome of patients with neurological complications was worse. However, few studies investigated the risk factors, pathophysiology and prognosis of COVID-19-associated encephalitis/encephalopathy. Here, we describe the presentation of pediatric cases of COVID-19-associated acute encephalitis/encephalopathy and explore the associated risk factors. Pediatric patients with confirmed SARS-CoV-2 infections were prospectively enrolled at admission at Chang Gung Memorial Hospital between April and August 2022. Patients were categorized into groups of acute encephalitis/encephalopathy, febrile convulsions or mild disease. Demographic descriptions, clinical manifestations and laboratory data were collected. Of 288 acute COVID-19 patients, there were 38 (13.2%) acute encephalitis/encephalopathy, 40 (13.9%) febrile convulsions, and 210 (72.9%) mild disease. Among acute encephalitis/encephalopathy group, the mean age was 68.3 ± 45.0 months. The common neurological symptoms were lethargy (65.8%), seizures (52.6%), and impaired consciousness (34.2%). Over 3 years old (adjusted odds ratio [aOR]: 7.57, p < 0.001), absolute neutrophil count ≥3150/μL (aOR: 5.46, p = 0.008), and procalcitonin ≥0.5 ng/mL (aOR: 4.32, p = 0.021) were independent factors for acute encephalitis/encephalopathy. Most cases of COVID-19-associated acute encephalitis/encephalopathy showed no evidence of direct viral invasion but associations with older age, increased peripheral neutrophil, and serum procalcitonin. These findings may imply the neutrophil-mediated systemic inflammatory response plays an important role on central nerve system, leading to cerebral dysfunction.


General practitioners' attitudes and behaviors toward HPV vaccination: A French national survey.
General practitioners (GPs) play a crucial role in human papillomavirus (HPV) vaccine acceptance in France. We sought to study: (1) GPs' perceptions of its risks and efficacy and their recommendation behavior; (2) the relative importance of factors associated with the frequency of their recommendations. Cross-sectional observational study in 2014 nested in a national panel of 1712 randomly selected GPs in private practice in France (response rate: 92.4%). We used model averaging to analyze the associations of self-reported frequency of GPs' HPV vaccine recommendations with their perception of its risk-benefit balance and their opinions about the utility of vaccines in general. Overall, 72% of participants reported frequently recommending HPV vaccination; 60% considered that not enough is known about its risks. The model averaging showed that the factors most associated with infrequent recommendation of this vaccine by GPs were: unfavorable perceptions of its risk-benefit balance (OR=0.13; 95%CI=0.09-0.21; partial R(2)=0.10), a decision not to vaccinate one's own daughter(s) with this vaccine (OR=0.13; 95%CI=0.07-0.24; partial R(2)=0.05), and doubts about vaccine utility in general (OR=0.78; 95%CI=0.71-0.86; partial R(2)=0.03). Although nearly three-quarters of French GPs frequently recommended the HPV vaccine, our findings indicate that a substantial percentage of them are hesitant about it. Doubts about its risks and efficacy strongly influence their recommendation behavior. More research is warranted to help design and evaluate tailored tools and multicomponent intervention strategies to address physician's hesitancy about this vaccine.


How are stereotypes maintained through communication? The influence of stereotype sharedness.
Recent research has suggested that interpersonal communication may be an important source of stereotype maintenance. When communicated through a chain of people, stereotype-relevant information tends to become more stereotypical, thus confirming the stereotypes held by recipients of communication. However, the underlying mechanisms of this phenomenon have yet to be fully determined. This article examines how the socially shared nature of stereotypes interacts with communication processes to maintain stereotypes in communication chains. In 3 experiments, participants communicated a stereotype-relevant story through 4-person chains using the method of serial reproduction. Manipulations included the extent to which communicators believed their audience and other community members shared and endorsed their stereotypes, and also the extent to which they actually shared the stereotypes. The shared nature of stereotypes was found to be a strong contributor to rendering the story more stereotypical in communication. This is discussed in relation to the maintenance of stereotypes through communication.


Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis.
Cell-based assays (CBAs) were shown to improve detection of acetylcholine receptor (AChR) antibodies in patients with myasthenia gravis (MG). Herein, we asked whether these assays were able to help determine the diagnosis in patients studied in routine clinical practice. To determine the diagnostic usefulness of CBAs in the diagnosis of MG and to compare the clinical features of patients with antibodies only to clustered AChRs with those of patients with seronegative MG (SNMG). All patients with clinical suspicion of MG who were seen within the Division of Clinical Neurology at the John Radcliffe Hospital in Oxford, England, between November 1, 2009, and November 30, 2013. Their serum antibodies and clinical features were studied. Radioimmunoprecipitation assay (RIPA) and CBA were used to test for standard AChR antibodies and antibodies to clustered AChRs in 138 patients. All available samples from patients with SNMG were retrospectively tested for lipoprotein receptor-related protein 4 (LRP4) antibodies. Demographic, clinical, neurophysiological, and laboratory data. In total, 138 patients were tested for antibodies to clustered AChRs, and 42 had a final diagnosis of MG. The clustered AChR CBA detected antibodies in 38.1% (16 of 42) of RIPA-negative patients with MG with 100% specificity. All patients with SNMG who were tested for LRP4 antibodies (21 of 26) were negative by CBA. Compared with patients with SNMG, patients with antibodies only to clustered AChRs had frequent prepubertal onset (62.5% [median age, 6 years; age range, 1-52 years] vs 11.5% [median age, 38 years; age range, 2-72 years], P ≤ .05), high prevalence of ocular MG (62.5% vs 42.3%), milder disease severity with less bulbar involvement (25.0% vs 46.2%), and absence of respiratory symptoms (0% vs 23.1%). Response to treatment and prognosis was good, with a reduced need for thymectomy (6.3% vs 19.2%) and a high proportion of patients going into remission (50.0% vs 8.3%, P ≤ .05). These observations also apply to the classic AChR MG phenotype seen in large series. Cell-based assay is a useful procedure in the routine diagnosis of RIPA-negative MG, particularly in children. Patients with antibodies only to clustered AChRs appear to be younger and have milder disease than other patients with MG. These observations will have implications in planning treatment.


Rifampicin and rifapentine significantly reduce concentrations of bedaquiline, a new anti-TB drug.
Bedaquiline is the first drug of a new class approved for the treatment of TB in decades. Bedaquiline is metabolized by cytochrome P450 (CYP) 3A4 to a less-active M2 metabolite. Its terminal half-life is extremely long (5-6 months), complicating evaluations of drug-drug interactions. Rifampicin and rifapentine, two anti-TB drugs now being optimized to shorten TB treatment duration, are potent inducers of CYP3A4. This analysis aimed to predict the effect of repeated doses of rifampicin or rifapentine on the steady-state pharmacokinetics of bedaquiline and its M2 metabolite from single-dose data using a model-based approach. Pharmacokinetic data for bedaquiline and M2 were obtained from a Phase I study involving 32 individuals each receiving two doses of bedaquiline, alone or together with multiple-dose rifampicin or rifapentine. Sampling was performed over 14 days following each bedaquiline dose. Pharmacokinetic analyses were performed using non-linear mixed-effects modelling. Models were used to simulate potential dose adjustments. Rifamycin co-administration increased bedaquiline clearance substantially: 4.78-fold [relative standard error (RSE) 9.10%] with rifampicin and 3.96-fold (RSE 5.00%) with rifapentine. Induction of M2 clearance was equally strong. Average steady-state concentrations of bedaquiline and M2 are predicted to decrease by 79% and 75% when given with rifampicin or rifapentine, respectively. Simulations indicated that increasing the bedaquiline dosage to mitigate the interaction would yield elevated M2 concentrations during the first treatment weeks. Rifamycin antibiotics reduce bedaquiline concentrations substantially. In line with current treatment guidelines for drug-susceptible TB, concomitant use is not recommended, even with dose adjustment.


[Immunocorrection in rheumatoid arthritis].
The clinical and immunological parameters were compared over time in 125 patients with rheumatoid arthritis subjected to immunocorrection. As a result of the study the drugs and their combinations used are distributed in the following order as regards their efficacy: combined treatment with prospidin and tactivin; prospidin; immunoglobulin therapy with high doses; combined therapy with thymohexin and immunoglobulin (low doses); thymohexin; prodigiosan; immunoglobulin (low doses). The dynamics of cellular immunity did not always correlate with the clinical efficacy of the immunocorrection. No relationship was discovered between the functional activity of natural killers and peripheral macrophages and the dynamics of the clinico-laboratory characteristics. Stimulation of endogenous and con A-induced suppression provided a therapeutic effect only in cases of the induction of both suppression types whereas the combined use of prospidin and tactivin allowed the reduction of the intensity and rate of side effects and maintained functions of peripheral macrophages. Immunocorrection which enabled the decrease of the level of lymphocytes expressing HLA-DR antigens in blood turned out most effective.


Dietary carotenoids increase yellow nonpigment coloration of female convict cichlids (Amantitlania nigrofasciata).
The carotenoid trade-off hypothesis states that diet-derived carotenoids are traded off among competing physiological demands, but this statement is rarely tested in ornamented females. In this study, reverse sexually dimorphic convict cichlids (Amantitlania nigrofasciata) were fed diets containing carotenoid supplementation at three biologically relevant levels for 12 wk. This treatment was followed by spectral, microscopic, and chemical analysis to determine how females allocated the pigments to tissues and how those decisions affected their ventral patch coloration. Yellow coloration of the integument increased with carotenoids in the diet, as did carotenoids deposited in ovaries, but diet did not change carotenoid allocation to skin. The results of this study suggest that females have the ability to modulate their expression of yellow coloration via an alternative coloration strategy. Gonadosomatic index and tank environment were also related to ventral patch color, supporting previous behavioral work highlighting the importance of social selection in reinforcing signal honesty.


Is transesophageal electrophysiologic study valuable in children with successful radiofrequency ablation of supraventricular tachycardia on follow-up for recurrence?
The aim of this study was to evaluate the efficacy of transesophageal electrophysiologic study (TEEPS) for the determination of supraventricular tachycardia (SVT) recurrences in symptomatic and asymptomatic children after successful radiofrequency ablation (RFA) for SVT. A total of 66 patients who underwent TEEPS after successful RFA were included. The demographic features, symptoms of the patients, and the characteristics of the recurrences induced by TEEPS were evaluated. The arrhythmia types induced during RFA were compared with those induced by TEEPS in terms of the compatibility of the diagnosis. Forty-two (63.6%) girls and 24 (36.4%) boys with a mean age of 11.8±3.4 years were followed-up for 44.1±15.7 months. The average time between RFA and TEEPS was 5.2±5.9 months. The diagnoses during RFA were atrioventricular nodal reentrant tachycardia (AVNRT) in 47 of 66 patients, atrioventricular reentrant tachycardia (AVRT) in 18 of 66 patients, and ectopic atrial tachycardia in 1 of 66 patients. SVT was induced by TEEPS in 2 of 25 symptomatic and 5 of 41 asymptomatic patients. The SVT inducibility rate was 5.5% (1/18) and 12.7% (6/47) in patients with AVRT and AVNRT, respectively. In addition, 85.7% (6/7) of all recurrences occurred within 3.5 months. The recurrences as AVNRT in 2 of 25 symptomatic patients occurred in the first month after RFA. AVNRT in 4 of 41 and AVRT in 1 of 41 asymptomatic patients were induced within 3.5 months and 15 months, respectively. TEEPS seems to be a valuable screening and diagnostic method for the determination of recurrence in symptomatic and asymptomatic children who underwent successful RFA.


[Therapy with nitrates in the post-infarct phase].
The beneficial effects of nitrates in patients with angina pectoris and acute myocardial infarction have positively influenced the prognosis of the treated patients. Studies of Jugdutt pointed out that there is a better prognosis also in the postinfarction period. Especially left ventricular over dilatation, which follows larger infarct, can be prevented by a consistent nitrate therapy.


Activities of Nigerian chewing stick extracts against Bacteroides gingivalis and Bacteroides melaninogenicus.
The in vitro activities of extracts of Nigerian chewing sticks against Bacteroides gingivalis and B. melaninogenicus are presented. The greatest inhibitory action was produced by Serindeia werneckei, whereas Fagara zanthoxyloides produced no appreciable inhibitory effect. A generally good correlation was found between the killing curves and MICs. Only extracts of Anogeissus leiocarpus showed acute toxicity in mice.


Ease of Application of Various Neuromuscular Devices for Routine Monitoring.
Subjective evaluations to confirm recovery from neuromuscular blockade with a peripheral nerve stimulator (PNS) is inadequate. Quantitative monitors are the only reliable method to confirm adequate recovery of neuromuscular function. Unfortunately, many clinicians are unfamiliar with such devices and there is concern that the introduction of objective monitoring would be exceedingly laborious and could cause workflow delays. This study investigates how long it takes experienced nurse anesthetists to apply various neuromuscular devices as well as their perception regarding the ease of application. Twenty nurse anesthetists were consented and participated in an educational session that familiarized them with 3 devices: SunStim Plus PNS (SunMed, Grand Rapids, MI), the acceleromyography-based IntelliVue NMT device (Philips, Amsterdam, the Netherlands), and electromyography-based TetraGraph device (Senzime B.V., Uppsala, Sweden). Participants were timed while placing each monitor on patients in a real-world setting. For the quantitative devices (IntelliVue NMT and TetraGraph), participants were also timed when obtaining calibrated baseline train-of-four (TOF) ratios. Friedman test and pairwise Wilcoxon signed-rank tests were used to evaluate the difference in time to connect different devices. Participants were surveyed about how easy they found it to utilize these devices. After adjusting for multiple comparison, time to connect was significantly less for PNS (median, 29; range, 16-58 seconds) compared to either the TetraGraph device (median, 62.8; range, 32-101 seconds; P < .001) or the IntelliVue NMT device (median, 46; range: 28-90 seconds; P < .001). The difference in time to connect between the TetraGraph device and the IntelliVue NMT device was not statistically significant (P = .053), but it took significantly less time to calibrate the TetraGraph device than the IntelliVue NMT device (median difference, -16; range, -88 to 49 seconds; P = .002). The participants found applying either the IntelliVue NMT device (P = .042) or the TetraGraph device (P = .048) more difficult than applying a PNS while finding it easier to calibrate the TetraGraph device versus the IntelliVue NMT device (P < .001). It takes 19 seconds longer to apply a quantitative neuromuscular monitor (the IntelliVue NMT device) than a PNS. While this difference reached significance, this relatively minimal additional time represents an inappropriate barrier to the application of quantitative monitors. Regardless of which quantitative monitor was utilized, these nurse anesthetists found the application and utilization of such devices relatively straightforward.


Social behavior of young dairy calves housed with limited or full social contact with a peer.
This study compared the effect of individual and pair housing and age at pair housing on the social behavior of young dairy calves. Twenty-seven pairs of calves were reared from birth until 6 wk either individually (limited social contact between bars; L calves), in pairs (full social contact; F calves), or individually for 3 wk and in pairs for the next 3 wk (LF calves). From 6 to 7 wk of age, the calves were housed in a group of 6 calves (each group consisted of 3 pair of calves, 1 pair from each treatment). Video recordings of undisturbed behavior were obtained from each pair on d 2, 12, 22, and 34 (age of the youngest calf in a pair) and from the group pens on d 44 and 49 (age of the youngest calf in the group). Behavioral recordings were performed using instantaneous recording at 5-min intervals on d 2, 22, and 34 over 16 h to investigate overall activity and social activity of the pairs. Six of 6 F calves and 2 of 6L calves were sniffing and licking another calf on d 2. Calves from treatments F and LF were sniffing and licking another calf more on d 22 compared with on d 34, but we observed no difference between treatments F and LF. On both days, the F calves and LF calves were sniffing and licking another calf more than were the L calves. No difference was found in duration of lying down in body contact with another calf between F and LF calves on d 22; however, on d 34, LF calves performed more of this behavior than did F calves. Continuous recordings of social behavior were conducted for 3h on d 12 and 34. On d 12, we found no difference between F and L calves in the total duration of being actively engaged in social behaviors. On d 34, F and LF calves were more actively engaged in social behaviors than were the L calves. After grouping, lying behavior and nearest neighbor during rest were recorded instantaneously at 15-min intervals for 16 h on d 44 and 49. From d 44 to 49, the duration of resting increased, the duration of resting with a neighbor increased, and the duration of resting with the previous companion decreased. No difference was found between treatments after grouping in duration of rest and rest with a neighbor. In conclusion, from the age of 3 wk of life, calves housed with full social contact performed more social behaviors than calves housed individually with limited social contact, whereas only minor differences were found in the social behavior of calves housed together from birth compared with those housed together from 3 wk of life.


Trauma, disease and collateral damage: conflict in cimicids.
The bed bugs and bat bugs (Hemiptera: Cimicidae) are unusual in being a gonochorist (separate male and female genders) taxon with obligate traumatic insemination. Males of all the species in this family have a lanceolate paramere (intromittent organ) which they use to pierce the female's body wall and inseminate directly into her haemocoel, despite the presence of a functional female genital tract. Mating is tightly linked to the feeding cycle in Cimex lectularius, the common bed bug. In this paper, I examine key aspects of the reproductive anatomy and behaviour of C. lectularius that underpin the nature of the conflict over mating rate in this species. I then examine the consequences of traumatic insemination for female fitness and examine potential mechanisms that might underpin those costs. Finally, the collateral consequences of the male reproductive tactic on other males of C. lectularius and the African bat bug, Afrocimex constrictus are examined.


Crystal structure of a recombinant anti-estradiol Fab fragment in complex with 17beta -estradiol.
The crystal structure of a Fab fragment of an anti-17beta-estradiol antibody 57-2 was determined in the absence and presence of the steroid ligand, 17beta-estradiol (E2), at 2.5 and 2.15-A resolutions, respectively. The antibody binds the steroid in a deep hydrophobic pocket formed at the interface between the variable domains. No major structural rearrangements take place upon ligand binding; however, a large part of the heavy chain variable domain near the binding pocket is unusually flexible and is partly stabilized when the steroid is bound. The nonpolar steroid skeleton of E2 is recognized by a number of hydrophobic interactions, whereas the two hydroxyl groups of E2 are hydrogen-bonded to the protein. Especially, the 17-hydroxyl group of E2 is recognized by an intricate hydrogen bonding network in which the 17-hydroxyl itself forms a rare four-center hydrogen bond with three polar amino acids; this hydrogen bonding arrangement accounts for the low cross-reactivity of the antibody with other estrogens such as estrone. The CDRH3 loop plays a prominent role in ligand binding. All the complementarity-determining regions of the light chain make direct contacts with the steroid, even CDRL2, which is rarely directly involved in the binding of haptens.