Role of p-glycoprotein in region-specific gastrointestinal absorption of talinolol in rats.
P-Glycoprotein (PGP) is nonuniformly distributed along the gastrointestinal (GI) tract; however, the data regarding regional differences in PGP function in the intestine are controversial. The aim of this work was to investigate the role of PGP efflux in region-specific absorption of talinolol from the GI tract in rats. Plasma talinolol concentrations were measured after several modes of administration, including high (40 mg/kg) and low (4 mg/kg) dose levels, to different segments of the GI tract (stomach versus colon), and codosing with PGP inhibitors (verapamil or cyclosporine). The bioavailability (F) of talinolol after high-dose administration to the stomach was significantly greater than that achieved by the low dose (approximately 18 versus 2%). Coadministration of low-dose talinolol with cyclosporine increased F by approximately 5-fold (p < 0.01). For the high dose, codosing with PGP inhibitors did not increase the extent of absorption. Talinolol demonstrated poor colonic absorption that was significantly increased by coadministration with cyclosporine (F = 0.76 versus 8.1%). Oral verapamil significantly increased systemic clearance and the steady state volume of distribution of intravenous talinolol. A semiphysiological model was developed that successfully captured the pharmacokinetic profiles of talinolol after various modes of administration. PGP-mediated efflux appears to be a major factor responsible for GI region-specific absorption of talinolol in rats, and gastroretentive dosage forms may provide an advantage in the delivery of talinolol and PGP substrate drugs.


Atypical Presentations and Management of Endocrine and Hepatic Immune-Related Adverse Events From Adjuvant Immune Checkpoint Inhibitor Therapy in Stage III Resected Melanoma.
Patients diagnosed with stage III melanoma who have undergone curative-intent surgery still remain at relatively high risk of disease recurrence. Recently approved adjuvant therapies with immune checkpoint inhibitors (ICIs) have brought increased relapse-free and overall survival rates. However, they have introduced a new range of side effects that can be difficult to diagnose, are challenging to treat, and may have lifelong consequences for patients. Oncologists and other members of the oncology care team should be aware of these side effects, including atypical presentations, and be prepared to intervene to prevent increased morbidity and mortality. Oncologists also need to have a low threshold for referral to other subspecialists, as many of these immune-related adverse events (irAEs) need to be comanaged using a multidisciplinary approach. Herein, we present a case that illustrates challenging presentations of endocrinopathy and hepatic irAEs in a patient with stage III melanoma receiving ICI therapy in the adjuvant setting.


Sternoclavicular joint infection: a comparison of two surgical approaches.
This study compares conventional open debridement with the recently proposed flap closure technique for sternoclavicular joint infection. This is a retrospective review of patients undergoing surgery for sternoclavicular joint infection during the last 7 years. Twenty patients underwent 35 operations for sternoclavicular joint infection from 2002 to 2009. The debridement and open wound procedure (10 of 20 patients, 50%) involved debridement of the clavicle, manubrium, and first rib and open wound care. The joint resection and flap closure procedure (10 of 20 patients, 50%) involved partial resection of the clavicle, manubrium, and first rib, with immediate (9 of 10) or early (1 of 10) wound closure with pectoralis major advancement flap. The two groups were comparable in comorbidities, duration of symptoms, radiologic findings, and microbiologic results. Despite an approach of planned reoperation for wound care, the open group had fewer mean procedures performed per patient (1.6±0.7 versus 1.9±1.6), owing to fewer unplanned procedures (0 versus 0.8 procedures/patient) than the flap group. The incidence of wound complications (hematoma, seroma) was lower in open patients (0 of 10 versus 5 of 10). The median length of hospitalization was shorter in the open group (5.5 versus 10.5 days), but all open patients (10 of 10; 100%) required prolonged wound care compared with 2 of 10 (20%) in the flap group. The only hospital mortality occurred in the flap group. Eventual wound healing was satisfactory in all survivors. For sternoclavicular joint infection, a single-stage resection and muscle advancement flap leads to a higher incidence of complications. Debridement with open wound care provides satisfactory outcomes with minimal perioperative complications but requires prolonged wound care.


Thyroid disease and cancer in kidney transplantation: a single-center analysis.
Thyroid diseases are frequent in patients with end-stage renal disease, but data on renal transplant recipients are conflicting. This study evaluated the incidence of thyroid disease and cancer in a population of kidney transplant recipients performed in a single center. Seven hundred sixty patients receiving a kidney transplantation between January 2000 and October 2017 were followed with thyroid ultrasonography to determine nodules together with thyroid hormone levels. Ultrasound-guided fine-needle aspiration citology (FNAc) was performed to the nodules > 10 mm . Two hundred four patients (26.8%) patients demonstrated functional or morphologic changes in the thyroid gland compared with pre-transplant period. Among the 204 patients with newly diagnosed thyroid disease, 165 patients had single or multiple nodular lesions less than 1 cm in diameter, and were followed yearly. Nodule size progression was observed in 23 patients (13.9%), and they underwent a FNAc. A total of sixty-two patients (30.3%) underwent FNAc. The biopsy samples were cytologically interpreted as benign in 20 patients (32.2%), suspicious in 40 patients (64.5%), or at high risk of cancer in 2 patients (3.2%). Forty-two patients underwent total thyroidectomy. At histological examination, 18 patients had a thyroid cancer (papillary cancer in 17 patients, follicular cancer in one). Thyroid cancer was more frequent in male patients with a mean time from transplant to diagnosis of 5.6 years. At a mean follow-up was 8 ± 1.2 years, all patients are alive with a normal functioning graft. Thyroid diseases are common in transplant recipients. Thyroid disease may evolve after transplantation, probably as a consequence of immunosuppression. A complete evaluation of thyroid disease is mandatory in kidney transplant recipients because early diagnosis and appropriate treatment of thyroid disease and cancer may significantly decrease the morbidity and mortality in these patients.


A solid-state light-matter interface at the single-photon level.
Coherent and reversible mapping of quantum information between light and matter is an important experimental challenge in quantum information science. In particular, it is an essential requirement for the implementation of quantum networks and quantum repeaters. So far, quantum interfaces between light and atoms have been demonstrated with atomic gases, and with single trapped atoms in cavities. Here we demonstrate the coherent and reversible mapping of a light field with less than one photon per pulse onto an ensemble of approximately 10(7) atoms naturally trapped in a solid. This is achieved by coherently absorbing the light field in a suitably prepared solid-state atomic medium. The state of the light is mapped onto collective atomic excitations at an optical transition and stored for a pre-determined time of up to 1 mus before being released in a well-defined spatio-temporal mode as a result of a collective interference. The coherence of the process is verified by performing an interference experiment with two stored weak pulses with a variable phase relation. Visibilities of more than 95 per cent are obtained, demonstrating the high coherence of the mapping process at the single-photon level. In addition, we show experimentally that our interface makes it possible to store and retrieve light fields in multiple temporal modes. Our results open the way to multimode solid-state quantum memories as a promising alternative to atomic gases.


Virus-induced transcriptional activation of host FUT genes associated with neo-expression of Ley in cytomegalovirus-infected and sialyl-Lex in varicella-zoster virus-infected diploid human cells.
Cell surface carbohydrate structures including sialyl-Lewis X (sLe(x)) and Lewis Y (Le(y)) are important ligands in normal and malignant tissues. The aim here was to determine the possible influence on the expression of such antigens by two viruses varicella-zoster virus (VZV) and cytomegalovirus (CMV) involved in persistent infections of humans. We found that infection of human diploid fibroblasts with both viruses resulted in transcriptional activation of several fucosyltransferase (FUT) genes that were either dormant or expressed at low levels in uninfected cells. Both viruses induced FUT3, FUT5, and FUT6, encoding alpha1,3- and/or alpha1,4-specific fucosyltransferases. CMV, but not VZV, induced transcription of FUT1 (encoding an alpha1,2-specific fucosyltransferase), FUT7, and FUT9. The changes in transcription of FUT genes were expectedly associated with expression of Le(y) in CMV-infected cells and sLe(x) in the VZV-infected fibroblasts although no expression of these antigens was observed in uninfected cells. One major explanation for this difference between CMV- and VZV-infected cells was that CMV, but not VZV, induced expression of FUT1, necessary for Le(y) expression. The induced carbohydrate antigens in CMV- and VZV-infected cells could be of significance for virus spread and possible escape from immune responses.


What Influences the Decision to Interview a Candidate for Medical School?
Holistic review, in which medical schools seek to balance applicant attributes and experiences alongside traditional academic metrics in making admissions decisions, has been in place for over a decade. Medical school applicants and the admissions' community are still trying to understand the impact of holistic review on the composition of those medical schools choose to interview and accept. The study cohort included all candidates who applied to Uniformed Services University of the Health Sciences (USU) in 2014, 2015, and 2016 (N = 8,920). We conducted logistic regression analysis to examine the associations between the sociodemographic, academic, and military service variables of applicants applying to the School of Medicine and offers for interview. Medical College Admission Test scores and undergraduate grade point averages were important in predicting who would receive an interview. Having military experience, being a woman, and being self-reported African American race also predicted a higher likelihood of receiving an interview invitation. For example, controlling for all other variables in the model, if an applicant had previous military experience, the odds of being invited for interview was about 4 times that of an applicant who had no previous military experience. Leave this for the text and discussion. The resulting pool of interviewed and accepted students more increasingly represented the Military Health Service population served. The use of holistic review generated a class with a composition different from that which would be predicted by Medical College Admission Test and grade point average alone. Further, holistic review produced an interview pool and class more representative of the wider Military Health Service beneficiary population. In the case of USU, holistic review allowed the school to better meet its mission to create a representative class able to "care for those in harm's way."


Parents' Perceptions of the Value of Children's Participation in Pediatric Rehabilitation Services: A Phenomenographic Study.
Ensuring that children have opportunities to be involved in decision-making regarding their own care is associated with quality improvement in pediatric rehabilitation. The aim of the study was to explore parents' perceptions of the value of children's participation in pediatric rehabilitation services. Semi-structured interviews were conducted with 17 parents of children with disabilities who visited pediatric rehabilitation services. A phenomenographic analysis method was used. Three categories developed from the analysis describing how participation generated value in terms of empowerment, self-awareness, and independence. The outcome space describes a hierarchical relationship between the categories and their influence on each other. Independence achieved through participation was a core aspect and is at the highest level in the hierarchy since it includes and depends on the outcomes from both empowerment and self-awareness. Parents' perceptions of the value of children's participation in pediatric rehabilitation services include the possibility for the child to use their entire capacity through values created in terms of empowerment, self-awareness, and independence, in order to live the best life possible. Children with disabilities are diverse as a group, and further research to identify barriers and facilitators of participation is needed to adjust interventions within pediatric rehabilitation services to ensure that children with disabilities can be increasingly empowered, self-aware, and independent.


The Impact of Post-Processing Temperature on PLGA Microparticle Properties.
Biodegradable poly(lactide-co-glycolide) (PLGA) microparticles loaded with either risperidone or naltrexone were prepared from an emulsification homogenization process. The objective of this study was to determine the impact the post-treatment temperature has on the properties and subsequent performance of the microparticles. The post-treatment temperature of an ethanolic solution was characterized from 10 ~ 35ºC for the naltrexone and risperidone micropartilces. The wash temperature resulted in a typical triphasic in vitro release pattern at low wash temperatures or a biphasic pattern consisting of an elevated release rate at higher post-treatment temperatures. The post-treatment temperature largely influences the particle morphology, residual solvent levels, glass transition temperature, and drug loading and is molecule dependent, whereby these characteristics subsequently influence the drug release rate. The study highlights the importance of both the post-treatment process and control during manufacturing to obtain a formulation within the desired product profile.


Hormonal effects on canine prostatic explants in organ culture.
Explants of canine prostate were cultured in a defined medium for periods of up to 5 days with and without added steroids. Testosterone and 5 alpha-dihydrotestosterone failed to maintain their histological integrity and induced a greatly increased formation of stromal elements. Epitestosterone and 5 alpha-dihydroepitestosterone were partially successful in maintaining epithelial height although secretory activity was not preserved. The only steroid that sustained epithelial height and secretory activity whilst keeping stromal growth at a minimum was 5 alpha-androstane-3 alpha, 17 alpha-diol. The three other epimeric androstanediols were ineffective.


Shape transformation and visible region plasmonic modulation of silver nanoplates by graphene oxide.
The plasmon band of Ag nanoplates can be continuously tuned over the visible region by simply stirring with graphene oxide (GO) nanosheets, accompanied with the shape transformation from triangle to round. The ability of GO to competitively adsorb ligands (from Ag nanoplates) has been considered to response for this interesting change. Through the protection of sufficient citrate ions, the resultant Ag nanoplates exhibit the excellent stability over a long time without noticeable change of their optical properties.


When is an herbivore not an herbivore? Detritivory facilitates herbivory in a freshwater system.
Herbivory is thought to be an inefficient diet, but it independently evolved from carnivorous ancestors in many metazoan groups, suggesting that plant-eating is adaptive in some circumstances. In this study, we tested two hypotheses to explain the adaptive evolution of herbivory: (i) the Heterotroph Facilitation hypothesis (herbivory is adaptive because herbivores supplement their diets with heterotrophic microbes); and (ii) the Lipid Allocation hypothesis (herbivory is adaptive because algae, which have high lipid concentrations, are nutritionally similar to carnivory). We tested these hypotheses using enclosure cages placed in the Everglades and stocked with Sailfin Mollies (Poecilia latipinna), a native herbivore. Using shading and phosphorus addition (P), we manipulated the heterotrophic microbe and lipid composition of colonizing epiphyton and examined the effects of varying food quality on Sailfin Molly life history. Epiphyton grown in "shade only" conditions had a 55% increase in bacterial fatty acids and 34% lower ratios of saturated + monounsaturated to polyunsaturated fatty acids relative to the other treatments. Ratio of autotroph to heterotroph biovolume varied throughout the experiment, with a 697% increase at 3 weeks and 98% decrease at 6 weeks compared to the other treatments. Gut contents revealed that fish fed selectively on epiphyton to compensate for apparent deficiencies in the available food. Fish raised in "shade only" cages experienced the highest survival, which was best explained by autotrophic biovolume and algal- and bacterial-derived fatty acids at 3 weeks (2-6× more likely than alternative models with ∆AICc > 2.00), and by percentage of bacterial fatty acids in the diet at 6 weeks (3-8× more likely than alternative models with ∆AICc > 2.00). There were no differences in fish growth among treatments. Autotrophic lipids play a role in early fish life history, but we did not find these to be the best predictors of life history later in the juvenile period. Instead, heterotrophic lipids facilitated the herbivorous diet and enhanced survival of juvenile fish in our experiment. Bacterial fatty acid content of the diet promoted herbivore survival, consistent with the Heterotroph Facilitation hypothesis. This is the first study to explicitly contrast Heterotrophic Facilitation and Lipid Allocation hypotheses for the adaptive evolution of herbivory in an aquatic system.


Multiple bulky cutaneous plasmacytomas with CNS relapse without bone marrow involvement during the course of a lambda light chain myeloma.
Primary cutaneous plasmacytomas, a localized collection of neoplastic plasma cells, may present without bone marrow involvement. Secondary plasmacytomas can complicate the clinical course of multiple myeloma (MM). Both types of cutaneous plasmacytoma are commonly observed in the terminal stages of MM. We present the case of a 37-year-old Turkish man diagnosed with lambda light chain MM. The patient had numerous firm plaque-shaped cutaneous lesions on the left side of the chest, the left shoulder, and the right preauricular region without concurrent bone marrow disease. Histopathological examination of the cutaneous plaque on the left side of the chest revealed neoplastic plasma cells infiltrating the dermal region. Furthermore, the cytologic examination of cerebrospinal fluid disclosed lymphoplasmacytic cells. The patient was treated with VDTPACE (bortezomib + dexamethasone + thalidomide + adriamycin + cyclophosphamide + etoposide), and the cutaneous lesions disappeared. Central nervous system involvement was treated with craniospinal irradiation and intrathecal chemotherapy. Cutaneous involvement of MM is an unusual clinical presentation, but a high level of suspicion is advisable in patients with MM and skin lesions. The involvement of the skin was associated with advanced disease status and, therefore, with a poor prognosis. This is the first reported case of cutaneous involvement of lambda light chain MM.


The effects of calcium and magnesium ions on the adenosine triphosphatase and inosine triphosphatase activities of myosin A.
1. The effects of Ca(2+) and Mg(2+) on the enzymic activity of myosin were studied with myosin preparations treated by the ion-exchange resin Chelex-100. A reaction mixture containing 0.05m-potassium chloride was chosen in which the effects of univalent ions such as K(+), Na(+) and Cl(-) do not change significantly with small variations in their concentrations. 2. The relationship between the rate of hydrolysis of ATP or ITP and the concentration of Ca(2+) suggests that a relatively weak binding of Ca(2+) either to myosin or to the substrate nucleotide is responsible for the activation of the enzymic activity. According to the experiments with an ultrafiltration technique, the binding of Ca(2+) to myosin proceeds in at least two steps, the first occurring at one site on every 500000 atomic mass units of myosin with an apparent association constant, K(app.), 1.3x10(6)m(-1), and the second seeming to be so weak that its binding parameters cannot be determined by the method used. The first type of Ca(2+) binding is not observable with N-ethylmaleimide-modified myosin, yet this modified myosin shows activation by Ca(2+) of its adenosine triphosphatase and inosine triphosphatase. 3. The inhibition by Mg(2+) can be related to a binding reaction of Mg(2+) with myosin having K(app.) approximately 10(6)m(-1). Mg(2+) replaces the Ca(2+) bound tightly to myosin. The K(app.) for Mg(2+)-myosin binding calculated by assuming a competition between Ca(2+) and Mg(2+) for the same site is 2.1x10(5)-3.0x10(5)m(-1). When myosin is modified with a thiol reagent (p-mercuribenzoate) at a certain ratio to myosin, the inhibition by Mg(2+) becomes unobservable. 4. The behaviour of the hydrolytic activity of myosin on ATP or ITP in the presence of both Ca(2+) and Mg(2+) is consistent with the explanation that the inhibition by Mg(2+) is due to the tight binding of Mg(2+) to myosin, whereas the activation by Ca(2+) is caused either by a weak binding of Ca(2+) to myosin or by CaATP(2-) or by both.


Face-to-face interventions for informing or educating parents about early childhood vaccination.
Early childhood vaccination is an essential global public health practice that saves two to three million lives each year, but many children do not receive all the recommended vaccines. To achieve and maintain appropriate coverage rates, vaccination programmes rely on people having sufficient awareness and acceptance of vaccines.Face-to-face information or educational interventions are widely used to help parents understand why vaccines are important; explain where, how and when to access services; and address hesitancy and concerns about vaccine safety or efficacy. Such interventions are interactive, and can be adapted to target particular populations or identified barriers.This is an update of a review originally published in 2013. To assess the effects of face-to-face interventions for informing or educating parents about early childhood vaccination on vaccination status and parental knowledge, attitudes and intention to vaccinate. We searched the CENTRAL, MEDLINE, Embase, five other databases, and two trial registries (July and August 2017). We screened reference lists of relevant articles, and contacted authors of included studies and experts in the field. We had no language or date restrictions. We included randomised controlled trials (RCTs) and cluster-RCTs evaluating the effects of face-to-face interventions delivered to parents or expectant parents to inform or educate them about early childhood vaccination, compared with control or with another face-to-face intervention. The World Health Organization recommends that children receive all early childhood vaccines, with the exception of human papillomavirus vaccine (HPV), which is delivered to adolescents. We used standard methodological procedures expected by Cochrane. Two authors independently reviewed all search results, extracted data and assessed the risk of bias of included studies. In this update, we found four new studies, for a total of ten studies. We included seven RCTs and three cluster-RCTs involving a total of 4527 participants, although we were unable to pool the data from one cluster-RCT. Three of the ten studies were conducted in low- or middle- income countries.All included studies compared face-to-face interventions with control. Most studies evaluated the effectiveness of a single intervention session delivered to individual parents. The interventions were an even mix of short (ten minutes or less) and longer sessions (15 minutes to several hours).Overall, elements of the study designs put them at moderate to high risk of bias. All studies but one were at low risk of bias for sequence generation (i.e. used a random number sequence). For allocation concealment (i.e. the person randomising participants was unaware of the study group to which participant would be allocated), three were at high risk and one was judged at unclear risk of bias. Due to the educational nature of the intervention, blinding of participants and personnel was not possible in any studies. The risk of bias due to blinding of outcome assessors was judged as low for four studies. Most studies were at unclear risk of bias for incomplete outcome data and selective reporting. Other potential sources of bias included failure to account for clustering in a cluster-RCT and significant unexplained baseline differences between groups. One cluster-RCT was at high risk for selective recruitment of participants.We judged the certainty of the evidence to be low for the outcomes of children's vaccination status, parents' attitudes or beliefs, intention to vaccinate, adverse effects (e.g. anxiety), and immunisation cost, and moderate for parents' knowledge or understanding. All studies had limitations in design. We downgraded the certainty of the evidence where we judged that studies had problems with randomisation or allocation concealment, or when outcomes were self-reported by participants who knew whether they'd received the intervention or not. We also downgraded the certainty for inconsistency (vaccination status), imprecision (intention to vaccinate and adverse effects), and indirectness (attitudes or beliefs, and cost).Low-certainty evidence from seven studies (3004 participants) suggested that face-to-face interventions to inform or educate parents may improve vaccination status (risk ratio (RR) 1.20, 95% confidence interval (CI) 1.04 to 1.37). Moderate-certainty evidence from four studies (657 participants) found that face-to-face interventions probably slightly improved parent knowledge (standardised mean difference (SMD) 0.19, 95% CI 0.00 to 0.38), and low-certainty evidence from two studies (179 participants) suggested they may slightly improve intention to vaccinate (SMD 0.55, 95% CI 0.24 to 0.85). Low-certainty evidence found the interventions may lead to little or no change in parent attitudes or beliefs about vaccination (SMD 0.03, 95% CI -0.20 to 0.27; three studies, 292 participants), or in parents' anxiety (mean difference (MD) -1.93, 95% CI -7.27 to 3.41; one study, 90 participants). Only one study (365 participants) measured the intervention cost of a case management strategy, reporting that the estimated additional cost per fully immunised child for the intervention was approximately eight times higher than usual care (low-certainty evidence). No included studies reported outcomes associated with parents' experience of the intervention (e.g. satisfaction). There is low- to moderate-certainty evidence suggesting that face-to-face information or education may improve or slightly improve children's vaccination status, parents' knowledge, and parents' intention to vaccinate.Face-to-face interventions may be more effective in populations where lack of awareness or understanding of vaccination is identified as a barrier (e.g. where people are unaware of new or optional vaccines). The effect of the intervention in a population where concerns about vaccines or vaccine hesitancy is the primary barrier is less clear. Reliable and validated scales for measuring more complex outcomes, such as attitudes or beliefs, are necessary in order to improve comparisons of the effects across studies.


Intradermal powder immunization with protein-containing vaccines.
The central importance for global public health policy of delivering life-saving vaccines for all children makes the development of efficacious and safe needle-free alternatives to hypodermic needles, preferably in a thermostable form, a matter of pressing urgency. This paper comprehensively reviews past in vivo studies on intradermal powder immunization with vaccine formulations that do not require refrigeration. Particular emphasis is given to the immune response in relation to antigen adjuvantation. While needle-free intradermal delivery of vaccines induces a predominantly Th2-type immune response, adjuvants powerfully enhance and modulate the magnitude and nature of the elicited immune response at various effector sites.


Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non-small cell lung cancer.
The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non-small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)-based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0-100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1-99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.


Association Between Lifelong Premature Ejaculation and Polymorphism of Tryptophan Hydroxylase 2 Gene in the Han Population.
Premature ejaculation (PE) is widely regarded as one of the most common sexual dysfunctions in men. The neurobiogenesis of PE is complex and involves the serotoninergic (5-HT) system. In this study, we investigated whether polymorphisms in the tryptophan hydroxylase 2 (TPH2) gene were associated with lifelong PE (LPE). A total of 121 men diagnosed with LPE were recruited from our outpatient clinics and 94 healthy controls from the health examination center. Intravaginal ejaculation latency time (IELT) was measured using a stopwatch. The PE diagnostic tool (PEDT) data were collected at the same time. All subjects with LPE and healthy controls were genotyped for polymorphisms in the TPH2 gene. Allele and genotype frequencies of single-nucleotide polymorphisms (SNPs) were compared between the patients and controls. The main outcome measures are IELT and PEDT to diagnose LPE. The association of LPE with TPH2 gene polymorphisms in these areas was investigated. The IELT, PEDT scores, and education levels in the LPE group were significantly different from those in the control group. Statistically significant differences were found in the SNPs of SNV019 and rs4290270. The frequencies of the G allele and G/A genotype of SNV019 were significantly higher in the patients with LPE than in the controls (P = .045 and .037, respectively). The A allele and A/A genotype of rs4290270 were more frequent in the patients with LPE than in the controls (P = .037 and .049, respectively). In the dominant model of inheritance, the SNV019 polymorphism in the patients with LPE was significantly different from that in the controls (odds ratio [95% confidence interval] = 2.936 [1.066-8.084], P = .037). In men with LPE, there was no statistically significant association between genotype and median IELT. The SNPs SNV019 and rs4290270 of the TPH2 gene seemed to be associated with LPE in the Han population. Men with the A allele of SNV019 or the T allele of rs4290270 may be less likely to suffer from LPE. Fu X, Zhang X, Jiang T, et al. Association Between Lifelong Premature Ejaculation and Polymorphism of Tryptophan Hydroxylase 2 Gene in the Han Population. Sex Med 2020;8:223-229.


Dentochronological separation estimates for pacific rim populations.
Dental morphology of American Indians, Asians, and Pacific islanders is used with a multivariate statistic to estimate when genetic separation occurred between several populations. These estimates generally match independent estimates of separation. This method, called dentochronology, gives an American Indian fission date from Asians of about 13,000 +/- 3,000 years ago, which agrees with archeological data and rules out a European origin because of temporal priority. Polynesians split from Southeast Asians 5,000 +/- 2,200 years ago and are not derived from Melanesians. Ainu-Jomon originated in Sundaland 14,000 +/- 3,300 years ago. Africans have been separated from Asian-Americans 60,000 +/- 6,100 years.


Sequencing the full-length of the phosphatase and tensin homolog (PTEN) gene in hepatocellular carcinoma (HCC) using the 454 GS20 and Illumina GA DNA sequencing platforms.
Phosphatase and tensin homolog (PTEN) is a tumor-suppressor gene that is mutated in cancer of the liver, pancreas, endometrium, and prostate. PTEN-dependent pathways are involved in mediating cell growth and invasion. To sequence the whole gene (including introns and exons), we have taken advantage of new technologies that allow for rapid, inexpensive sequencing to great depth. DNA from 15 HCC specimens were pooled, and long-range PCR was performed by using the GeneAmp XL PCR kit. Primer parameters included: length of 20-30 base pairs (bp), melting temperature of -68 degrees C, and G/C content of 50-60%. PCR products were then column-purified and pooled, and DNA libraries were prepared for "shotgun sequencing" on both the 454 GS and Illumina GA sequencing platforms. We successfully amplified approximately 98.9% of the PTEN gene by using one long-range PCR protocol applied to 24 primer sets, resulting in 20 amplicons approximately 6.5 kilobases (kb) in length, 2 amplicons approximately 10 kb in length, and 2 amplicons approximately 2.5 kb in length. Sequencing of fragmented PCR products on both sequencing platforms identified six high-frequency SNPs that were catalogued in dbSNP as known variants. Shotgun sequencing based on a single long-range PCR protocol in pooled samples is an efficient and relatively inexpensive way to sequence an entire gene.


A geometrical method to improve performance of the support vector machine.
The performance of a support vector machine (SVM) largely depends on the kernel function used. This letter investigates a geometrical method to optimize the kernel function. The method is a modification of the one proposed by S. Amari and S. Wu. Its concern is the use of the prior knowledge obtained in a primary step training to conformally rescale the kernel function, so that the separation between the two classes of data is enlarged. The result is that the new algorithm works efficiently and overcomes the susceptibility of the original method.


Extracellular domain shedding influences specific tumor uptake and organ distribution of the EGFR PET tracer 89Zr-imgatuzumab.
Preclinical positron emission tomography (PET) imaging revealed a mismatch between in vivo epidermal growth factor receptor (EGFR) expression and EGFR antibody tracer tumor uptake. Shed EGFR ectodomain (sEGFR), which is present in cancer patient sera, can potentially bind tracer and therefore influence tracer kinetics. To optimize EGFR-PET, we examined the influence of sEGFR levels on tracer kinetics and tumor uptake of EGFR monoclonal antibody 89Zr-imgatuzumab in varying xenograft models. Human cancer cell lines A431 (EGFR overexpressing, epidermoid), A549 and H441 (both EGFR medium expressing, non-small cell lung cancer) were xenografted in mice. Xenografted mice received 10, 25 or 160 μg 89Zr-imgatuzumab, co-injected with equal doses 111In-IgG control. MicroPET scans were made 24, 72 and 144 h post injection, followed by biodistribution analysis. sEGFR levels in liver and plasma samples were determined by ELISA. 89Zr-imgatuzumab uptake in A431 tumors was highest (29.8 ± 5.4 %ID/g) in the 160 μg dose group. Contrary, highest uptake in A549 and H441 tumors was found at the lowest (10 μg) 89Zr-imgatuzumab dose. High 89Zr-imgatuzumab liver accumulation was found in A431 xenografted mice, which decreased with antibody dose increments. 89Zr-imgatuzumab liver uptake in A549 and H441 xenografted mice was low at all doses. sEGFR levels in liver and plasma of A431 bearing mice were up to 1000-fold higher than levels found in A549, H441 and non-tumor xenografted mice. 89Zr-imgatuzumab effectively visualizes EGFR-expressing tumors. High sEGFR levels can redirect 89Zr-imgatuzumab to the liver, in which case tumor visualization can be improved by increasing tracer antibody dose.


Insights on the Impact of External and Internal Boosting on Varicella-Zoster Virus Reactivation Based on Evidence From the First Decade of the United States Universal Varicella Vaccination Program.
Since the licensure of the varicella vaccine in the United States in 1995 and the implementation of the universal varicella vaccination program, varicella infection rates, and associated morbidity and mortality rates have decreased. However, controversy exists over whether universal vaccination has resulted in an increased incidence of herpes zoster (HZ). In 1965, Dr. Hope-Simpson hypothesized that exogenous exposures to the wild-type varicella-zoster virus (wt-VZV) provide immune boosts that inhibit HZ; therefore, reducing the amount of circulating wt-VZV may have the negative effect of increasing the incidence of HZ. A historical review of data from the Centers for Disease Control and Prevention-sponsored Antelope Valley Varicella Active Surveillance Project, along with other studies, is provided to investigate the exogenous boosting hypothesis in the first decade post-vaccine licensure. These data indicated that adoption of universal varicella vaccination led to (1) significant HZ incidence rate increases among children, adolescents, and adults with a history of wild-type varicella and (2) decline in varicella vaccine efficacy after the initial post-licensure period. These effects were likely due to reduced exogenous exposures from children shedding wt-VZV. Appropriate methodologies for ongoing research are also discussed, both in studies during the first decade post-licensure and more recent work.


Improving Quality and Reducing Waste in Allied Health Workplace Education Programs: A Pragmatic Operational Education Framework Approach.
Efficient utilisation of education resources is required for the delivery of effective learning opportunities for allied health professionals. This study aimed to develop an education framework to support delivery of high-quality education within existing education resources. This study was conducted in a large metropolitan health service. Homogenous and purposive sampling methods were utilised in Phase 1 (n=43) and 2 (n=14) consultation stages. Participants included 25 allied health professionals, 22 managers, 1 educator, and 3 executives. Field notes taken during 43 semi-structured interviews and 4 focus groups were member-checked, and semantic thematic analysis methods were utilised. Framework design was informed by existing published framework development guides. The framework model contains governance, planning, delivery, and evaluation and research elements and identifies performance indicators, practice examples, and support tools for a range of stakeholders. Themes integrated into framework content include improving quality of education and training provided and delivery efficiency, greater understanding of education role requirements, and workforce support for education-specific knowledge and skill development. This framework supports efficient delivery of allied health workforce education and training to the highest standard, whilst pragmatically considering current allied health education workforce demands.


Clinical Outcome and Postoperative CT Measurements of Microendoscopic Decompression for Lumbar Spinal Stenosis.
This was a retrospective case series. To retrospectively evaluate the clinical outcome of microendoscopic decompression for lumbar spinal stenosis (LSS) including an evaluation of the extent of decompression using computed tomography. Microendoscopic decompression has been a widely applied procedure to treat LSS with satisfactory outcomes and comparatively fewer complications and revision. However, few reports showed computed tomography (CT) measurements of the lumbar spine to assess the postoperative decompression. This study included 103 patients (55 males and 48 females; mean age, 69 y) who underwent microendoscopic decompression for treatment of LSS between January 2009 and January 2011. All patients underwent preoperative CT and postoperative CT at 6 months and 2 years of follow-up to measure the vertebral canal area and the sagittal diameter of the lateral recess at the outer rim. The Japanese Orthopedic Association (JOA) scale, Oswestry Disability Index, and Visual Analogue Scale were used to evaluate clinical efficacy. The mean vertebral canal area and sagittal diameter of the lateral recess were significantly larger at 6 months and 2 years after surgery compared with 1 day before surgery (P<0.001). The mean JOA scale scores were significantly higher at 6 and 24 months following surgery compared with before surgery (P<0.001). The mean Oswestry Disability Index scores and Visual Analogue Scale scores at 6 months and 2 years after surgery were significantly lower compared with before surgery (both P<0.001). The mean JOA recovery rates at 6 months and 2 years of follow-up were 61% and 64.3%, respectively. The results confirm that microendoscopic decompression for LSS is safe and effective. This study is one of the first to obtain CT measurements of the lumbar spine to assess the postoperative decompression of this procedure.


Coinfection of Ugandan red colobus (Procolobus [Piliocolobus] rufomitratus tephrosceles) with novel, divergent delta-, lenti-, and spumaretroviruses.
Nonhuman primates host a plethora of potentially zoonotic microbes, with simian retroviruses receiving heightened attention due to their roles in the origins of human immunodeficiency viruses type 1 (HIV-1) and HIV-2. However, incomplete taxonomic and geographic sampling of potential hosts, especially the African colobines, has left the full range of primate retrovirus diversity unexplored. Blood samples collected from 31 wild-living red colobus monkeys (Procolobus [Piliocolobus] rufomitratus tephrosceles) from Kibale National Park, Uganda, were tested for antibodies to simian immunodeficiency virus (SIV), simian T-cell lymphotrophic virus (STLV), and simian foamy virus (SFV) and for nucleic acids of these same viruses using genus-specific PCRs. Of 31 red colobus tested, 22.6% were seroreactive to SIV, 6.4% were seroreactive to STLV, and 97% were seroreactive to SFV. Phylogenetic analyses of SIV polymerase (pol), STLV tax and long terminal repeat (LTR), and SFV pol and LTR sequences revealed unique SIV and SFV strains and a novel STLV lineage, each divergent from corresponding retroviral lineages previously described in Western red colobus (Procolobus badius badius) or black-and-white colobus (Colobus guereza). Phylogenetic analyses of host mitochondrial DNA sequences revealed that red colobus populations in East and West Africa diverged from one another approximately 4.25 million years ago. These results indicate that geographic subdivisions within the red colobus taxonomic complex exert a strong influence on retroviral phylogeny and that studying retroviral diversity in closely related primate taxa should be particularly informative for understanding host-virus coevolution.


Clinical audit activities in surgery.
Large scale audits can attract the participation of the majority of surgeons. They require careful planning and must be supported by an infrastructure to co-ordinate the running of the audit and to ensure accuracy of data. Audits can be important sources of information for the development of evidence-based guidelines, and this approach is a good strategy for bringing the lessons obtained from the audit to the profession. Audits that work closely with professional bodies produce the best results and are enhanced by patient representation. Risk stratification is an essential component of comparative studies and should be incorporated to ensure that multi-centre audits are systematic.


Foamy virus assembly with emphasis on pol encapsidation.
Foamy viruses (FVs) differ from all other genera of retroviruses (orthoretroviruses) in many aspects of viral replication. In this review, we discuss FV assembly, with special emphasis on Pol incorporation. FV assembly takes place intracellularly, near the pericentriolar region, at a site similar to that used by betaretroviruses. The regions of Gag, Pol and genomic RNA required for viral assembly are described. In contrast to orthoretroviral Pol, which is synthesized as a Gag-Pol fusion protein and packaged through Gag-Gag interactions, FV Pol is synthesized from a spliced mRNA lacking all Gag sequences. Thus, encapsidation of FV Pol requires a different mechanism. We detail how WT Pol lacking Gag sequences is incorporated into virus particles. In addition, a mutant in which Pol is expressed as an orthoretroviral-like Gag-Pol fusion protein is discussed. We also discuss temporal regulation of the protease, reverse transcriptase and integrase activities of WT FV Pol.


In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta.
To better understand the role of human equilibrative (hENTs) and concentrative (hCNTs) nucleoside transporters in physiology and pharmacology, we investigated the regional, cellular, and spatial distribution of two hCNTs (hCNT1 and hCNT2) and two hENTs (hENT1 and hENT2) in four human tissues. Using in situ hybridization and immunohistochemical techniques, we found that the duodenum expressed hCNT1 and hCNT2 mRNAs in enterocytes and hENT1 and hENT2 mRNAs in crypt cells. In these cells, the hCNT and hENT proteins were predominantly localized in the apical and lateral membrane, respectively. Hepatocytes expressed higher levels of mRNAs of hENT1, hCNT1, and hENT2 than of hCNT2 and expressed all these proteins at hepatocyte cell borders and in the cytoplasm. While the kidney expressed hCNT1 and hCNT2 mRNAs in the proximal tubules, hENT1 and hENT2 mRNAs were present in the distal tubules, glomeruli, endothelial cells, and vascular smooth muscle cells. Proximal tubules adjacent to corticomedullary junctions expressed hENT1, hCNT1, and hCNT2 mRNA. Immunolocalization studies revealed predominant localization of hCNTs in the brush-border membrane of the proximal tubular epithelial cells and hENTs in the basolateral membrane of the distal tubular epithelial cells. Chorionic villi sections of human term placenta expressed mRNAs and proteins for hENT1 and hENT2 but only mRNA for hCNT2. Immunolocalization studies showed presence of hENT1 in the brush-border membrane of the syncytiotrophoblasts. These data are critical for a better understanding of the role of nucleoside transporters in the physiological and pharmacological effects of nucleosides and nucleoside drugs, respectively.


[APPLICATION OF COMPRESSION MINI-SCREWS IN TREATMENT OF PATIENTS WITH INJURY OF ELBOW JOINT BONES].
A case report presents the experience of application of compression pileateless mini-screws (Gerbert's screws) in treatment of intra-articular fractures, which formed the elbow joint (44 cases). There were performed 32 operations concerning fracture of head of radius, 10 operations on the occasion of fractures of distal section of the humerus and 2 operations on the coronoid process. Long-term treatment results were followed-up in 31 patients during more than 6 months. On basis of analysis of treatment results the authors made a conclusion that the application of mini-screws in case of bone fractures, which formed the elbow joint, allowed realization of stable osteosynthesis after anatomic reposition of articular surfaces, obtaining good anatomical and functional result and shortened the terms of patient's treatment.


Rhizobium meliloti genes involved in sulfate activation: the two copies of nodPQ and a new locus, saa.
The nitrogen-fixing symbiont Rhizobium meliloti establishes nodules on leguminous host plants. Nodulation (nod) genes used for this process are located in a cluster on the pSym-a megaplasmid of R. meliloti. These genes include nodP and nodQ (here termed nodPQ), which encode ATP sulfurylase and APS kinase, enzymes that catalyze the conversion of ATP and SO(4)2- into the activated sulfate form 3'-phosphoadenosine 5'-phosphosulfate (PAPS), an intermediate in cysteine synthesis. In Rhizobium, PAPS is also a precursor for sulfated and N-acylated oligosaccharide Nod-factor signals that cause symbiotic responses on specific host plants such as alfalfa. We previously found a highly conserved second copy of nodPQ in R. meliloti. We report here the mapping and cloning of this second copy, and its location on the second megaplasmid, pSym-b. The function of nodP2Q2 is equivalent to that of nodP1Q1 in complementation tests of R. meliloti and Escherichia coli mutants in ATP sulfurylase and adenosine 5'-phosphosulfate (APS) kinase. Mutations in nodP2Q2 do not have as severe an effect on symbiosis or plant host range as do those in nodP1Q1, however, possibly reflecting differences in expression and/or channeling of metabolites to specific enzymes involved in sulfate transfer. Strains mutated or deleted for both copies of nodQ are severely defective in symbiotic phenotypes, but remain prototrophic. This suggests the existence in R. meliloti of a third locus for ATP sulfurylase and APS kinase activities. We have found a new locus saa (sulfur amino acid), which may also encode these activities.


Contribution of Caudal Müllerian Duct Mesenchyme to Prostate Development.
A fundamental understanding of prostate development and tissue homeostasis has the high potential to reveal mechanisms for prostate disease initiation and identify novel therapeutic approaches for disease prevention and treatment. Our current understanding of prostate lineage specification stems from the use of developmental model systems that rely upon the embryonic preprostatic urogenital sinus mesenchyme to induce the formation of mature prostate epithelial cells. It is unclear, however, how the urogenital sinus epithelium can derive both adult urethral glands and prostate epithelia. Furthermore, the vast disparity in disease initiation between these two glands highlights key developmental factors that predispose prostate epithelia to hyperplasia and cancer. In this study we demonstrate that the caudal Müllerian duct mesenchyme (CMDM) drives prostate epithelial differentiation and is a key determinant in cell lineage specification between urethral glands and prostate epithelia. Utilizing both human embryonic stem cells and mouse embryonic tissues, we document that the CMDM is capable of inducing the specification of androgen receptor, prostate-specific antigen, NKX3.1, and Hoxb13-positive prostate epithelial cells. These results help to explain key developmental differences between prostate and urethral gland differentiation, and implicate factors secreted by the caudal Müllerian duct as novel targets for prostate disease prevention and treatment.


Identification and characterization of a bacitracin resistance network in Enterococcus faecalis.
Resistance of Enterococcus faecalis against antimicrobial peptides, both of host origin and produced by other bacteria of the gut microflora, is likely to be an important factor in the bacterium's success as an intestinal commensal. The aim of this study was to identify proteins with a role in resistance against the model antimicrobial peptide bacitracin. Proteome analysis of bacitracin-treated and untreated cells showed that bacitracin stress induced the expression of cell wall-biosynthetic proteins and caused metabolic rearrangements. Among the proteins with increased production, an ATP-binding cassette (ABC) transporter with similarity to known peptide antibiotic resistance systems was identified and shown to mediate resistance against bacitracin. Expression of the transporter was dependent on a two-component regulatory system and a second ABC transporter, which were identified by genome analysis. Both resistance and the regulatory pathway could be functionally transferred to Bacillus subtilis, proving the function and sufficiency of these components for bacitracin resistance. Our data therefore show that the two ABC transporters and the two-component system form a resistance network against antimicrobial peptides in E. faecalis, where one transporter acts as the sensor that activates the TCS to induce production of the second transporter, which mediates the actual resistance.


The Botsha Bophelo Adolescent Health Study: A profile of adolescents in Soweto, South Africa.
Youth between the ages of 15 years to 24 years account for almost half of new HIV infections in South Africa. To describe the study details of the Botsha Bophelo Adolescent Health Study (BBAHS) which was an investigation of HIV risk among adolescents living in Soweto, South Africa. Eligibility criteria for the BBAHS included being 14 years - 19 years old and living in one of the 41 identified formal and informal areas in the township of Soweto. A cross-sectional survey was developed between investigators and an adolescent community advisory board consisting of previously validated scales and original questions including demographics, sexual and reproductive health, health service utilisation and psychosocial behaviours. Between 2010 and 2012, interviewers administered surveys among 830 adolescents (57% females), whose median age was 17 years (Q1, Q3: 16, 18), and found that 43% of participants identified their ethnicity as Zulu, 52% reported high food insecurity, 37% reported at least one parent had died, 15% reported living in a shack and 83% identified as heterosexual. Over half of the participants (55%) reported ever having sex (49% of females and 64% of males), 11% of whom initiated sex at < 15 years of age (3% females and 21% males). Almost half (47%) reported ever testing for HIV, 3% (n = 12) of whom self-reported being HIV-positive and 33% (n = 4) were on antiretroviral therapy. Our study highlights important individual, relational and structural level determinants of HIV risk for adolescent men and women growing up within HIV hyperendemic settings.


Association between mild traumatic brain injury and mental health problems and self-reported cognitive dysfunction in Iraq and Afghanistan Veterans.
The Department of Veterans Affairs traumatic brain injury (TBI) screening program is intended to detect and expedite treatment for TBI and postconcussive symptoms. Between April 14, 2007, and May 31, 2012, of 66,089 Iraq and Afghanistan Veterans who screened positive on first-level TBI screening and later completed comprehensive TBI evaluation that includes the Neurobehavioral Symptoms Inventory, 72% reported moderate to very severe cognitive impairment (problems with attention, concentration, memory, etc.) that interfered with daily activities. This included 42% who were found not to have sustained combat-related mild TBI (mTBI). In contrast, 70.0% received a posttraumatic stress disorder (PTSD) diagnosis and 45.8% received a depression diagnosis. Compared with Veterans without mTBI, PTSD, or depression diagnoses, the lowest risk for self-reported cognitive impairment was in Veterans with confirmed mTBI only; a greater risk was found in those with PTSD diagnoses, with the greatest risk in Veterans with PTSD, depression, and confirmed mTBI, suggesting only a weakly additive effect of mTBI. These findings suggest that Veterans with multiple mental health comorbidities, not just those with TBI, report moderate to very severe cognitive impairment. Mental health treatment for conditions such as PTSD and depression (with or without TBI) may result in improvements in cognitive functioning and/or include assessment and support for Veterans experiencing cognitive problems.


Metoidioplasty: techniques and outcomes.
Phalloplasty represents the latest step in female-to-male transitioning and still remains a great challenge for transgender surgeons. Since we have two options in this transitioning-metoidioplasty and total phalloplasty-the transgender surgeon has to fully inform the individual about all aspects such as surgical steps, outcomes, advantages and disadvantages, possible complications, and expectations. Total phalloplasty with the creation of a neophallus of a similar volume to that in genetic males, is a complex and multi-staged procedure. Many different tissues (i.e., flaps) can be used, and the ideal procedure is still not established. In contrast to the above complexities involved in total phalloplasty, metoidioplasty presents a simple and one-stage procedure for the creation of a neophallus from a hormonally enlarged clitoris. This technique is very promising for individuals who desire gender-affirmation surgery without having to undergo the difficult and multistage creation of a male-sized neophallus. Also, this technique prevents scarring to the extragenital region, making the final results more acceptable for transgender individuals. Our goal is to objectively present the techniques for metoidioplasty and to define their value based on postoperative results.


Effectiveness of an intensive care unit family education intervention on delirium knowledge: a pre-test post-test quasi-experimental study.
To create, validate, and refine an intensive care unit (ICU) delirium education intervention to prepare family members to partner with the ICU care team to detect delirium symptoms and prevent and manage delirium using nonpharmacological strategies. In this pre-test post-test quasi-experimental study, consecutive eligible family members of critically ill patients admitted to an ICU completed an ICU Family Education Delirium intervention in two parts: 1) six-minute video on ICU delirium (risk factors, prevention/management, symptoms, communication with the ICU care team), and 2) two case vignettes to practice detecting delirium using family-administered delirium detection questionnaires (Family Confusion Assessment Method [FAM-CAM] and Sour Seven). Family members' delirium knowledge was measured before, immediately after, and two weeks following the intervention using the Caregiver ICU Delirium Knowledge Questionnaire (CIDKQ). Of 99 family members recruited over eight months, 81 (82%) completed the intervention and 63 (63/81, 78%) completed all follow-up questionnaires. Family members' delirium knowledge improved significantly following the intervention (pre-CIDKQ, 14; 95% confidence interval [CI], 13 to 15; post-CIDKQ, 17; 95% CI, 16 to 17; P < 0.001) and was retained two weeks after the intervention (CIDKQ 16; 95% CI, 16 to 17; P < 0.001). This included increased knowledge regarding delirium risk factors (e.g., medication, mechanical ventilation), prevention/management (e.g., orientation, day/night routine), and symptoms of delirium. More family members correctly detected delirium symptoms in case vignettes using the Sour Seven (92%) compared with the FAM-CAM (78%). A video-based ICU delirium education intervention is effective in educating family members about prevention, detection, and management of delirium.


Nucleotide pyrophosphatase and phosphodiesterase. I. Organ distribution and activities in body fluids.
We estimated nucleotide pyrophosphatase and phosphodiesterase I activities in human and rat organs and in body fluids from man and dog. The highest organ activities were found in epididymis, kidney, liver, and intestine. In body fluids, the activity was highest in seminal plasma, followed by intestinal lymph, serum, heart lymph, cerebrospinal fluid, milk, and urine. The ratio nucleotide pyrophosphatase/phosphodiesterase I and the urea resistance of phosphodiesterase I differed among human organs, body fluids, and blood cells. Different isoenzymes probably exist. The activities in serum share several properties with those in several organs--e.g. pH-optimum 9.6-9.8, dependency on Zn2+, and the effects of inhibitors. Phosphodiesterase I in erythrocytes, which has not been described previously, differs from enzyme from other sources by lower pH optimum (8.5), dependency on Mg2+, inhibition by Zn2+, and stimulation by dithiothreitol.


Sonography of the rotator cuff: analysis of interobserver variability.
The purpose of our study was to determine the interobserver variability in the sonographic evaluation of the rotator cuff. Two radiologists independently scanned 61 patients with shoulder pain. Each radiologist categorized the rotator cuff as normal, partially torn, or fully torn. When a tear was present, the tendons involved were specified. All diagnoses were made prospectively without knowledge of the findings of the other radiologist. The radiologists were in full agreement in the categorization of 92% (56/61) of the patients. In four of the five discrepant cases, the disagreement was whether there was a full-thickness or a partial-thickness tear. The radiologists were in agreement concerning which tendons were involved in 80% (41/51) of the patients in whom a tear was detected by both observers. In all 10 discrepant cases, the disagreement was whether a tear involved both the supraspinatus and infraspinatus tendons or was isolated to one or the other of these tendons. The level of interobserver variability in the sonographic detection and characterization of rotator cuff tears is low.


Primary histologic diagnosis using automated whole slide imaging: a validation study.
Only prototypes 5 years ago, high-speed, automated whole slide imaging (WSI) systems (also called digital slide systems, virtual microscopes or wide field imagers) are becoming increasingly capable and robust. Modern devices can capture a slide in 5 minutes at spatial sampling periods of less than 0.5 micron/pixel. The capacity to rapidly digitize large numbers of slides should eventually have a profound, positive impact on pathology. It is important, however, that pathologists validate these systems during development, not only to identify their limitations but to guide their evolution. Three pathologists fully signed out 25 cases representing 31 parts. The laboratory information system was used to simulate real-world sign-out conditions including entering a full diagnostic field and comment (when appropriate) and ordering special stains and recuts. For each case, discrepancies between diagnoses were documented by committee and a "consensus" report was formed and then compared with the microscope-based, sign-out report from the clinical archive. In 17 of 25 cases there were no discrepancies between the individual study pathologist reports. In 8 of the remaining cases, there were 12 discrepancies, including 3 in which image quality could be at least partially implicated. When the WSI consensus diagnoses were compared with the original sign-out diagnoses, no significant discrepancies were found. Full text of the pathologist reports, the WSI consensus diagnoses, and the original sign-out diagnoses are available as an attachment to this publication. The results indicated that the image information contained in current whole slide images is sufficient for pathologists to make reliable diagnostic decisions and compose complex diagnostic reports. This is a very positive result; however, this does not mean that WSI is as good as a microscope. Virtually every slide had focal areas in which image quality (focus and dynamic range) was less than perfect. In some cases, there was evidence of over-compression and regions made "soft" by less than perfect focus. We expect systems will continue to get better, image quality and speed will continue to improve, but that further validation studies will be needed to guide development of this promising technology.


[Clinical manifestations of ischemic heart disease in the subacute period of myocardial infarction and post-infarct cardiosclerosis depending on the status of coronary arteries].
Multifactor discriminant analysis was used on a computer to examine 100 patients with myocardial infarction in the subacute period (at week 4 of the disease onset) and 76 in the postinfarction period (at months 2-120 of postinfarction). A complex of clinical and coronary signs was defined, which differentiated patients with subacute myocardial infarction and postinfarct cardiosclerosis, as well as those with postinfarct stable and progressive angina pectoris.


Effect of soy addition on microwavable pocket-type flat doughs.
Microwavable frozen baked goods are widely used by the food industry. However, the altered heat and mass transfer patterns associated with microwave radiation result in tough and rubbery baked products due to reduced plasticization of the polymers. Ingredients with high water-holding capacity and high content of polar lipids have been shown to enhance gluten plasticization and to improve water retention. Therefore, this study explored the physicochemical changes imparted by microwave baking of pocket-type flat doughs with and without soy added at 10%, 20%, and 26% and compared these to their conventionally baked counterparts. Microwave baking resulted in a soft, rubbery, and tough wheat product with increased "freezable" water. Soy was added to the formulation as a means to improve polymer plasticization. Conventional baking of soy doughs resulted in rubbery and tough products due to changes in water state and mobility (freezable water approximately 15 compared with 7.09 of the control). However, soy reduced the cohesiveness of the microwave baked products reaching the lowest value at 20% soy addition (cohesiveness 0.33 ± 1, comparable to that of the conventionally baked control). These data suggest that reduction of water mobility induced by soy proteins and polar lipids (confirmed by thermogravimetric analysis [TGA] and ¹H nuclear magnetic resonance [¹H NMR]) possibly plasticized the starch-gluten network of microwave baked soy doughs. Thus, soy was shown to improve the texture of microwave baked pocket-type flat doughs although further formula optimization is warranted. Microwavable pocket-type flat doughs are used frequently by the food industry to enrobe meat, vegetable, and sweet items for convenient meal delivery. Microwave heating of such doughs induces the development of crustless products compared to conventionally baked products, resulting in a tough and rubbery texture. Partial substitution of wheat flour with soy, in the form of soy flour and soy milk powder, prevented the deleterious textural changes associated with microwave heating. These results suggest that soy is a functional ingredient for the textural improvement of microwavable pocket-type flat doughs.


Using Plate-Wash PCR and High-Throughput Sequencing to Measure Cultivated Diversity for Natural Product Discovery Efforts.
Molecular techniques continue to reveal a growing disparity between the immense diversity of microbial life and the small proportion that is in pure culture. The disparity, originally dubbed "the great plate count anomaly" by Staley and Konopka, has become even more vexing given our increased understanding of the importance of microbiomes to a host and the role of microorganisms in the vital biogeochemical functions of our biosphere. Searching for novel antimicrobial drug targets often focuses on screening a broad diversity of microorganisms. If diverse microorganisms are to be screened, they need to be cultivated. Recent innovative research has used molecular techniques to assess the efficacy of cultivation efforts, providing invaluable feedback to cultivation strategies for isolating targeted and/or novel microorganisms. Here, we aimed to determine the efficiency of cultivating representative microorganisms from a non-human, mammalian microbiome, identify those microorganisms, and determine the bioactivity of isolates. Sequence-based data indicated that around 57% of the ASVs detected in the original inoculum were cultivated in our experiments, but nearly 53% of the total ASVs that were present in our cultivation experiments were not detected in the original inoculum. In light of our controls, our data suggests that when molecular tools were used to characterize our cultivation efforts, they provided a more complete and more complex, understanding of which organisms were present compared to what was eventually detected during cultivation. Lastly, about 3% of the isolates collected from our cultivation experiments showed inhibitory bioactivity against an already multidrug-resistant pathogen panel, further highlighting the importance of informing and directing future cultivation efforts with molecular tools.


Development of clinical competence - a longitudinal survey of nurse practitioner students.
In order to achieve a sustainable standard of advanced clinical competence for nurse practitioners leading to a credible role, it is important to investigate the development of clinical competence among nurse practitioner students. The aim of the present study is to analyse the development of nurse practitioner students' self-assessed clinical competence from the beginning of their education to after completion of their clinical studies. The study involved the application of a longitudinal survey design adhering to STROBE guidelines. The participants consisted of 36 registered nurses from a nurse practitioner programme at a Norwegian university. The Professional Nurse Self-Assessment Scale II was used for data collection during the period August 2015 to May 2020. The students developed their clinical competence the most for direct clinical practice. Our findings are inconclusive in terms of whether the students developed clinical competence regarding consultation, coaching and guidance, and collaboration. However, they do indicate a lack of development in some aspects of clinical leadership. The students with the lowest level of clinical competence developed their clinical competence regarding direct clinical practice significantly more than the students with the highest level of clinical competence. The differences between students with high and low levels of clinical competence were levelled out during their education. Thus, the students as a whole became a more homogenous group after completion of their clinical studies. Previous work experience in primary healthcare was a statistically significant, yet minor, predictor of the development of clinical competence. Our findings indicate that the students developed their clinical competence for direct clinical practice in accordance with the intended learning outcomes of the university's Master's programme and international standards for nurse practitioners. It is imperative that the clinical field supports nurse practitioners by facilitating extended work-task fits that are appropriate to their newly developed clinical competence. We refrain from concluding with a recommendation that prior clinical work experience should be an entry requirement for nurse practitioner programmes. However, we recommend an evaluation of the nurse practitioner education programme with the aim of investigating whether the curriculum meets the academic standards of clinical leadership expected in advanced level of nursing.


Anatomical study of the pterygomaxillary area for implant placement: cone beam computed tomographic scanning in 100 patients.
The aim of this study was to describe the average angulation and dimensions of the pterygomaxillary area in the atrophic maxilla to facilitate the orientation of pterygoid implants during their placement. A retrospective radiologic study was made. A virtual pterygoid implant, 13, 15, or 18 mm long, was placed in the pterygomaxillary area following the axis of the bone, with a distance of at least 2 mm maintained between the artery and palatine nerve and the implant. The long axis of the implant was inclined slightly toward the palatal to follow the cortical palatal bone. The angles between the long axis of the virtual implant and Frankfort horizontal were measured in both sagittal and frontal views. To calculate the average length of the pterygomaxillary area, the virtual long axis of the implant was measured from the alveolar crest to the pterygomaxillary suture. The average anteroposterior axis inclination of the pterygomaxillary area was 72.5 ± 4.9 degrees relative to Frankfort horizontal. The average angulation of the palatal vestibule was 81.3 ± 42.8 degrees relative to Frankfort horizontal. The average length of the pterygomaxillary area was 22.5 ± 4.8 mm. Pterygoid implant placement requires thorough knowledge of each patient's anatomy and individual needs. The mean position of the pterygomaxillary buttress axis was 72.5 ± 4.9 degrees to the distal and 81.3 ± 2.8 degrees to the palatal relative to Frankfort horizontal. Placement of pterygoid implants in this inclination may increase accuracy of implant placement. The average length from the tuberosity to the most apical point of the pterygoid apophysis was 22.5 ± 4.8 mm. These results suggest that an implant 15 to 18 mm in length would fit in the pterygomaxillary area to reach the cortical bone.


Predicting cardiac safety using human induced pluripotent stem cell-derived cardiomyocytes combined with multi-electrode array (MEA) technology: A conference report.
Safety pharmacology studies that evaluate drug candidates for potential cardiovascular liabilities remain a critical component of drug development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have recently emerged as a new and promising tool for preclinical hazard identification and risk assessment of drugs. Recently, Pluriomics organized its first User Meeting entitled 'Combining Pluricyte® Cardiomyocytes & MEA for Safety Pharmacology applications', consisting of scientific sessions and live demonstrations, which provided the opportunity to discuss the application of hiPSC-CMs (Pluricyte® Cardiomyocytes) in cardiac safety assessment to support early decision making in safety pharmacology. This report summarizes the outline and outcome of this Pluriomics User Meeting, which took place on November 24-25, 2016 in Leiden (The Netherlands). To reflect the content of the communications presented at this meeting we have cited key scientific articles and reviews.


WHO informal consultation on regulatory considerations for evaluation of the quality, safety and efficacy of RNA-based prophylactic vaccines for infectious diseases, 20-22 April 2021.
This paper presents the key outcomes of the above WHO informal consultation with global stakeholders including regulatory authorities, vaccine developers and manufacturers, academia and other international health organizations and institutions involved in the development, evaluation and use of messenger RNA (mRNA) vaccines. The aim of the consultation was to further clarify the main principles to be presented in an upcoming WHO guidance document on the regulatory considerations in evaluating the quality, safety and efficacy of mRNA prophylactic vaccines for infectious diseases. This WHO guidance document is intended to facilitate global mRNA vaccine development and regulatory convergence in the assessment of such vaccines. The urgent need to develop such a document as a new WHO written standard is outlined in this report along with the key scientific and regulatory challenges. A number of key conclusions are provided at the end of this report along with an update on the steps taken following this meeting.


Acrochordons as a cutaneous sign of impaired carbohydrate metabolism, hyperlipidemia, liver enzyme abnormalities and hypertension: A case-control study.
Acrochordons are common and benign skin tumours. A few studies with contradictory results have been reported regarding the abnormalities of carbohydrate and/or lipid metabolisms in patients with acrochordons. We aimed to determine if the presence of acrochordons could be a marker of diabetes, hyperlipidemia, liver enzyme abnormalities and hypertension by comparing with a control group. A total of 110 patients having two or more acrochordons and age- and gender-matched 110 controls were included in the study. Localization, size and the total number of acrochordons were recorded in the patient group. Fasting plasma glucose (FPG), serum lipids and liver enzyme levels were tested in patient and controls. All participants underwent a standard 2-h oral glucose tolerance test with 75 g glucose. Diabetes mellitus and impaired glucose intolerance were diagnosed according to the American Diabetes Association criteria. Arterial blood pressures were measured in two groups. A total of 56 patients and 10 controls were diagnosed with overt DM. Thirteen per cent of the patients and 9% of controls had an impaired glucose tolerance test. The difference was statistically significant for the diagnosis of DM and not significant for the impaired glucose tolerance. The mean levels of FPG, total cholesterol, LDL cholesterol, triglyceride, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyltransferase and alkaline phosphatase were significantly higher in patients than those in controls. Furthermore, serum levels of HDL were less in patients. Patients with acrochordons had higher systolic and diastolic blood pressures than controls. The results of our study suggest that acrochordons may represent a cutaneous sign for impaired carbohydrate or lipid metabolism, liver enzyme abnormalities and hypertension.


The Effectiveness of Cognitive Bias Modification Interventions for Substance Addictions: A Meta-Analysis.
Cognitive bias modification (CBM) interventions, presumably targeting automatic processes, are considered particularly promising for addictions. We conducted a meta-analysis examining randomized controlled trials (RCTs) of CBM for substance addiction outcomes. Studies were identified through systematic searches in bibliographical databases. We included RCTs of CBM interventions, alone or in combination with other treatments, for any type of addiction. We examined trial risk of bias, publication bias and possible moderators. Effects sizes were computed for post-test and follow-up, using a random-effects model. We grouped outcome measures and reported results for addiction (all related measures), craving and cognitive bias. We identified 25 trials, 18 for alcohol problems, and 7 for smoking. At post-test, there was no significant effect of CBM for addiction, g = 0.08 (95% CI -0.02 to 0.18) or craving, g = 0.05 (95% CI -0.06 to 0.16), but there was a significant, moderate effect on cognitive bias, g = 0.60 (95% CI 0.39 to 0.79). Results were similar for alcohol and smoking outcomes taken separately. Follow-up addiction outcomes were reported in 7 trials, resulting in a small but significant effect of CBM, g = 0.18 (95% CI 0.03 to 0.32). Results for addiction and craving did not differ by substance type, sample type, delivery setting, bias targeted or number of sessions. Risk of bias was high or uncertain in most trials, for most criteria considered. Meta-regression analyses revealed significant inverse relationships between risk of bias and effect sizes for addiction outcomes and craving. The relationship between cognitive bias and respectively addiction ESs was not significant. There was consistent evidence of publication bias in the form of funnel plot asymmetry. Our results cast serious doubts on the clinical utility of CBM interventions for addiction problems, but sounder methodological trials are necessary before this issue can be settled. We found no indication that positive effects on biases translate into effects on addiction outcomes.


Polarimetric imaging-based cancer bladder tissue's detection: A comparative study of bulk and formalin-fixed paraffin-embedded samples.
The polarimetry imaging technique as a promising technique for pathological diagnosis provides a handy tool for identifying and discriminating cancerous tissues. In this paper, the optical polarization properties of bulk bladder tissues without any further processing and Formalin-Fixed Paraffin-Embedded (FFPE) blocks of bladder tissues have been measured. The images of the Muller matrix for both normal and cancerous samples have been obtained and for quantitative analysis and to provide a more precise comparison, two methods have been applied; the Mueller matrix polar decomposition (MMPD), and the Mueller matrix transformation (MMT). The results have shown that some of the extracted parameters from these methods can be used to identify the microstructural differentiations between normal and cancerous tissues. The results revealed a good accord between the obtained optical parameters for bulk and FFPE bladder tissues. By measuring the polarimetric properties of the tissue right after resection, and also in the early stages of pathology (FFPE tissues), this method can be applied in vivo to perform an optical biopsy; Furthermore, this method has the potential to significantly shortens the duration of pathological diagnosis. The approach seems remarkable, simple, precise, and economical compared to the existing techniques for the detection of cancerous samples.


From actors to authors: a first account about the involvement of patients in the informed consent governance of a major Italian translational research hospital.
From 2007 to 2009 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, one of the major public research hospitals in Italy, has invested on a participatory action to promote a good practice of informed consent. The project focused on the improvement and innovation of informed consent considered as a participated act through the involvement of all the actors at stake. The main purpose was to improve the informative practices through the participatory innovation of institutional and organizational elements as conditions of possibility. Therefore the project has pursued the involvement of managers, healthcare professionals, patients and their associations in the institutional governance of informed consent. The involvement of citizens and patients within the whole process meant to put them in charge not just as actors or final evaluators of a good practice, but as co-authors in defining standards, tools and conditions for a good practice. Several actions were taken, including a phase of analysis which involved 20 patients from 8 Associations, a phase of innovation and education where 113 patients and citizens worked together with clinicians from 53 Units in deliberative laboratories, the institution of a multidisciplinary committee inclusive of representatives from 6 associations of patients.The project has produced different outcomes: new institutional guidelines adopted by the hospital; the renewal of consent forms and procedures as part of an explicit shared informative process; an increased implementation of institutional standards of good informative practice; the measure and communication of the outcomes of care and their bench-marking; bottom-up building of paths of validation; the creation of participatory electronic tools; an innovative education on the field for patients and clinicians.


Local moment formation and Kondo screening in impurity trimers.
We study theoretically a triangular cluster of three magnetic impurities, hybridizing locally with conduction electrons of a metallic host. Such a cluster is the simplest to exhibit frustration, an important generic feature of many complex molecular systems in which different interactions compete. Here, low-energy doublet states of the trimer are favored by effective exchange interactions produced by strong electronic repulsion in localized impurity orbitals. Parity symmetry protects a level crossing of such states on tuning microscopic parameters, while an avoided crossing arises in the general distorted case. Upon coupling to a metallic host, the behavior is shown to be immensely rich because collective quantum many-body effects now also compete. In particular, impurity degrees of freedom are totally screened at low temperatures in a Kondo-screened Fermi liquid phase, while degenerate ground states persist in a local moment phase. Local frustration drives the quantum phase transition between the two, which may be first order or of Kosterlitz-Thouless type, depending on symmetries. Unusual mechanisms for local moment formation and Kondo screening are found due to the orbital structure of the impurity trimer. Our results are of relevance for triple quantum dot devices. The problem is studied by a combination of analytical arguments and the numerical renormalization group.


Ocean acidification reduces the crystallographic control in juvenile mussel shells.
Global climate change threatens the oceans as anthropogenic carbon dioxide causes ocean acidification and reduced carbonate saturation. Future projections indicate under saturation of aragonite, and potentially calcite, in the oceans by 2100. Calcifying organisms are those most at risk from such ocean acidification, as carbonate is vital in the biomineralisation of their calcium carbonate protective shells. This study highlights the importance of multi-generational studies to investigate how marine organisms can potentially adapt to future projected global climate change. Mytilus edulis is an economically important marine calcifier vulnerable to decreasing carbonate saturation as their shells comprise two calcium carbonate polymorphs: aragonite and calcite. M. edulis specimens were cultured under current and projected pCO2 (380, 550, 750 and 1000μatm), following 6months of experimental culture, adults produced second generation juvenile mussels. Juvenile mussel shells were examined for structural and crystallographic orientation of aragonite and calcite. At 1000μatm pCO2, juvenile mussels spawned and grown under this high pCO2 do not produce aragonite which is more vulnerable to carbonate under-saturation than calcite. Calcite and aragonite were produced at 380, 550 and 750μatm pCO2. Electron back scatter diffraction analyses reveal less constraint in crystallographic orientation with increased pCO2. Shell formation is maintained, although the nacre crystals appear corroded and crystals are not so closely layered together. The differences in ultrastructure and crystallography in shells formed by juveniles spawned from adults in high pCO2 conditions may prove instrumental in their ability to survive ocean acidification.


Evaluation of a Canadian telepsychiatry service.
A telepsychiatry pilot project linking five rural general hospitals and Alberta Hospital Ponoka was implemented in June 1996 as a response to both a scarcity of psychiatric resources in the Province of Alberta and the emphasis on community-based care. Psychiatrists located at Alberta Hospital Ponoka provided psychiatric consultations using videoconferencing technology in response to referrals from general practitioners. The project was evaluated through the use of questionnaires administered to consumers, service providers, and psychiatric consultants. Questionnaires were supplemented by interviews, site visits, logs, telephone interviews with consumers, and surveys to general practitioners at the rural sites. A total of 109 consultations occurred during the pilot stage. Results strongly suggested acceptance and satisfaction with the consultation by consumers, general practitioners and psychiatrists. The patient's perceived benefits included timeliness of service, service within their own community, decreased work time loss for self or family, and positive outcomes as a result of specialist expertise. Up until September 30, 1998 a total of 535 consultations had been completed, 381 of which were new referrals and 154 of which were follow up referrals. Seventy-two different physicians referred to the service. The practice profile is dramatically different to outpatient psychiatric practice in which approximately 90% of patient contacts are follow-up visits.


Accuracy of turbo spin-echo diffusion-weighted imaging signal intensity measurements for the diagnosis of cholesteatoma.
We aimed to evaluate the diagnostic accuracy of turbo spin-echo diffusion-weighted imaging (TSE-DWI) at 3 T, for cholesteatoma (CS) diagnosis, using qualitative and quantitative methods with numerical assessment of signal intensity (SI), signal intensity ratios (SIR), and apparent diffusion coefficient (ADC) values. In this retrospective study, two blinded observers independently evaluated the preoperative TSE-DWI images of 57 patients who were imaged with a presumed diagnosis of CS. Qualitative assessment with respect to the SI of the adjacent cortex and quantitative measurements of SI, SIR, and ADC values were performed. Surgery with histopathologic examination revealed 30 CS patients and 27 patients with non-cholesteatoma (NCS) lesions including chronic inflammation and cholesterol granuloma. On TSE-DWI, 96.7% of the CS lesions and none of the NCS lesions appeared hyperintense compared with the cortex. The mean SI and SIR indices of the CS group were significantly higher and the mean ADC values significantly lower compared with those of the NCS group (P < 0.001). Using specific cutoff values for SI (92.5) and SIR (0.9), CS could be diagnosed with 100% sensitivity and specificity. The use of quantitative imaging further increased the sensitivity of the TSE-DWI technique. The quantitative indices of SI, SIR, and ADC of TSE-DWI appear to be highly accurate parameters that can be used to confirm the diagnosis of CS.


Self-bloodletting: an unusual form of self-mutilation in adolescence.
In this paper, we introduce an adolescent suffering from a rare form of self-mutilation, "self-bloodletting", and discuss dynamics of this maladaptive behavior. Deliberate bloodletting is a rare, but not unheard of, form of self-mutilation associated with eating and personality disorders. Although there are already several case reports in the adult psychiatry literature regarding the clinical features of Lasthenie de Ferjol Syndrome or factitious anemia, this is the first reported adolescent case of self-bloodletting.


Antibiofilm and Anti-Inflammatory Activities of Houttuynia cordata Decoction for Oral Care.
Dental biofilms that form in the oral cavity play a critical role in the pathogenesis of several infectious oral diseases, including dental caries, periodontal disease, and oral candidiasis. Houttuynia cordata (HC, Saururaceae) is a widely used traditional medicine, for both internal and external application. A decoction of dried HC leaves (dHC) has long been consumed as a health-promoting herbal tea in Japan. We have recently reported that a water solution of HC poultice ethanol extract (wHCP) exerts antimicrobial and antibiofilm effects against several important oral pathogens. It also exhibits anti-inflammatory effects on human keratinocytes. In our current study, we examined the effects of dHC on infectious oral pathogens and inflammation. Our results demonstrated that dHC exerts moderate antimicrobial effects against methicillin-resistant Staphylococcus aureus (MRSA) and other oral microorganisms. dHC also exhibited antibiofilm effects against MRSA, Fusobacterium nucleatum (involved in dental plaque formation), and Candida albicans and inhibitory effects on interleukin-8, CCL20, IP-10, and GROα productions by human oral keratinocytes stimulated by Porphyromonas gingivalis lipopolysaccharide (a cause of periodontal disease), without cytotoxic effects. This suggests that dHC exhibits multiple activities in microorganisms and host cells. dHC can be easily prepared and may be effective in preventing infectious oral diseases.


Delivery of Positive End-Expiratory Pressure Using Self-Inflating Bags during Newborn Resuscitation Is Possible Despite Mask Leak.
Ventilation is the key intervention to resuscitate non-breathing newborns. Positive end-expiratory pressure (PEEP) may facilitate lung-liquid clearance and help establish functional residual capacity. The aim of this study was to describe how mask leak and ventilation rates affect delivered PEEP and tidal volumes during newborn resuscitations using a self-inflating bag with an integrated PEEP valve. This was an observational study including near-term/term newborns who received bag-mask ventilation (BMV) with a new self-inflating bag with a novel 6 mbar PEEP valve, without external gas flow, between October 1, 2016 and June 30, 2018 in rural Tanzania. Helping Babies Breathe-trained midwives performed most of the resuscitations. Pressures and flow were continuously measured and recorded by resuscitation monitors. In total, 198 newborns with a median gestation of 39 weeks (25th, 75th percentiles 37, 40) and birth weight of 3,100 g (2,580, 3,500) were included. The median delivered PEEP and expired (tidal) volume at different levels of mask leak were 6.0 mbar and 11.3 mL/kg at 0-20% mask leak, 5.5 mbar and 9.3 mL/kg at 20-40%, 5.2 mbar and 7.8 mL/kg at 40-60%, 4.6 mbar and 5.0 mL/kg at 60-80%, and 1.0 mbar and 0.6 mL/kg at 80-100% mask leak. A high ventilation rate (>60/min) nearly halved expired volumes compared to <60/min for 0-60% leak. The BMV rate had a negligible effect on peak inflation pressure (PIP) and PEEP. Mask leak up to 80% did not impair the provision of recommended PEEP or tidal volumes during BMV with a self-inflating bag. High or low ventilation rates did not significantly affect PIP or PEEP. Expired volumes were reduced at ventilation rates >60/min.


Occurrence of neoplasia in patients with rheumatoid arthritis enrolled in a DMARD Registry. Rheumatoid Arthritis Azathioprine Registry Steering Committee.
The Rheumatoid Arthritis Azathioprine Registry (RAAR) was established in 1982 to examine the safety of azathioprine (AZA) and other disease modifying agents (DMARD) in the treatment of RA. In yearly followup over the past 7 years, 20 malignant conditions have been reported in 530 DMARD treated adult patients with RA. Incidence density ratios (IDR) and standardized morbidity ratios (SMR) were calculated to assess cancer risk. For all cancers the SMR was 1.52 (95% CI 0.90-2.60). For men the SMR was 1.71 (95% CI 0.84-3.52); for women the SMR was 1.52 (95% CI 0.89-2.60). Adjusted for age, the IDR was highest in the 70-79-year-old study population (3.41). The age and sex adjusted SMR for lymphoproliferative disorders and myeloma was 8.05 (95% CI 3.30-20.81). The SMR for lung cancer (n = 6) was also increased (3.37; 95% CI 1.58-7.34). Compared with the general population, patients with RA requiring DMARD therapy may be at increased risk of malignancy, particularly lymphoproliferative disorders. The RAAR is an important prospective technique which will ultimately permit assessment of neoplasia risk by type and duration of DMARD therapy.


Decompression to altitude: assumptions, experimental evidence, and future directions.
Although differences exist, hypobaric and hyperbaric exposures share common physiological, biochemical, and clinical features, and their comparison may provide further insight into the mechanisms of decompression stress. Although altitude decompression illness (DCI) has been experienced by high-altitude Air Force pilots and is common in ground-based experiments simulating decompression profiles of extravehicular activities (EVAs) or astronauts' space walks, no case has been reported during actual EVAs in the non-weight-bearing microgravity environment of orbital space missions. We are uncertain whether gravity influences decompression outcomes via nitrogen tissue washout or via alterations related to skeletal muscle activity. However, robust experimental evidence demonstrated the role of skeletal muscle exercise, activities, and/or movement in bubble formation and DCI occurrence. Dualism of effects of exercise, positive or negative, on bubble formation and DCI is a striking feature in hypobaric exposure. Therefore, the discussion and the structure of this review are centered on those highlighted unresolved topics about the relationship between muscle activity, decompression, and microgravity. This article also provides, in the context of altitude decompression, an overview of the role of denitrogenation, metabolic gases, gas micronuclei, stabilization of bubbles, biochemical pathways activated by bubbles, nitric oxide, oxygen, anthropometric or physiological variables, Doppler-detectable bubbles, and potential arterialization of bubbles. These findings and uncertainties will produce further physiological challenges to solve in order to line up for the programmed human return to the Moon, the preparation for human exploration of Mars, and the EVAs implementation in a non-zero gravity environment.