On the reliability and validity of physician ratings for vulvodynia and the discriminant validity of its subtypes.
This study aimed to test the reliability and validity of physician ratings in a broadly defined sample of women with vulvodynia and to examine the external validity of the vulvodynia subtypes. Participants were 50 women who were independently diagnosed with vulvodynia by two study gynecologists. Physician ratings corresponding to Friedrich's three criteria for vulvar vestibulitis were taken at the two examinations. Each participant's diagnosis was subtyped as vulvar vestibulitis (VV) or dysesthetic vulvodynia (DV) based upon the physician ratings. Participants completed standardized measures of pain, sexual function, psychological function, and quality of life to examine the discriminant validity of the subtypes. Test-retest reliability for the physician ratings of Friedrich's three criteria was stable for two of the three criteria (i.e., pain on attempted vaginal entry and tenderness to pressure localized within the vulvar vestibule). When these criteria were used to categorize participants as having VV or DV, the subtypes were not statistically different for measures used to examine the discriminant validity of the subtypes. While the distribution of patients changed when premenopausal state was added to the inclusion criteria for VV, the subtypes differed little on the outcome measures. Findings from the present study suggest that physician ratings for Friedrich's criteria can be operationalized and found to be reliable and valid in a wide range of women with vulvodynia. The absence of differences between subtypes on measures of pain, sexual function, psychological function, and quality of life challenge the clinical significance of these subtypes and support the theory that vulvodynia represents a continuum of chronic vulvar pain rather than two distinct entities.


Positional integratomic approach in identification of genomic candidate regions for Parkinson's disease.
Recent abundance of data from studies employing high-throughput technologies to reveal alterations in human disease on genomic, transcriptomic, proteomic and other levels, offer the possibility to integrate this information into a comprehensive picture of molecular events occurring in human disease. Diversity of data originating from these studies presents a methodological obstacle in the integration process, also due to difficulties in choosing the optimal unified denominator that would allow inclusion of variables from various types of studies. We present a novel approach for integration of such multi-origin data based on positions of genetic alterations occurring in human diseases. Parkinson's disease (PD) was chosen as a model for evaluation of our methodology. Datasets from various types of studies in PD (linkage, genome-wide association, transcriptomic and proteomic studies) were obtained from online repositories or were extracted from available research papers. Subsequently, human genome assembly was subdivided into 10 kb regions, and significant signals from aforementioned studies were arranged into their corresponding regions according to their genomic position. For each region, rank product values were calculated and significance values were estimated by permuting the original dataset. Altogether, 179 regions (representing 33 contiguous genomic regions) had significant accumulation of signals when P-value cut-off was set at 0.0001. Identified regions with significant accumulation of signals contained 29 plausible candidate genes for PD. In conclusion, we present a novel approach for identification of candidate regions and genes for various human disorders, based on the positional integration of data across various types of omic studies.


Will you give my kidney back? Organ restitution in living-related kidney transplantation: ethical analyses.
In this article, we perform a thought experiment about living donor kidney transplantation. If a living kidney donor becomes in need of renal replacement treatment due to dysfunction of the remaining kidney after donation, can the donor ask the recipient to give back the kidney that had been donated? We call this problem organ restitution and discussed it from the ethical viewpoint. Living organ transplantation is a kind of 'designated donation' and subsequently has a contract-like character. First, assuming a case in which original donor (A) wishes the return of the organ which had been transplanted into B, and the original recipient (B) agrees, organ restitution will be permissible based on contract-like agreement. However, careful and detailed consideration is necessary to determine whether this leaves no room to question the authenticity of B's consent. Second, if B offers to give back the organ to A, then B's act is a supererogatory act, and is praiseworthy and meritorious. Such an offer is a matter of virtue, not obligation. Third, if A wishes B to return the organ, but B does not wish/allow this to happen, it is likely difficult to justify returning the organ to A by violating B's right to bodily integrity. But B's refusal to return the donated organ cannot be deemed praiseworthy, because B forgets the great kindness once received from A. Rather than calling this an obligation, we encourage B to consider such virtuous conduct.


Monitoring Exposure to Five Chemical Warfare Agents Using the Dried Urine Spot Technique and Liquid Chromatography-Mass Spectrometry/Mass Spectrometry-In Vivo Determination of Sarin Metabolite in Mice.
Dried urine spot (DUS) is a micro-sample collection technique, known for its advantages in handling, storage and shipping. It also uses only a small volume of urine, an essential consideration in working with small animals, or in acute medical situations. Alkyl-phosphonic acids are the direct and indicative metabolites of organophosphorus chemical warfare agents (OP-CWAs) and are present in blood and urine shortly after exposure. They are therefore crucially important for monitoring casualties in war and terror scenarios. We report here a new approach for the determination of the metabolites of five CWAs in urine using DUS. The method is based on a simple and rapid sample preparation, using only 50 µL of urine, spotted and dried on DBS paper, extracted using 300 µL methanol/water and analyzed via targeted LC-MS/MS. The detection limits for the five CWAs, sarin (GB), soman (GD), cyclosarin (GF), VX and RVX in human urine were from 0.5 to 5 ng/mL. Recoveries of (40-80%) were obtained in the range of 10-300 ng/mL, with a linear response (R2 > 0.964, R > 0.982). The method is highly stable, even with DUS samples stored up to 5 months at room temperature before analysis. It was implemented in a sarin in vivo exposure experiment on mice, applied for the time course determination of isopropyl methylphosphonic acid (IMPA, sarin hydrolysis product) in mice urine. IMPA was detectable even with samples drawn 60 h after the mice's (IN) exposure to 1 LD50 sarin. This method was also evaluated in a non-targeted screening for multiple potential CWA analogs (LC-Orbitrap HRMS analysis followed by automatic peak detection and library searches). The method developed here is applicable for rapid CWA casualty monitoring.


Immediate Postextraction Screw-Retained Partial and Full-Arch Rehabilitation: A 3-Year Follow-up Retrospective Clinical Study.
The aim of this study was to document the performance of a novel technique (OnlyOne), involving immediate restoration of postextraction implants supporting a partial or full-arch restoration. A retrospective analysis of patients with at least 3 years of follow-up was performed. Implants were tilted mesiodistally and vestibulopalatally according to the available bone. Prosthetically guided definitive abutments were connected at surgery and never disconnected. Anorganic bovine bone grafting was done to preserve the buccal bone and the ridge contour. Patients received a screw-retained provisional prosthesis within 24 hours of surgery and a final screw-retained prosthesis within 1 year. Prostheses emerged from natural soft tissue. Clinical and radiographic evaluation was routinely performed. A total of 70 patients received 153 implants in fresh extraction sockets. The mean follow-up was 38.0 ± 3.0 months (range 36 to 51 months). One implant failed at the 3-year follow-up. Implant survival was 99.3%. Marginal bone level change averaged -0.68 ± 1.2 mm at the last radiographic control. Immediate placement and restoration of implants designed for high primary stability with a definitive abutment placed at surgery and final screw-retained prosthesis with no artificial gingiva is a viable procedure with excellent medium-term outcomes.


A novel genetic locus modulates infarct volume independently of the extent of collateral circulation.
In the mouse model of permanent, middle cerebral artery occlusion, infarct volume varies widely across inbred strains but generally is inversely correlated with collateral vessel number. However, we also observed certain mouse strains that share similar collateral vessel anatomy but exhibit significantly different infarct volume. To identify genetic factors determining infarct volume in a collateral vessel-independent manner, we performed quantitative trait locus analysis on a F2 cross between C57BL/6J and C3H/HeJ strains. We mapped four novel loci (Civq4 through Civq7) that modulate infarct volume. Civq4, on chromosome 8, is the strongest locus (logarithm of the odds 9.8) that contributes 21% of the phenotypic variance of infarct volume in the cross. The Civq4 and Civq6 loci represent transgressive B6 alleles that render animals susceptible to larger infarcts. Based on genomic sequence and microarray analyses, we propose candidate genes for the Civq4 locus. By selecting inbred strains with similar collateral vessel anatomy but that vary significantly in infarct volume, we have mapped four loci determining infarct volume in a mouse model of ischemic stroke. Two of the loci appear to modulate infarct volume through a collateral vessel-independent mechanism. Based on strain-specific sequence variants and differences in transcript levels, Msr1 and Mtmr7 appear to be strong candidate genes for Civq4. Identifying the underlying genetic factors of these loci will elucidate the genetic architecture response to cerebral ischemia, shed new light on disease mechanisms of ischemic stroke, and identify potential therapeutic targets for clinical applications.


Stu2 promotes mitotic spindle elongation in anaphase.
During anaphase, mitotic spindles elongate up to five times their metaphase length. This process, known as anaphase B, is essential for correct segregation of chromosomes. Here, we examine the control of spindle length during anaphase in the budding yeast Saccharomyces cerevisiae. We show that microtubule stabilization during anaphase requires the microtubule-associated protein Stu2. We further show that the activity of Stu2 is opposed by the activity of the kinesin-related protein Kip3. Reexamination of the kinesin homology tree suggests that KIP3 is the S. cerevisiae orthologue of the microtubule-destabilizing subfamily of kinesins (Kin I). We conclude that a balance of activity between evolutionally conserved microtubule-stabilizing and microtubule-destabilizing factors is essential for correct spindle elongation during anaphase B.


Interactions of endothelin-1 with dexamethasone in primary cultured human trabecular meshwork cells.
Concentrations of aqueous humor endothelin (ET)-1 are increased in patients with primary open-angle glaucoma (POAG) as well as in animal models of glaucoma. Glucocorticoids have also been associated with glaucoma, in that topical administration of glucocorticoids can increase intraocular pressure by increasing outflow resistance in the trabecular meshwork (TM) in some individuals. Recent research has shown that dexamethasone (Dex), a synthetic glucocorticoid, can increase the release of ET-1 from human nonpigmented ciliary epithelial (HNPE) cells, a source of aqueous ET-1. In the present study, the downstream interaction of ET-1 with Dex in target TM cells, an action that may alter outflow resistance, was investigated. A normal primary human TM (NTM) cell line and a TM cell line derived from a glaucomatous eye (GTM) were used. The cells were treated with vehicle or Dex. The mRNA levels of prepro-ET-1, endothelin receptor A (ET(A)), and endothelin receptor B (ET(B)) were measured by quantitative RT-PCR (QPCR). The protein expression of ET(A) and ET(B) receptors were investigated by Western blot analysis using polyclonal anti-ET(A) and anti-ET(B) antibodies, respectively, on plasma membrane fractions. Intracellular Ca(2+) ([Ca(2+)](i)) mobilization mediated by ET-1 was measured using the Fura-2 AM fluorescent probe technique as an index of ET receptor function. ET-1-stimulated nitric oxide (NO) release was measured using a Griess colorimetric NO synthase assay kit. Both NTM and GTM cultured cells expressed prepro-ET-1 mRNA less abundantly than did HNPE cells, and Dex treatment had no effect on the mRNA expression of the ET-1 gene. TM cells expressed mRNA of ET(A) receptors as detected by QPCR, whereas the ET(B) message was not clearly delineated. Western blot analysis showed that both ET(A) and ET(B) receptor proteins were present. The ET(A) receptor was linked to calcium mobilization as ET-1 produced an increase in intracellular calcium release, and this increase was blocked with a selective ET(A) receptor antagonist. Dex failed to induce any change in the expression of the ET(A) receptor in both NTM and GTM cells, and this was supported by the absence of a Dex effect on the ET-1-induced calcium response. However, Dex treatment diminished ET(B) receptor protein expression and produced a decrease in ET-1-stimulated release of NO, a response mediated by ET(B) receptors in TM cells. The Dex-induced increase in ET-1 released by HNPE cells coupled to the downstream Dex-induced specific suppression of ET(B) receptor protein expression and declines in ET-1-mediated increase in NO released by TM cells could increase contraction and decrease relaxation of the TM and contribute to the declines in conventional aqueous humor outflow and increases in intraocular pressure that occur with glucocorticoids.


Transcutaneous bilirubinometry in Chinese and Malay neonates.
An evaluation of the Minolta/Airshields transcutaneous bilirubinometer (TcB) was made in 68 Chinese and 57 Malay fullterm infants, 18 Chinese premature infants and 9 infants undergoing phototherapy. A close correlation between the TcB index and bilirubin values was observed at all three sites measured--forehead, sternum and upper back--in both Chinese and Malay infants; though this correlation was not as close in premature infants. A high degree of reproducibility was demonstrated. The correlation was significantly closer in bilirubin values not exceeding 200 umol/l compared with values exceeding 200 umol/l. The TcB is a useful screening device for neonatal jaundice.


Infectious agents as causes of non-Hodgkin lymphoma.
Among exposures presently viewed as possible etiologic factors in non-Hodgkin lymphoma (NHL), infections are close to being regarded as established causes. Infectious agents causing NHL can be classified, according to mechanism, into three broad groups. First, some viruses can directly transform lymphocytes. Lymphocyte-transforming viruses include Epstein Barr virus (linked to Burkitt's lymphoma, NHLs in immunosuppressed individuals, and extranodal natural killer/T-cell NHL), human herpesvirus 8 (primary effusion lymphoma), and human T lymphotropic virus type I (adult T-cell leukemia/lymphoma). Second, human immunodeficiency virus is unique in causing profound depletion of CD4+ T lymphocytes, leading to acquired immunodeficiency syndrome and an associated high risk for some NHL subtypes. Third, recent evidence suggests that some infections increase NHL risk through chronic immune stimulation. These infections include hepatitis C virus as well as certain bacteria that cause chronic site-specific inflammation and seem to increase risk for localized mucosa-associated lymphoid tissue NHLs. Establishing that an infectious agent causes NHL depends on showing that the agent is present in persons with NHL as well as laboratory experiments elucidating the mechanisms involved. Only epidemiologic studies can provide evidence that infection is actually a risk factor by showing that infection is more frequent in NHL cases than in controls. Given the range of mechanisms by which infections could plausibly cause NHL and our growing molecular understanding of this malignancy, this field of research deserves continued attention.


Achieving remission or low disease activity is associated with better outcomes in patients with systemic lupus erythematosus: a systematic literature review.
Remission and low disease activity (LDA) have been proposed as the treatment goals for patients with systemic lupus erythematosus (SLE). Several definitions for each have been proposed in the literature. To assess the impact of remission/LDA according to various definitions on relevant outcomes in patients with SLE. This systematic literature review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using PubMed (1946-week 2, April 2021), Cochrane library (1985-week 2, week 2, April 2021) and EMBASE (1974-week 2, April 2021). We included longitudinal and cross-sectional studies in patients with SLE reporting the impact of remission and LDA (regardless their definition) on mortality, damage accrual, flares, health-related quality of life and other outcomes (cardiovascular risk, hospitalisation and direct costs). The quality of evidence was evaluated using the Newcastle-Ottawa Scale. We identified 7497 articles; of them, 31 studies met the inclusion criteria and were evaluated. Some articles reported a positive association with survival, although this was not confirmed in all of them. Organ damage accrual was the most frequently reported outcome, and remission and LDA were reported as protective of this outcome (risk measures varying from 0.04 to 0.95 depending on the definition). Similarly, both states were associated with a lower probability of SLE flares, hospitalisations and a better health-related quality of life, in particular the physical domain. Remission and LDA are associated with improvement in multiple outcomes in patients with SLE, thus reinforcing their relevance in clinical practice. CRD42020162724.


Radiation Therapy for Invasive Breast Cancer Increases the Risk of Second Primary Lung Cancer: A Nationwide Population-Based Cohort Analysis.
Although the risk factors for lung cancer are well documented, whether previous radiation therapy (RT) to treat breast cancer (BC) increases the incidence of second primary lung cancer remains unclear. We determined the overall incidence of second primary lung cancer after previous RT for all clinical stages of BC. After an analysis of the Longitudinal Health Insurance Database, 986,713 individuals were randomly enrolled from 2000 to 2010 for cohort analysis. All women with newly diagnosed invasive BC, aged 18 years or older, and without other types of malignancy before 2000 or in the follow-up periods were enrolled and allocated to the RT or non-RT groups. Age, comorbidities, insurance premium, urbanization level, location, date of event, and hospital care level were analyzed. The hazard ratios of parameters were calculated by Cox regression analysis. A total of 7408 individuals met the inclusion criteria, including 5695 patients with BC who underwent RT and 128 (2.25%) in whom lung cancer developed. In contrast, lung cancer was diagnosed in only four of 1713 individuals in the non-RT group (0.23%) during the follow-up period. Cox regression analysis showed that the adjusted hazard ratio was 10.078 times higher in the RT group than in the non-RT group for individuals with previous BC. The incidence of second primary lung cancer was significantly higher in the RT group than in the non-RT group for individuals with previous BC. Patients with BC treated by RT should be extensively surveyed to assess the incidence of subsequent lung cancer.


Uprooting Medical Violence: Excavating the Roots of Settler Colonialism and Systemic Anti-Black Racism within Healthcare.
In this issue, Dryden (2023) disrupts the myth of neutrality in healthcare and outlines the importance of naming anti-Black racism in order to dismantle it. In this commentary, I take up Dryden's (2023) call to study the relationship between colonialism, anti-Blackness and healthcare. I utilize historical and present-day examples that uncover the roots of settler colonialism and slavery within North American healthcare systems. Finally, I explore how dispossessed communities have resisted medical violence. I call on healthcare workers to fight for non-reformist reforms, uplift self-determining care and engage in resistance toward liberatory futures.


Force-field-enhanced neural network interactions: from local equivariant embedding to atom-in-molecule properties and long-range effects.
We introduce FENNIX (Force-Field-Enhanced Neural Network InteraXions), a hybrid approach between machine-learning and force-fields. We leverage state-of-the-art equivariant neural networks to predict local energy contributions and multiple atom-in-molecule properties that are then used as geometry-dependent parameters for physically-motivated energy terms which account for long-range electrostatics and dispersion. Using high-accuracy ab initio data (small organic molecules/dimers), we trained a first version of the model. Exhibiting accurate gas-phase energy predictions, FENNIX is transferable to the condensed phase. It is able to produce stable Molecular Dynamics simulations, including nuclear quantum effects, for water predicting accurate liquid properties. The extrapolating power of the hybrid physically-driven machine learning FENNIX approach is exemplified by computing: (i) the solvated alanine dipeptide free energy landscape; (ii) the reactive dissociation of small molecules.


Rupture rates of untreated large abdominal aortic aneurysms in patients unfit for elective repair.
Elective abdominal aortic aneurysm (AAA) surgery relies on balancing the risk of the intervention against the risk of the aneurysm causing death. Although much is known about intervention at 5.5 cm, little is known about the fate of the patient unfit for elective surgery at this threshold. Medical therapy and endovascular surgery have revolutionized management of aortic aneurysms in the last 20 years and are thought to have affected rupture rates. MEDLINE via PubMed, EMBASE, and the Cochrane Library Database were searched for studies reporting follow-up of untreated large AAA approach from inception to January 2014. Data were pooled using random-effects analysis with standardized mean differences and 95% confidence intervals (CIs) reported. The primary end points were rupture rates and all-cause mortality per year by AAA size. The search strategy identified 1892 citations, of which 11 studies comprising 1514 patients experiencing 347 ruptured AAA were included. The overall incidence of ruptured AAA in patients with AAA >5.5 cm was 5.3% (95% CI, 3.1%-7.5%) per year. This represented cumulative yearly rupture rates of 3.5% (95% CI, -1.6% to 8.7%) in AAAs 5.5 to 6.0 cm, 4.1% (95% CI, -0.7% to 9.0%) in AAAs 6.1 to 7.0 cm, and 6.3% (95% CI, -1.8% to 14.3%) in AAAs >7.0 cm. There was no heterogeneity between studies (I(2) = 0%). Only 32% of these patients were offered repair on rupturing an AAA, with a perioperative mortality of 58% (95% CI, 32%-83%). The risk of death from causes other than AAA was higher than the risk of death from rupture. Rupture rates of untreated AAA were lower than those currently quoted in the literature. Non-AAA-related mortality in this group of patients is high.


The effect of "Narrative writing reflection" method on the hope of patient with COVID-19: A health promotion intervention.
Corona virus disease disease as a life-threatening respiratory disease causes psychological problems including hopelessness in patients. So the aim of this study was to determine the effect of Narrative writing reflection on hope of patient with COVID-19. The study was experimental with a pre-test-post-test and with the control group design. The subjects were randomly divided into the intervention (n = 30) and control (n = 30) groups. The intervention group received Narrative writing reflection. The control group was receiving routine care. Before and after the intervention, the patients were asked to complete the 12-item Herth Hope Index. Data were analyzed with by using spss software and paired t test and independent t-test with a significance level of P < 0.05. Independent t-test showed that the hope scores before intervention in both intervention and control groups were not statistically significant (P > 0.05), whereas there was a significant difference between two groups after the intervention (P < 0.05). The results of this study showed that the use of mindfulness methods such as narrative writing in hospitalized and quarantined patients who are unable to communicate with the outside environment could increase the hope in patient.


Metabolic effects of coconut, safflower, or menhaden oil feeding in lean and obese Zucker rats.
The aim of the present investigation was to study the effects of fish oil feeding in obese Zucker rats to establish its suitability as an animal model of hyperlipidaemia, and to understand the possible mechanism of fish oil-induced perturbations in cell metabolism. Lean and obese Zucker rats were fed on diets containing 180 g coconut, safflower, or menhaden oil/kg for 10 weeks. Body-weights and food intakes of lean coconut (LC), safflower (LS), and menhaden (LM) groups were similar. Obese menhaden (OM) rats had lower food intakes and body-weights compared with obese coconut (OC) and obese safflower (OS) groups, but values for all obese rats were higher than those for lean rats. Liver weights were higher in obese compared with lean rats, but on a percentage body-weight basis menhaden oil rats had higher values within genotype. Serum cholesterol and triacylglycerol levels were lower in the OM group compared with the OC and OS groups, and in the LM group compared with the LC group. Glucose and insulin levels were highest in OS rats followed by OC and OM rats and then the lean rats. Serum triiodothyronine and thyroxine were lower in OM rats compared with OC and OS rats. Liver mitochondrial state 3 rates with glutamate-malate and succinate were lower; mitochondrial beta-oxidation was unaffected and peroxisomal beta-oxidation was higher in menhaden oil rats compared with both coconut and safflower oil rats. In general, consumption of menhaden oil lowered hepatic malic enzyme (EC 188.8.131.52, 18.104.22.168), glucose-6-phosphate dehydrogenase (EC 126.96.36.199) and glutathione peroxidase (EC 220.127.116.11) activities and elevated long-chain fatty acyl-CoA hydrolase (EC 184.108.40.206) activity when compared with the two other diets. It is concluded that obese Zucker rats do respond like human subjects to fish oil feeding but not to vegetable oils. The hypolipidaemic effect of fish oil appears to be mediated through a lowering of lipogenic enzymes, glucose-6-phosphate dehydrogenase and malic enzyme.


Extracellular ATP is a central signaling molecule in plant stress responses.
Because of their sessile nature, plants have developed a number of sophisticated signaling systems to adapt to environmental changes. Previous research has shown that extracellular ATP is an important signaling molecule used by plants and functions in a variety of processes, including growth, development, and stress responses. Recently, DORN1 was identified as the first plant purinoceptor, essential for the plant response to ATP. The identification of the receptor is a milestone for our overall understanding of various physiological events regulated by extracellular ATP. In this review, we will discuss the possible roles of DORN1 providing future direction for research into the role of extracellular ATP in plants.


Chromosome abnormalities in human leukemia as indicators of mutagenic exposure.
It is from an analysis of these data that I proposed that losses of all or part of the long arm of chromosomes 5 and/or 7 may be indicators of exposure to mutagenic agents (8). Moreover, our analysis of the regions of chromosomes 5 and 7 that are consistently missing can define the critical region of each chromosome with some precision. Looked at from another perspective, the frequency of losses of chromosomes 5 and/or 7 may be an indicator of the proportion of ANLL in each particular population that is related to some mutagenic exposure. These aberrations are most frequent in cells of patients who were previously exposed to various cytotoxic regimens for treatment of a primary (usually malignant) disease; these patients are considered to have 2 degrees ANLL. Among patients with ANLL de novo, abnormalities of chromosomes 5 and 7 are much more frequent in older than younger patients. Finally, among adult patients with ANLL de novo, -5 and -7 are more common in those whose occupations could potentially expose them to mutagenic agents such as chemicals, pesticides, or petroleum products. With regard to chromosome 5, most of these deletions are interstitial and always include 5q23 through q31, which I have called the critical region. Although I am less certain with regard to chromosome 7, it appears that the critical region that is consistently deleted may be 7q32 or 7q34-35.


Follow-up of radiologically totally implanted central venous access ports of the upper arm: long-term complications in 127,750 catheter-days.
The purpose of this article is to retrospectively evaluate radiologically totally implanted central venous access ports (VAPs) of the upper arm in terms of safety, technical feasibility, and device-related complications. Five hundred seven consecutive patients (mean [± SD] age, 59.2 ± 11.4 years) who received a totally implanted central VAP between January 2005 and July 2010 were included. The insertion procedure was performed in an interventional radiology suite using the Seldinger technique. Neither antibiotic prophylaxis nor long-term anticoagulation was administered. In 507 patients, a total of 523 devices were implanted. Of these 523 procedures, 512 complete datasets were available during follow-up. The primary technical success rate was 99.04%. All procedures were completed without major complications. During follow-up and with a total number of 127,750 days of totally implanted central VAP implantation (248 ± 279 days/patient; range, 1-1687 days/patient), 50 devices had to be revised because of complications (9.8%). Complications occurred at a mean of 114 ± 183 days (range, 1-1113 days) after placement. Early complications were noted in 21 of 512 cases (4.1%), and late complications were noted in 29 of 512 cases (5.7%). Complications were as follows: local infections, 4.9% (25/512); systemic infections, 0.4% (2/512); venous thrombosis, 1.6% (8/512); paralysis of the median nerve, 0.6% (3/512); skin dehiscence at the port site, 0.2% (1/512); and mechanical problems including catheter line displacement, port hub rotation, and catheter fracture, 2.1% (11/512). Radiologic placement of a totally implanted central VAP is a safe procedure with a low rate of both early and late device-related complications. The method is effective for delivery of chemotherapy, parenteral nutrition, and frequent IV medication.


Autism spectrum disorder symptoms from ages 2 to 19 years: Implications for diagnosing adolescents and young adults.
This study explored change in social-communicative symptoms in 140 individuals with childhood autism spectrum disorder (ASD) diagnoses. Trajectories of caregiver-reported social-communicative symptoms were examined for three groups (verbal, delayed speech, minimally verbal) from ages 2 to 19 years. Groups showed comparable levels of social-communicative impairment at 2 years and significant decreases in overall symptom levels across the 17-year period (P < .001). Across three subdomains, main effects of time and language (P < .001) reflected patterns of overall improvement, although children with more impaired language tended to have more caregiver-reported symptoms relative to verbal peers. A significant time-by-language interaction (P < .001) reflected that trajectories of socioemotional reciprocity symptoms differed according to patterns of language development. In contrast, improvements in the nonverbal communication domain were seen across language groups, whereas deficits in the development and maintenance of relationships improved for only verbal children. Verbal adults showed significant reductions in the prevalence of kseveral symptoms exhibited during childhood. Improvements suggest that symptoms indicative of ASD in young children may no longer be diagnostic markers in adolescents and adults. Relative stability of several items suggests that impaired facial expression may be a core ASD symptom that warrants more systematic study across the lifespan. Research investigating the manifestation of ASD in older individuals is needed to foster development of appropriate assessment tools and interventions. Differential relationships to developmental factors within the broader social-communication domain underscores a need to focus on more narrowly defined symptom constructs when exploring links between pathophysiology and observable phenotypes. Autism Research 2019, 12: 89-99. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: In a sample of 140 participants with autism spectrum disorder (ASD) followed from 2 to 19 years old, this study found that overall social-communicative symptoms improve across childhood and adolescence. However, timing and amount of change varied for different symptom categories and participants with different language abilities. Findings suggest that some older adolescents and adults with ASD may not exhibit the same difficulties observed in young children with ASD. More research is needed to better understand the strengths and needs of young adults with ASD.


The modulation of endometriosis by lncRNA MALAT1 via NF-κB/iNOS.
Endometriosis (Ems) is one benign disorder that frequently leads to chronic pelvic pain, dysmenorrhea or even infertility. Featured as the ectopic growth of active endometrial tissues on tissues beyond the muscular layer, Ems has complicated pathogenesis mechanisms that are not fully illustrated. Long non-coding (lnc) RNA MALAT1 participates in various biological activities, including cell growth, proliferation, apoptosis, organogenesis, inflammation, and tumors. However, its expression and function in Ems are not clear yet. Real-time PCR measured differential expression of MALAT1 in normal and ectopic endometrial tissues. Cultured endometrial cells were transfected with siRNA for MALAT1, whose expression was measured by real-time PCR. MTT assay measured endometrial cell proliferation, whose invasion was measured by transwell assay. Western blot tested the expression and NF-κB/iNOS, and MMP9 proteins. LncRNA MALAT1 showed upregulation in ectopic endometrial tissues (p<0.05 comparing to control group). Transfection of MALAT1 siRNA suppressed its expression in endometrial cells, inhibited cell proliferation or invasion, enhanced caspase 3 activity, decreased NF-κB/iNOS or MMP-9 expression (p<0.05 comparing to control group). LncRNA MALAT1 can facilitate endometrial cell apoptosis and modulate MMP-9 expression via NF-κB/iNOS pathway, thus, mediating Ems pathogenesis.


Challenges in the Evaluation of Interventions to Improve Engagement Along the HIV Care Continuum in the United States: A Systematic Review.
In the United States (US), there are high levels of disengagement along the HIV care continuum. We sought to characterize the heterogeneity in research studies and interventions to improve care engagement among people living with diagnosed HIV infection. We performed a systematic literature search for interventions to improve HIV linkage to care, retention in care, reengagement in care and adherence to antiretroviral therapy (ART) in the US published from 2007-mid 2015. Study designs and outcomes were allowed to vary in included studies. We grouped interventions into categories, target populations, and whether results were significantly improved. We identified 152 studies, 7 (5%) linkage studies, 33 (22%) retention studies, 4 (3%) reengagement studies, and 117 (77%) adherence studies. 'Linkage' studies utilized 11 different outcome definitions, while 'retention' studies utilized 39, with very little consistency in effect measurements. The majority (59%) of studies reported significantly improved outcomes, but this proportion and corresponding effect sizes varied substantially across study categories. This review highlights a paucity of assessments of linkage and reengagement interventions; limited generalizability of results; and substantial heterogeneity in intervention types, outcome definitions, and effect measures. In order to make strides against the HIV epidemic in the US, care continuum research must be improved and benchmarked against an integrated, comprehensive framework.


Natural variants modify Klebsiella pneumoniae carbapenemase (KPC) acyl-enzyme conformational dynamics to extend antibiotic resistance.
Class A serine β-lactamases (SBLs) are key antibiotic resistance determinants in Gram-negative bacteria. SBLs neutralize β-lactams via a hydrolytically labile covalent acyl-enzyme intermediate. Klebsiella pneumoniae carbapenemase (KPC) is a widespread SBL that hydrolyzes carbapenems, the most potent β-lactams; known KPC variants differ in turnover of expanded-spectrum oxyimino-cephalosporins (ESOCs), for example, cefotaxime and ceftazidime. Here, we compare ESOC hydrolysis by the parent enzyme KPC-2 and its clinically observed double variant (P104R/V240G) KPC-4. Kinetic analyses show that KPC-2 hydrolyzes cefotaxime more efficiently than the bulkier ceftazidime, with improved ESOC turnover by KPC-4 resulting from enhanced turnover (kcat), rather than altered KM values. High-resolution crystal structures of ESOC acyl-enzyme complexes with deacylation-deficient (E166Q) KPC-2 and KPC-4 mutants show that ceftazidime acylation causes rearrangement of three loops; the Ω, 240, and 270 loops, which border the active site. However, these rearrangements are less pronounced in the KPC-4 than the KPC-2 ceftazidime acyl-enzyme and are not observed in the KPC-2:cefotaxime acyl-enzyme. Molecular dynamics simulations of KPC:ceftazidime acyl-enyzmes reveal that the deacylation general base E166, located on the Ω loop, adopts two distinct conformations in KPC-2, either pointing "in" or "out" of the active site; with only the "in" form compatible with deacylation. The "out" conformation was not sampled in the KPC-4 acyl-enzyme, indicating that efficient ESOC breakdown is dependent upon the ordering and conformation of the KPC Ω loop. The results explain how point mutations expand the activity spectrum of the clinically important KPC SBLs to include ESOCs through their effects on the conformational dynamics of the acyl-enzyme intermediate.


Acidification effects on biofouling communities: winners and losers.
How ocean acidification affects marine life is a major concern for science and society. However, its impacts on encrusting biofouling communities, that are both the initial colonizers of hard substrata and of great economic importance, are almost unknown. We showed that community composition changed significantly, from 92% spirorbids, 3% ascidians and 4% sponges initially to 47% spirorbids, 23% ascidians and 29% sponges after 100 days in acidified conditions (pH 7.7). In low pH, numbers of the spirorbid Neodexiospira pseudocorrugata were reduced ×5 compared to controls. The two ascidians present behaved differently with Aplidium sp. decreasing ×10 in pH 7.7, whereas Molgula sp. numbers were ×4 higher in low pH than controls. Calcareous sponge (Leucosolenia sp.) numbers increased ×2.5 in pH 7.7 over controls. The diatom and filamentous algal community was also more poorly developed in the low pH treatments compared to controls. Colonization of new surfaces likewise showed large decreases in spirorbid numbers, but numbers of sponges and Molgula sp. increased. Spirorbid losses appeared due to both recruitment failure and loss of existing tubes. Spirorbid tubes are comprised of a loose prismatic fabric of calcite crystals. Loss of tube materials appeared due to changes in the binding matrix and not crystal dissolution, as SEM analyses showed crystal surfaces were not pitted or dissolved in low pH conditions. Biofouling communities face dramatic future changes with reductions in groups with hard exposed exoskeletons and domination by soft-bodied ascidians and sponges.


Comparison of Robotic and Conventional Unicompartmental Knee Arthroplasty Outcomes in Patients with Osteoarthritis: A Retrospective Cohort Study.
Robotic-arm-assisted unicompartmental knee arthroplasty (RUKA) was developed to increase the accuracy of bone alignment and implant positioning. This retrospective study explored whether RUKA has more favorable overall outcomes than conventional unicompartmental knee arthroplasty (CUKA). A total of 158 patients with medial compartment osteoarthritis were recruited, of which 85 had undergone RUKA with the Mako system and 73 had undergone CUKA. The accuracy of component positioning and bone anatomical alignment was compared using preoperative and postoperative radiograph. Clinical outcomes were evaluated using questionnaires, which the patients completed preoperatively and then postoperatively at six months, one year, and two years. In total, 52 patients from the RUKA group and 61 from the CUKA group were eligible for analysis. The preoperative health scores and Kellgren-Lawrence scores were higher in the RUKA group. RUKA exhibited higher implant positioning accuracy, thus providing a superior femoral implant angle, properly aligned implant placement, and a low rate of overhang. RUKA also achieved higher accuracy in bone anatomical alignment (tibial axis angle and anatomical axis angle) than CUKA, but surgical time was longer, and blood loss was greater. No significant differences were observed in the clinical outcomes of the two procedures.


Fibrosis stage is an independent predictor of outcome in primary biliary cholangitis despite biochemical treatment response.
Fibrosis stage predicts prognosis in patients with chronic liver disease independent of aetiology, although its precise role in risk stratification in patients with primary biliary cholangitis (PBC) remains undefined. To assess the utility of baseline fibrosis stage in predicting long-term outcomes in the context of biochemical risk stratification METHODS: In a large and globally representative cohort of patients with PBC, liver biopsies performed from 1980 to 2014 were evaluated. The predictive ability of histologic fibrosis stage in addition to treatment response at 1 year (Toronto/Paris-II criteria), as well as non-invasive markers of fibrosis (AST/ALT ratio [AAR], AST to platelet ratio index [APRI], FIB-4), for transplant-free survival was assessed with Cox proportional-hazards models. There were 1828 patients with baseline liver biopsy. Advanced histologic fibrosis (stage 3/4) was an independent predictor of survival in addition to non-invasive measures of fibrosis with the hazard ratios ranging from 1.59 to 2.73 (P < .001). Patients with advanced histologic fibrosis stage had worse survival despite biochemical treatment response, with a 10-year survival of 76.0%-86.6% compared to 94.5%-95.1% depending on the treatment response criteria used. Poor correlations were observed between non-invasive measures of fibrosis and histologic fibrosis stage. Assessment of fibrosis stage grants prognostic value beyond biochemical treatment response at 1 year. This highlights the need to incorporate fibrosis stage in individual risk stratification in patients with PBC, partly to identify those that may derive benefit from novel therapies.


Ultrasensitive Detection of Clostridioides difficile Toxins in Stool by Use of Single-Molecule Counting Technology: Comparison with Detection of Free Toxin by Cell Culture Cytotoxicity Neutralization Assay.
Laboratory tests for Clostridioides difficile infection (CDI) rely on the detection of free toxin or molecular detection of toxin genes. The Singulex Clarity C. diff toxins A/B assay is a rapid, automated, and ultrasensitive assay that detects C. difficile toxins A and B in stool. We compared CDI assays across two prospective multicenter studies to set a cutoff for the Clarity assay and to independently validate the performance compared with that of a cell culture cytotoxicity neutralization assay (CCCNA). The cutoff was set by two sites testing fresh samples from 897 subjects with suspected CDI and then validated at four sites testing fresh samples from 1,005 subjects with suspected CDI. CCCNA testing was performed at a centralized laboratory. Samples with discrepant results between the Clarity assay and CCCNA were retested with CCCNA when the Clarity result agreed with that of at least one comparator method; toxin enzyme immunoassays (EIA), glutamate dehydrogenase (GDH) detection, and PCR were performed on all samples. The cutoff for the Clarity assay was set at 12.0 pg/ml. Compared to results with CCCNA, the Clarity assay initially had 85.2% positive agreement and 92.4% negative agreement. However, when samples with discrepant results between the Clarity assay and CCCNA in the validation study were retested by CCCNA, 13/17 (76.5%) Clarity-negative but CCCNA-positive samples (Clarity+/CCCNA-) became CCCNA-, and 5/26 (19.2%) Clarity+/CCCNA- samples became CCCNA+, resulting in a 96.3% positive agreement and 93.0% negative agreement between Clarity and CCCNA results. The toxin EIA had 59.8% positive agreement with CCCNA. The Clarity assay was the most sensitive free-toxin immunoassay, capable of providing CDI diagnosis in a single-step solution. A different CCCNA result was reported for 42% of retested samples, increasing the positive agreement between Clarity and CCCNA from 85.2% to 96.3% and indicating the challenges of comparing free-toxin results to CCCNA results as a reference standard.


Estimation of corneal endothelial pump function in long-term contact lens wearers.
To study the effects of long-term contact lens wear on morphologic and physiologic properties of corneal endothelial cells. The endothelial permeability to fluorescein and the rate of corneal deswelling from hypoxia-induced edema were measured in 20 long-term (mean, 17+/-9 years; range, 5-33 years) contact lens wearers and 20 age-matched control subjects. From these data, the relative endothelial pump rate in each subject was estimated, based on the pump-leak hypothesis of corneal hydration control. Corneal autofluorescence and the aqueous humor flow rate were determined by fluorescein fluorophotometry. Images of corneal endothelial cells were recorded by using specular microscopy, and morphologic indices (cell density, coefficient of variation of cell area, percentage of hexagonal cells, and skewness) were determined. No statistically significant differences were found between the contact lens and control groups in endothelial permeability, corneal deswelling, relative endothelial pump rate ([mean +/- SD] 1.07+/-0.33 relative pump units versus 1.01+/-0.25 relative pump units; contact lens versus control; P = 0.57), and endothelial cell density. Contact lens wearers had a significantly higher aqueous humor flow rate (3.57+/-1.03 microl/min versus 2.77+/-0.51 microl/min; P = 0.005), coefficient of variation of cell area (0.35+/-0.09 versus 0.28+/-0.04; P = 0.006), and corneal autofluorescence (3.1+/-0.6 ng/ml versus 2.3+/-0.3 ng/ml fluorescein equivalents; P < 0.001) than did non-contact lens wearers. Despite the known effects of long-term contact lens wear on corneal endothelial morphometry, no effect on endothelial function was found.


New normative standards of conditional reasoning and the dual-source model.
There has been a major shift in research on human reasoning toward Bayesian and probabilistic approaches, which has been called a new paradigm. The new paradigm sees most everyday and scientific reasoning as taking place in a context of uncertainty, and inference is from uncertain beliefs and not from arbitrary assumptions. In this manuscript we present an empirical test of normative standards in the new paradigm using a novel probabilized conditional reasoning task. Our results indicated that for everyday conditional with at least a weak causal connection between antecedent and consequent only the conditional probability of the consequent given antecedent contributes unique variance to predicting the probability of conditional, but not the probability of the conjunction, nor the probability of the material conditional. Regarding normative accounts of reasoning, we found significant evidence that participants' responses were confidence preserving (i.e., p-valid in the sense of Adams, 1998) for MP inferences, but not for MT inferences. Additionally, only for MP inferences and to a lesser degree for DA inferences did the rate of responses inside the coherence intervals defined by mental probability logic (Pfeifer and Kleiter, 2005, 2010) exceed chance levels. In contrast to the normative accounts, the dual-source model (Klauer et al., 2010) is a descriptive model. It posits that participants integrate their background knowledge (i.e., the type of information primary to the normative approaches) and their subjective probability that a conclusion is seen as warranted based on its logical form. Model fits showed that the dual-source model, which employed participants' responses to a deductive task with abstract contents to estimate the form-based component, provided as good an account of the data as a model that solely used data from the probabilized conditional reasoning task.


Inheritance and reproductive consequences of floral anthocyanin deficiency in Silene dioica (Caryophyllaceae).
• Flower color is one of the most important traits for pollinator attraction. However, natural plant populations often harbor rare flower color variants resulting from mutations in biochemical pathways for floral pigment production. It is unclear how such mutations can persist because they can affect not only pollinator visitation but also plant fertility and performance.• We collected rare white-flowered (anthocyanin-deficient) and common pink-flowered morphs of Silene dioica from natural populations in Switzerland. First- and second-generation hybrids between pink and white morphs, as well as backcrosses toward white morphs were produced, and the proportion of white-flowered offspring was determined. We compared seed siring ability and seed production between morphs using hand pollination experiments. Moreover, we scored the transfer of pollen analogues (fluorescent dyes) in a 50:50 array of the two morphs.• The proportions of white-flowered plants in the offspring of our crosses were consistent with more than one recessive mutation as the cause of floral anthocyanin deficiency and further suggested a role of maternal effects for flower color. Seed siring ability and seed set did not differ significantly between pink and white morphs. Pollen transfer occurred preferentially within morphs.• Overall, our results imply that the white morph of S. dioica likely is caused by recessive mutations that do not impair reproduction. However, as this flower color polymorphism led to assortative mating in our experiment, it may represent standing genetic variation with the potential to contribute to evolutionary divergence.


Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study.
Pituitary stalk interruption syndrome (PSIS) is a rare disorder characterized by an absent or ectopic posterior pituitary, absent or interrupted pituitary stalk and anterior pituitary hypoplasia on magnetic resonance imaging (MRI), as well in some cases a range of heterogeneous somatic anomalies. The triad can be incomplete. Here, we performed exome sequencing on 16 sporadic patients, aged 0.4 to 13.7 years diagnosed with isolated or complex PSIS. Growth hormone deficiency was isolated in 10 cases, or associated with thyrotropin deficiency in 6 others (isolated (2 cases), associated with adrenocorticotropin deficiency (1 case), gonadotropins deficiency (1 case), or multiple deficiencies (2 cases)). Additional phenotypic anomalies were present in six cases (37.5%) including four with ophthalmic disorders. In 13 patients variants were identified that may contribute to the phenotype. However, only a single individual carried a variant classified as pathogenic. This child presented with the typical clinical presentation of Okur-Chung neurodevelopmental syndrome due to a CSNK2A1 missense variant. We also identified variants in the holoprosencephaly associated genes GLI2 and PTCH1. A likely pathogenic novel splice site variant in the GLI2 gene was observed in a child with PSIS and megacisterna magna. In the remaining 11 cases 26 variants in genes associated with pituitary development or function were identified and were classified of unknown significance. Compared with syndromic forms the diagnostic yield in the isolated forms of PSIS is low. Although we identified rare or novel missense variants in several hypogonadotropic hypogonadism genes (e.g. FGF17, HS6ST1, KISS1R, CHD7, IL17RD) definitively linking them to the PSIS phenotype is premature. A major challenge remains to identify pathogenic variants in cases with isolated PSIS.


Children's active commuting to school: current knowledge and future directions.
Driven largely by international declines in rates of walking and bicycling to school and the noted health benefits of physical activity for children, research on children's active commuting to school has expanded rapidly during the past 5 years. We summarize research on predictors and health consequences of active commuting to school and outline and evaluate programs specific to children's walking and bicycling to school. Literature on children's active commuting to school published before June 2007 was compiled by searching PubMed, PsycINFO, and the National Transportation Library databases; conducting Internet searches on program-based activities; and reviewing relevant transportation journals published during the last 4 years. Children who walk or bicycle to school have higher daily levels of physical activity and better cardiovascular fitness than do children who do not actively commute to school. A wide range of predictors of children's active commuting behaviors was identified, including demographic factors, individual and family factors, school factors (including the immediate area surrounding schools), and social and physical environmental factors. Safe Routes to School and the Walking School Bus are 2 public health efforts that promote walking and bicycling to school. Although evaluations of these programs are limited, evidence exists that these activities are viewed positively by key stakeholders and have positive effects on children's active commuting to school. Future efforts to promote walking and bicycling to school will be facilitated by building on current research, combining the strengths of scientific rigor with the predesign and postdesign provided by intervention activities, and disseminating results broadly and rapidly.


Cladribine in the treatment of hairy-cell leukaemia.
Cladribine, a purine nucleoside analogue, is a safe and effective treatment for patients with hairy-cell leukaemia. It is administered at a dose of 0.09 mg/kg daily as a continuous intravenous infusion over 7 days. This chapter discusses the history, rationale, chemical structure and mechanism of action of cladribine. The indications for therapy and guidelines for clinical usage are reviewed. The response of hairy-cell leukaemia to cladribine, the acute and chronic complications and the risk for second malignancies are summarized. The chapter concludes with a section on salvage therapy.


Explicit and Contextual Vocabulary Intervention: Effects on Word and Definition Learning.
Two single-case studies examined the effects of a vocabulary intervention on K-second grade Deaf or Hard-of-Hearing (DHH) children's vocabulary learning. The intervention consisted of (a) explicit instruction that included fast mapping, and drill and practice games and (b) in-context activities that included book reading, conceptual activities, and conversation. Study 1 compared the effectiveness of in-context alone and explicit+in-context instruction for four DHH children. This multiple baseline across content study showed that children learned more words rapidly in the explicit + in-context condition. Study 2 examined the effects of the explicit+in-context intervention on five DHH children's word and definition learning and use of new words in spontaneous communication. A multiple baseline study across participants showed that all children learned the targeted vocabulary, improved expression of definitions, and used target words in spontaneous language. We discuss the value of explicit and in-context instruction on breadth and depth of vocabulary learning.


Epidemiology and prevention of pancreatic cancer.
Pancreatic cancer is an uncommon tumor, but because the mortality rate approaches 100%, this form of cancer has now become a common cause of cancer mortality. In the United States it is the fourth most frequent cause of cancer mortality; in Japan it ranks as the fifth commonest cause of death from cancer. Smoking is the major known risk factor for pancreatic cancer, accounting for approximately 25-30% of all cases. Some of the time-dependent changes in the frequency of pancreatic cancer can be explained by smoking trends. Aggressive public health measures to control smoking would substantially reduce the burden of pancreatic cancer. Dietary factors are less important for pancreatic cancer than for other digestive tract tumors, but consumption of a diet with adequate quantities of fruits and vegetables, plus control of calories either by dietary measures or by exercise will help to prevent this lethal tumor. There are more than a dozen inherited germline mutations that increase the risk of pancreatic cancer. Of these, hereditary pancreatitis confers the greatest risk, while BRCA2 mutations are the commonest inherited disorder. In addition to germline defects, there are several common polymorphisms in genes that control detoxification of environmental carcinogens that may alter the risk of pancreatic cancer. More research will be needed in this area, to explain and to clarify the interaction between genes and environmental factors.


Evidence for Limited Early Spread of COVID-19 Within the United States, January-February 2020.
From January 21 through February 23, 2020, public health agencies detected 14 U.S. cases of coronavirus disease 2019 (COVID-19), all related to travel from China (1,2). The first nontravel-related U.S. case was confirmed on February 26 in a California resident who had become ill on February 13 (3). Two days later, on February 28, a second nontravel-related case was confirmed in the state of Washington (4,5). Examination of four lines of evidence provides insight into the timing of introduction and early transmission of SARS-CoV-2, the virus that causes COVID-19, into the United States before the detection of these two cases. First, syndromic surveillance based on emergency department records from counties affected early by the pandemic did not show an increase in visits for COVID-19-like illness before February 28. Second, retrospective SARS-CoV-2 testing of approximately 11,000 respiratory specimens from several U.S. locations beginning January 1 identified no positive results before February 20. Third, analysis of viral RNA sequences from early cases suggested that a single lineage of virus imported directly or indirectly from China began circulating in the United States between January 18 and February 9, followed by several SARS-CoV-2 importations from Europe. Finally, the occurrence of three cases, one in a California resident who died on February 6, a second in another resident of the same county who died February 17, and a third in an unidentified passenger or crew member aboard a Pacific cruise ship that left San Francisco on February 11, confirms cryptic circulation of the virus by early February. These data indicate that sustained, community transmission had begun before detection of the first two nontravel-related U.S. cases, likely resulting from the importation of a single lineage of virus from China in late January or early February, followed by several importations from Europe. The widespread emergence of COVID-19 throughout the United States after February highlights the importance of robust public health systems to respond rapidly to emerging infectious threats.


"Sacbe", a Comprehensive Intervention to Decrease Body Mass Index in Children with Adiposity: A Pilot Study.
Interventions in children with adiposity decrease less than 0.2 the body mass index (BMI) z-score less than 0.2 and only in 21⁻23% of cases. Experts recommend focusing on the habits of a healthy lifestyle (HLS) but considering the sociocultural context of children and their parents. Our objective was to achieve a higher percentage of success in lowering the BMI z-score in children with adiposity and their parents through a pilot program "Sacbe" based on HLS, sensitive to the sociocultural context previously explored and with the active participation of parents. This is a pilot study in children aged 8 to 18 years with adiposity according to the BMI z-score. The program consisted of two workshops on HLS and nutrition given by the pediatric endocrinologist in group sessions with 3⁻5 families and reinforcements in each visit by registered dietitians. We recorded lifestyle habits and anthropometric characteristics of children and their parents at the baseline visit and every month for 3⁻4 months. Forty-nine families, 55 children and 64 parents participated, 60% of the children were female, the average age was 13.95 ± 3.3 years, 72.7% and 86.7% lowered the z score of the BMI due to intention to treat and protocol analysis (p < 0.001), respectively; BMI z-score decreased by 0.22 ± 0.21, from 2.13 ± 0.57 to 1.91 ± 0.58 (p < 0.001). In total, 83% of the parents involved were mothers, the average age was 45.8 ± 9.4 years, 77% lost weight and body fat (p < 0.001), the frequency of unhealthy habits decreased. The results of "Sacbe" exceeded expectations by combining the active participation of parents, sessions in groups, and the education on various components of an HLS inside sociocultural context. The main challenge will be to standardize and reproduce this type of complex interventions, as well as to assure long-term success.


[CME/Answers: Rare Clinical Presentation of Bacterial Meningitis].
CME/Answers: Rare Clinical Presentation of Bacterial Meningitis Abstract. We report the case of a 59-year-old woman presenting with watery rhinorrhea and light cough since three days and new onset of headache. The evaluation proved a bacterial meningitis. We started an inpatient therapy according to the established guidelines. Due to recurrent vigilance reduction and increasing rhinorrhea we performed a liquid analysis with beta-trace testing, which proved a rhinoliquorrhea. Through an exploration of the skull base liquor leaks were detected and sufficiently closed.


Comparison of salivary IgA secretion rate collected by the aspiration method and swab method.
Salivary immunoglobulin A (IgA) is used as an immunity marker, as saliva can be easily collected, noninvasively with little stress. However, several saliva collection methods can be used. Our comparison between samples collected using different methods demonstrated that the salivary IgA secretion rate in samples collected using an aspiration method was significantly correlated with that in samples collected using a swab method. Moreover, the significant circadian variation in salivary IgA secretion rate in the aspirated saliva suggested that the aspiration method does not suppress salivary IgA secretion rate variability compared with the swab method. Therefore, the aspiration method should be considered as the preferable saliva collection method.


Stimulation of HCO3- transport in isolated proximal bullfrog duodenum by prostaglandins.
An in vitro preparation of proximal duodenum from the bullfrog transported alkali into the luminal solution (approximately 1 mueq x h-1 x cm-2) and generated a transepithelial electrical potential difference (5-10 mV, lumen negative). Transport was inhibited by 2,4-dinitrophenol (10(-5) M), CN- (5 X 10(-3) M), indomethacin (5 X 10(-5) M), and acetazolamide (5 X 10(-3) M) indicating that metabolism is required. Both alkali transport and the electrical potential difference showed a dose-dependent increase on administration of the prostaglandins E2, 16,16-dimethyl E2, and F2 alpha. The minimal concentration stimulating transport was lower with the E-type prostaglandins (10(-8) M than with F2 alpha (10(-6) M), and the former also produced greater maximal responses. In addition to metabolic-dependent transport of alkali, there was passive transmucosal migration of HCO3-, amounting to approximately 40% of basal (unstimulated) transport and sensitive to variation of the transmucosal hydrostatic pressure. Morphological examination showed that the preparation is devoid of Brunner glands. Stimulation of duodenal epithelial HCO3- transport by prostaglandins may contribute to their previously demonstrated ability to prevent duodenal ulceration.


Pre-clinical Safety and Efficacy of Lentiviral Vector-Mediated Ex Vivo Stem Cell Gene Therapy for the Treatment of Mucopolysaccharidosis IIIA.
Hematopoietic stem cell gene therapy is a promising therapeutic strategy for the treatment of neurological disorders, since transplanted gene-corrected cells can traffic to the brain, bypassing the blood-brain barrier, to deliver therapeutic protein to the CNS. We have developed this approach for the treatment of Mucopolysaccharidosis type IIIA (MPSIIIA), a devastating lysosomal storage disease that causes progressive cognitive decline, leading to death in early adulthood. In a previous pre-clinical proof-of-concept study, we demonstrated neurological correction of MPSIIIA utilizing hematopoietic stem cell gene therapy via a lentiviral vector encoding the SGSH gene. Prior to moving to clinical trial, we have undertaken further studies to evaluate the efficiency of gene transfer into human cells and also safety studies of biodistribution and genotoxicity. Here, we have optimized hCD34+ cell transduction with clinical grade SGSH vector to provide improved pharmacodynamics and cell viability and validated effective scale-up and cryopreservation to generate an investigational medicinal product. Utilizing a humanized NSG mouse model, we demonstrate effective engraftment and biodistribution, with no vector shedding or transmission to germline cells. SGSH vector genotoxicity assessment demonstrated low transformation potential, comparable to other lentiviral vectors in the clinic. This data establishes pre-clinical safety and efficacy of HSCGT for MPSIIIA.


Nanofiber Composite Microchannel-Containing Injectable Hydrogels for Cartilage Tissue Regeneration.
Articular cartilage tissue is incapable of self-repair and therapies for cartilage defects are still lacking. Injectable hydrogels have drawn much attention in the field of cartilage regeneration. Herein, the novel design of nanofiber composite microchannel-containing hydrogels inspired by the tunnel-piled structure of subway tunnels is proposed. Based on the aldehydized polyethylene glycol/carboxymethyl chitosan (APA/CMCS) hydrogels, thermosensitive gelatin microrods (GMs) are used as a pore-forming agent, and coaxial electrospinning polylactic acid/gelatin fibers (PGFs) loaded with kartogenin (KGN) are used as a reinforcing agent and a drug delivery system to construct the nanofiber composite microchannel-containing injectable hydrogels (APA/CMCS/KGN@PGF/GM hydrogels). The in situ formation, micromorphology and porosity, swelling and degradation, mechanical properties, self-healing behavior, as well as drug release of the nanofiber composite microchannel-containing hydrogels are investigated. The hydrogel exhibits good self-healing ability, and the introduction of PGF nanofibers can significantly improve the mechanical properties. The drug delivery system can realize sustained release of KGN to match the process of cartilage repair. The microchannel structure effectively promotes bone marrow mesenchymal stem cell (BMSC) proliferation and ingrowth within the hydrogels. In vitro and animal experiments indicate that the APA/CMCS/KGN@PGF/GM hydrogels can enhance the chondrogenesis of BMSCs and promote neocartilage formation in the rabbit cartilage defect model.


Factors affecting the consumption of iodized salt by pregnant women in Karachi.
Globally iodine deficiency disorder (IDD) is a major preventable cause of cognitive impairment in new born. In developing countries, every year 38 million newborn develop cognitive impairment as a result of iodine deficiency. Iodine consumption by pregnant women is affected by many factors. Hence, we conducted this study to identify factors associated with IDD. To know the effects of different factors on use of iodized salt by pregnant women visiting antenatal outpatient department (OPD) at a public sector tertiary care hospital of Karachi. Pregnant women (n=360) visiting antenatal OPD at public sector tertiary care hospital of Karachi were interviewed using a structured questionnaire. Systematic random sampling method was employed. Data was collected from March 2017 to January 2018. Chi-square test was applied to identify factors associated with IDD. Thirty one (31% ) of pregnant women were consuming iodized salt in their homes. The percentage of participants who heard about iodized salt for the first time was 24%. Twelve percent (12%) reported that price of iodized salt is more than that of normal salt. Ninety eight (98%) of pregnant women replied that they were not informed about the importance of iodine or iodine requirement during pregnancy by their doctor or health care provider. A statistically significant association was observed between educational status (p=0.001) and household income (p<0.001) with the use of iodized salt. Low education, low income of study participants are identified as factors related to limited consumption and incorrect practices related to the use of iodized salt. In order to address iodine deficiency, there is a need to not only sensitize the expectant mothers about the adverse outcome of maternal iodine deficiency for their unborn child but also to introduce an awareness program at the antenatal clinics by the Health Professional for the antenatal care seeking women. There is also an immense need of support from Government side as well to make strategies and policy changes at the national level to ensure the availability, accessibility and affordability of iodized salt.


Hymenasplenium volubile: documentation of its gametophytes and the first record of a hemiepiphyte in the Aspleniaceae.
Through careful field examination of the growth habit of the gametophytes and sporophytes of Hymenasplenium volubile across an ontogenetic series, we aim to understand better the evolution of epiphytism in this poorly understood group of ferns. We made field observations of H. volubile sporophytes and gametophytes, and brought specimens back to the lab for microscopic analysis. In the field, sporophytes at each ontogenetic stage were photographed to document the species' growth habit. We used an existing phylogeny to optimize growth form of New World Hymenasplenium. Young sporophytes were at first fully epiphytic and produced one or two long feeding roots that extend to the soil where they branch profusely. The feeding roots remain in contact with the soil throughout the life of the plant. Thus, H. volubile is a hemiepiphyte. While immature, gametophytes are appressed to the tree trunk, but, as their gametangia mature, their lower margin lifts upward, imparting a shelf-like appearance to the thallus. The thallus attaches to the substrate by branched rhizoids produced along the margin of the thallus in contact with the substrate. Hemiepiphytes are a key link in the evolution of epiphytic ferns and may act as a bridge between the forest floor and the canopy. Our finding is the first report of hemiepiphytism in Aspleniaceae, a large lineage with many epiphytic and terrestrial taxa. This work serves as an important model to understand the evolution of epiphytism in this group specifically and in ferns in general. The majority of our understanding of fern gametophyte biology is derived from laboratory studies. Our efforts represent a fundamental contribution to understanding fern gametophyte ecology in a field setting.


A framework for understanding "evidence" in prevention research and programs.
This report provides a multidimensional framework for understanding the meaning of evidence in prevention science. Six themes comprise the framework, each with impact on the meaning of evidence. (1) There are rigorous prevention scientific strategies now in use; each has shared but also unique requirements for the meaning of evidence. Some are directed at individuals, others at small social contexts, others at larger societal structures. (2) The phases of prevention research have shared but also unique requirements for evidence. These include efficacy, effectiveness, sustainability, going-to-scale, and sustaining programs systemwide. (3) Prevention programs address different segments of the population defined by levels of risk: the total population; a smaller subpopulation at increased risk; or a still smaller subpopulation at very high risk. The levels influence the meaning of evidence. (4) Economic analysis and economic evidence must become a central part of prevention research. These are needed for appropriate policy decision making and for assessing long-term benefits. (5) Collaboration is required for rigor in prevention research: including researchers, but also policy makers, program advocates and leaders, and community and institutional leaders. Broad ownership is critical for implementing rigorous research and for sustaining program fidelity. (6) Acceptance of a multidimensional framework for understanding "evidence" is essential across those agencies and institutions that carry out and/or use prevention science. The more widely the vision of the prevention field is shared, and the more the various qualities and rules of evidence are accepted and implemented, the better the quality will be of prevention research and programs.


Black Holes in compression therapy - A quest for data.
Although compression therapy is considered a crucial conservative treatment in chronic venous disease, strong evidence is missing for many clinical indications. This literature review aims to point out what strong evidence we have for compression therapy and all the clinical scenarios where strong evidence still needs to be included. The research was conducted on MEDLINE with PubMed, Scopus and Web of Science. The time range was set between Jan 1980 and Oct 2022. Only articles in the English language were included. The main problem with compression therapy is the low scientific quality of many studies on compression. Consequently, we have robust data on the effectiveness of compression therapy only for advanced venous insufficiency (C3-C6), deep vein thrombosis and lymphedema. We have data on the efficacy of compression for venous symptoms control and in sports recovery, but the low quality of studies cannot result in a strong recommendation. For compression in post-venous procedures, superficial venous thrombosis, thromboprophylaxis, post-thrombotic syndrome prevention and treatment, and sports performance, we have either no data or very debated data not allowing any recommendation. We need high-level scientific studies to assess if compression therapy can be effective or definitely ineffective in the clinical indications where we still have paucity or contrasting data.


Sequential Thiol-Ene and Tetrazine Click Reactions for the Polymerization and Functionalization of Hydrogel Microparticles.
Click chemistry is a versatile tool for the synthesis and functionalization of polymeric biomaterials. Here, we describe a versatile new strategy for producing bioactive, protein-functionalized poly(ethylene glycol) (PEG) hydrogel microparticles that is based on sequential thiol-ene and tetrazine click reactions. Briefly, tetra-functional PEG-norbornene macromer and dithiothreitol (SH) cross-linker were combined at a 0.75:1 [SH]:[norbornene] ratio, emulsified in a continuous Dextran phase, and then photopolymerized to form PEG hydrogel microparticles that varied from 8 to 30 μm in diameter, depending on the PEG concentration used. Subsequently, tetrazine-functionalized protein was conjugated to unreacted norbornene groups in the PEG microparticles. Tetrazine-mediated protein tethering to the microparticles was first demonstrated using fluorescein-labeled ovalbumin as a model protein. Subsequently, bioactive protein tethering was demonstrated using alkaline phosphatase (ALP) and glucose oxidase (GOx). Enzyme activity assays demonstrated that both ALP and GOx maintained their bioactivity and imparted tunable bioactivity to the microparticles that depended on the amount of enzyme added. ALP-functionalized microparticles were also observed to initiate calcium phosphate mineralization in vitro when incubated with calcium glycerophosphate. Collectively, these results show that protein-functionalized hydrogel microparticles with tunable bioactive properties can be easily synthesized using sequential click chemistry reactions. This approach has potential for future applications in tissue engineering, drug delivery, and biosensing.


[Cost analysis of rapid methods for diagnosis of multidrug resistant tuberculosis in different epidemiologic groups in Perú].
To evaluate the costs of three methods for the diagnosis of drug susceptibility in tuberculosis, and to compare the cost per case of Multidrug-resistant tuberculosis (MDR TB) diagnosed with these (MODS, GRIESS and Genotype MTBDR plus®) in 4 epidemiologic groups in Peru. In the basis of programmatic figures, we divided the population in 4 groups: new cases from Lima/Callao, new cases from other provinces, previously treated patients from Lima/Callao and previously treated from other provinces. We calculated the costs of each test with the standard methodology of the Ministry of Health, from the perspective of the health system. Finally, we calculated the cost per patient diagnosed with MDR TB for each epidemiologic group. The estimated costs per test for MODS, GRIESS, and Genotype MTBDR plus® were 14.83. 15.51 and 176.41 nuevos soles respectively (the local currency, 1 nuevos sol=0.36 US dollars for August, 2011). The cost per patient diagnosed with GRIESS and MODS was lower than 200 nuevos soles in 3 out of the 4 groups. The costs per diagnosed MDR TB were higher than 2,000 nuevos soles with Genotype MTBDR plus® in the two groups of new patients, and lower than 1,000 nuevos soles in the group of previously treated patients. In high-prevalence groups, like the previously treated patients, the costs per diagnosis of MDR TB with the 3 evaluated tests were low, nevertheless, the costs with the molecular test in the low- prevalence groups were high. The use of the molecular tests must be optimized in high prevalence areas.


Diagnosing pulmonary embolism: a comparison of clinical probability scores.
Pulmonary embolism (PE) is a major cause of community and in-hospital mortality. This study aimed to compare the performance of the British Thoracic Society (BTS) score to the Wells' score in diagnosing PE. Data from two separate prospective diagnostic PE studies were analysed. All patients underwent gold standard investigation to determine the presence or absence of PE, together with a 3-month follow-up. The posttest prevalence of PE was compared using both scores and the receiver operating characteristic (ROC) curves. Seven hundred and seventy-nine patients were consented and investigated for PE. In patients with pleuritic chest pain, respiratory rate <20 breaths/min and absence of dyspnoea, 4·0% [95% confidence interval (CI) 1·9-7·9%] had PE. The BTS score allocated 463/779 patients as low probability, compared to 565/779 according to the Wells' score. Both scores identified a low risk group in the Manchester Investigation of Pulmonary Embolism Diagnosis cohort, however the BTS low probability group in the Thromboembolism Assessment and Diagnosis study had a prevalence of 9·7% (95% CI 5·8-15·9%). For the BTS score, the areas under the ROC curves were 0·67 (95% CI 0·61-0·72) and 0·71 (95% CI 0·61-0·75). For the Wells' score these were 0·76 (95%CI 0·71-0·81) and 0·68 (95%CI 0·64-0·73). Given the lack of BTS validation studies to date, the Wells' score appears to be the safer assessment option.


Th1 and Th2 clones differ in their response to a tolerogenic signal.
Th1 and Th2 clones specific for human gamma globulin (HGG) were compared and shown to differ in terms of the effects of tolerance induction on Ag-induced proliferation and helper activity. In developing a method to induce tolerance, splenic APC that had been pulsed with HGG and then fixed with 0.15% paraformaldehyde (HGG-FAPC) were used as a means to present Ag to the Th clones in the absence of costimulatory signals. Both Th1 and Th2 clones recognized HGG-FAPC as evidenced by their ability to proliferate to HGG-FAPC. Unlike Th2, Th1 proliferated to HGG-FAPC only in the presence of T cell-depleted allogeneic spleen cells as a source of accessory cell signals. The inability of Th1 cells to proliferate in the absence of costimulatory signals was due to Ag-specific inactivation: Th1 clones preincubated with HGG-FAPC were unable to proliferate when recultured with HGG and irradiated APC. In contrast to Th1 clones, Th2 clones showed no decrease in their Ag-induced proliferative capacity after exposure to any concentration of HGG-FAPC. However, when examined by using a second assay system, that of providing help for anti-HGG antibody production by primed B cells, Th2 preincubated with HGG-FAPC were markedly inhibited (up to 90%) in their ability to provide help. Preincubation with HGG-FAPC also inhibited the helper activity of the one Th1 clone that was found to induce a significant secondary antibody response. Taken together, the results suggest that exposure of Th1 to tolerogen in the form of HGG-pulsed fixed APC inactivates Th1 proliferative capacity, and possibly Th1 helper activity as well. Exposure of Th2 cells to a tolerogen suppresses the mechanism by which the Th2 cells provide Ag-induced B cell help, but does not inhibit the mechanism by which they proliferate to HGG. Furthermore, the results define a model that incorporates Ag processing as well as Ag presentation in the induction of tolerance in vitro.


Hepatocellular carcinoma development in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Is it going to be the "Plague" of the 21st century? A literature review focusing on pathogenesis, prevention and treatment.
Liver carcinogenesis in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is a subject of intense research nowadays, since NAFLD is the most common chronic liver disease, affecting a great percentage of the population worldwide, while hepatocellular carcinoma (HCC), which represents the most common primary liver malignancy, is the third leading cause of cancer-related mortality. The underlying pathogenic pathways of both NAFLD and HCC are not completely understood, but there is growing evidence that they share many common pathophysiologic mechanisms and risk factors. Due to lack of solid evidence, though, the ultimate goal of designing effective diagnostic tools, treatment options and screening policies remain unmet for the time being. This review article aims to present recent data available regarding pathogenesis, diagnosis and management of HCC and NAFLD, as well as to highlight the importance of the development of HCC in the setting of NAFLD and NASH.


Antibiotic Irrigation of Pocket for Implant-Based Breast Augmentation to Prevent Capsular Contracture: A Systematic Review.
In vitro and in vivo studies have described a number of different antibiotic solutions for irrigation of the pocket in implant-based breast augmentation in an attempt to prevent the formation of capsular contracture (CC). Our objective was to evaluate the evidence that antibiotic irrigation reduced the rate of CC. A systematic search of MEDLINE, EMBASE, and CENTRAL was conducted from inception to January 2016. We included studies which examined the use of intraoperative antibiotic irrigation in women undergoing primary breast augmentation. Our primary outcome was the rate of CC. Included studies were assessed for methodological quality using validated tools. Seven studies were included in the final analysis: 1 randomized controlled trial (RCT) and 6 non-randomized studies. The mean follow-up ranged from 14 to 72 months. The rate of CC was less than 2% in 8 studies, between 3% and 6% in 4 studies, and 13.9% in 1 study. Included studies demonstrated significant clinical and methodological heterogeneity. The solitary low-quality RCT concluded that antibiotic irrigation was superior to saline irrigation. Three non-randomized studies demonstrated no significant difference in the rate of CC with the use of antibiotics. One non-randomized controlled study showed that the use of mixture of antibiotic and povidone-iodine significantly lowered the rate of CC. The available evidence on the use of antibiotic irrigation to prevent CC is weak and it is based on studies with high risk of bias. Methodologically robust studies are necessary to answer the question whether antibiotic breast pocket irrigation prevents CC.


Low-temperature vibronic spectroscopy of condensed chromophore exhibiting inhomogeneous distribution of vibrational frequencies in a mixed quantum-classical environment.
This work has been motivated by the recent paper by the author [M. Toutounji, Phys. Chem. Chem. Phys., 2021, 23, 21981] whereby a mixed quantum-classical Liouville equation was used to probe the spectroscopy and dynamics of a spin-boson system. A mixed quantum-classical Liouville equation treats the system of interest quantum mechanically, the bath classically, and the coupling term mixed quantum-classical mechanically. This paper offers a two-fold advantage: correcting the treatment of the electronic transition decay (width in frequency domain) and assessing the local heterogeneous vibrational structure. The homogeneous linear absorption spectrum of a chromophore embedded in a mixed quantum-classical environment at low temperature is composed of a sharp peak called a zero-phonon line (ZPL) and a broad phonon sideband (PSB), whereby the ZPL and the PSB are assimilated by a Lorentzian function and Voigt profiles, respectively. The PSB, in this case, is characterized by a local heterogeneous structure due to a dispersive medium of vibrations, modeled by vibrational Gaussian distributions to represent the arising inhomogeneous broadening and Lorentzians to model the homogeneous vibrations. This description seems to model proteins and amorphous solids exhibiting a local heterogeneous structure as both electronic and vibrational inhomogeneous broadening seems to be large in these media. This work provides a derivation of linear absorption lineshape and vibronic transition dipole moment time correlation functions, both of which account for pure electronic dephasing (ZPL width) the Voigt profile description of the phonon profiles (PSB) in dispersive media.


Decreased sleep quality in high myopia children.
The aim of the present study was to evaluate sleep quality in myopic children and adults. This cross sectional study surveyed 486 participants aged from 10 to 59 years with refractive errors using a questionnaire containing the Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS). Children (< 20 years) in the high myopia group exhibited the poorest PSQI scores (P < 0.01), while the adults showed no such correlations. Subscales of PSQI and HADS in children disclosed that the high myopia groups had the shortest sleep duration (P < 0.01), worst subjective sleep scores (P < 0.001), and latest bedtime (P < 0.05). Regression analyses in children significantly correlated myopic errors with PSQI (P < 0.05), sleep duration (P < 0.01), and bedtime (P < 0.01). Sleep efficacy (P < 0.05) and daytime dysfunction (P < 0.05) were significantly better in contact-lens users compared to the respective non-user groups across all participants. In conclusion, sleep quality in children was significantly correlated with myopic error, with the high myopia group worst affected.


Five Factors of Impulsivity: Unique Pathways to Borderline and Antisocial Personality Features and Subsequent Alcohol Problems.
Impulsivity, a multidimensional behavioral mechanism, commonly preceding externalizing maladaptive behavior and psychopathology, is a diagnostic criterion central to both antisocial and borderline personality disorders (American Psychiatric Association; APA, 2013). This study tested a path model of associations between five facets of impulsivity (negative urgency, positive urgency, lack of premeditation, lack of perseverance, and sensation seeking), borderline personality features, antisocial personality features, and two alcohol outcomes (consumption and alcohol-related problems) in a sample of college students (N = 624; 69% female, 31% male) between the ages of 18-25 (M = 19.77, SD = 1.55). The model demonstrated good fit with X 2 (14, N = 624) = 17.48, p = .231; RMSEA = .020 [90% CI: .000 - .046]; CFI = .998; SRMR = .019. Negative urgency and (lack of) perseverance predicted borderline personality features. Positive urgency, sensation seeking, (lack of) premeditation, and negative urgency predicted antisocial personality features. Antisocial, but not borderline personality features, were significantly associated with alcohol consumption. However, both antisocial and borderline personality features significantly predicted alcohol problems. Overall, the results demonstrate that impulsivity facets can differentially predict personality psychopathology and illustrate distinct paths to alcohol consumption and problems.


Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease.
The relationship between Alzheimer disease (AD) and aging is not currently known. In this study, postmortem frontal- and occipital-pole brain samples were obtained from 16 subjects with AD, 8 age-matched controls, and 5 young controls. These samples were analyzed both for protein oxidation products (carbonyl) and the activities of two enzymes vulnerable to mixed-function oxidation, glutamine synthetase and creatine kinase. Glutamine synthetase is more sensitive to mixed-function oxidation than creatine kinase. Carbonyl content rises exponentially with age, at double the rate in the frontal pole compared with the occipital pole. Compared with young controls, both aged groups (AD and age-matched controls) have increased carbonyl content and decreased glutamine synthetase and creatine kinase activities, which are more marked in the frontal than occipital pole in all instances. We conclude that protein oxidation products accumulate in the brain and that oxidation-vulnerable enzyme activities decrease with aging in the same regional pattern (frontal more affected than occipital). However, only glutamine synthetase activity distinguishes AD from age-matched controls: Because glutamine synthetase activity is differentially reduced in the frontal pole in AD, we suggest that AD may represent a specific brain vulnerability to age-related oxidation.


Twenty-four hour fasting increases endotoxin lethality in the rat.
The effect of 24 h food deprivation on endotoxin (ET) lethality in SpD rats was studied. Fed and fasted animals received either 6 h i.v. infusions or i.p. boluses of ET at low, intermediate and high doses, and survival for seven days observed. Fasting was associated with 208-240% greater mortality when ET was infused i.v., and 87-200% when given i.p. ET doses LD10-LD80 gave a linear relationship with mortality. In non-fasted control rats liver glycogen content reduced by 1.28 mumols/min/g dry liver wt over the first post-prandial six hours, and increased by 65-99% in a dose dependent manner after ET (p less than 0.01). Evidence was also obtained relating both liver damage (assessed blind by histopathological scoring) and leucopenia with endotoxin dose, results which were modified by nutritional status. The evidence supports the role of liver glycogen as a protective substrate resource in endotoxic shock.


Mechanistic insight on the combined effect of albumin and hydrogen peroxide on surface oxide composition and extent of metal release from Ti6Al4V.
The titanium-aluminium (6 wt%)-vanadium (4 wt%) (Ti6Al4V) alloy is widely used as an orthopedic and dental implant material due to its high corrosion resistance in such environments. The corrosion resistance is usually determined by means of electrochemical methods, which may not be able to detect other chemical surface reactions. Literature findings report a synergistic effect of the combination of the abundant protein albumin and hydrogen peroxide (H2 O2 ) on the extent of metal release and corrosion of Ti6Al4V. The objectives of this study were to gain further mechanistic insight on the interplay of H2 O2 and albumin on the metal release process of Ti6Al4V with special focus on (1) kinetics and (2) H2 O2 and albumin concentrations. This was accomplished mainly by metal release and surface oxide composition investigations, which confirmed the combined effect of H2 O2 and albumin on the metal release process, although not detectable by electrochemical open circuit potential measurements. A concentration of 30 mM H2 O2 induced substantial changes in the surface oxide characteristics, an oxide which became thicker and enriched in aluminum. Bovine serum albumin (BSA) seemed to be able to deplete this aluminum content from the outermost surface or at least to delay its surface enrichment. This effect increased with increased BSA concentration, and for time periods longer than 24 h. This study hence suggests that short-term (accelerated) corrosion resistance measurements are not sufficient to predict potential health effects of Ti6Al4V alloys since also chemical dissolution mechanisms play a large role for metal release, possibly in a synergistic way. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 855-867, 2019.


Association of objectively measured sleep with frailty and 5-year mortality in community-dwelling older adults.
To determine whether actigraphy-measured sleep was independently associated with risk of frailty and mortality over a 5-year period among older adults. We used data from Waves 2 (W2) and 3 (W3) (2010-2015) of the National Social Life, Health and Aging Project, a prospective cohort of community-dwelling older adults born between 1920 and 1947. One-third of W2 respondents were randomly selected to participate in a sleep study, of whom N = 727 consented and N = 615 were included in the analytic sample. Participants were instructed to wear a wrist actigraph for 72 h (2.93 ± 0.01 nights). Actigraphic sleep parameters were averaged across nights and included total sleep time, percent sleep, sleep fragmentation index, and wake after sleep onset. Subjective sleep was collected via questionnaire. Frailty was assessed using modified Fried Frailty Index. Vital status was ascertained at the time of the W3 interview. W3 frailty/mortality status was analyzed jointly with a four-level variable: robust, pre-frail, frail, and deceased. Associations were modeled per 10-unit increase. After controlling for baseline frailty (robust and pre-frail categories), age, sex, education, body mass index, and sleep time preference, a higher sleep fragmentation index was associated with frailty (OR = 1.70, 95% CI: 1.02-2.84) and mortality (OR = 2.12, 95% CI: 1.09-4.09). Greater wake after sleep onset (OR = 1.24, 95% CI: 1.02-1.50) and lower percent sleep (OR = 0.41, 95% CI: 0.17-0.97) were associated with mortality. Among community-dwelling older adults, actigraphic sleep is associated with frailty and all-cause mortality over a 5-year period. Further investigation is warranted to elucidate the physiological mechanisms underlying these associations.


On the clinical value of calibrated displacement apexcardiography.
A new type of displacement transducer for recording the calibrated left apexcardiogram (QLAC) has been evaluated in 69 normal subjects and 99 cardiac patients. Total displacement of QLAC (TD), its peak first derviative (peak dD/dt (t-peak dD/dt). A strong corretation exists between peak dD/dt and TD in normal subjects (r=0.95) and the deviation from the normal relationship allows a separation between normal and abnormal ventricular function. In normal subjects (dD/dt/Dt) max averaged 34.2 plus or minus 5.7 sec-1; it was signigicantly lower in patients with congestive cardiomyopathy (26.5 plus or minus 6.3 sec-1 p greater than 0.005). This index correlates with left ventricular end-diastolic pressure (LVEDP) (R = - 0.69) and with ejection fraction (R - 0.66) and behaves as expected during positive and NEGATIVE INOTROPIC interventions. The index (dD/dt/Dt) max is superior to TD and peak dD/dt, being less variable independent of thorax circumference and better correlated with hemodynamic parameters. The index t-peak dD/dt was 53.9 plus or minus 9.5 msec in normal subjects and 81.6 plus or minus 18.9 msec in patients with congestive cardiomyopathy (p greater than 0.001). This time-interval correlates weakly with LVEDP (R = 0.04) and with ejection fraction (R = - 0.66). It is concluded that the normalized first derivative of QLAC provides useful information on left ventricular function.