The role of antifungals in the management of patients with severe asthma.
In patients with asthma, the inhalation of elevated amounts of fungal spores and hyphae may precipitate the onset of asthma or worsen control to the extent of being life-threatening. Sensitisation to fungi, especially Aspergillus fumigatus, is found in 15% to 48% of asthmatics in secondary care and is linked to worse asthma control, hospitalisation, bronchiectasis and fixed airflow obstruction, irrespective of whether allergic bronchopulmonary aspergillosis (ABPA) is diagnosed. ABPA represents a florid response to the presence of Aspergillus spp. but up to 70% of patients with severe asthma exhibit sensitisation to different fungi without meeting the diagnostic criteria for ABPA. The presence of persistent endobronchial colonisation with fungi, especially A. fumigatus, is linked to significantly higher rates of radiological abnormalities, lower post-bronchodilator FEV1 and significantly less reversibility to short acting bronchodilators. The therapeutic benefit for antifungal intervention in severe asthma is based on the assumption that reductions in airway fungal burden may result in improvements in asthma control, lung function and symptoms (especially cough). This contention is supported by several prospective studies which demonstrate the effectiveness of antifungals for the treatment of ABPA. Significantly, these studies confirm lower toxicity of treatment with azoles versus high dose oral corticosteroid dosing regimens for ABPA. Here we review recent evidence for the role of fungi in the progression of severe asthma and provide recommendations for the use of antifungal agents in patients with severe asthma, airways fungal infection (mycosis) and fungal colonisation. Documenting fungal airways colonisation and sensitisation in those with severe asthma opens up alternative therapy options of antifungal therapy, which may be particularly valuable in low resource settings.


Amino acid substitution in the lactose carrier protein with the use of amber suppressors.
Five lacY mutants with amber stop codons at known positions were each placed into 12 different suppressor strains. The 60 amino acid substitutions obtained in this manner were tested for growth on lactose-minimal medium plates and for transport of lactose, melibiose, and thiomethylgalactoside. Most of the amino acid substitutions in the regions of the putative loops (between transmembrane alpha helices) resulted in a reasonable growth rate on lactose with moderate-to-good transport activity. In one strain (glycine substituted for Trp-10), abnormal sugar recognition was found. The substitution of proline for Trp-33 (in the region of the first alpha helix) showed no activity, while four additional substitutions (lysine, leucine, cysteine, and glutamic acid) showed low activity. Altered sugar specificity was observed when Trp-33 was replaced by serine, glutamine, tyrosine, alanine, histidine, or phenylalanine. It is concluded that Trp-33 may be involved directly or indirectly in sugar recognition.


Identification of the type II cytochrome c maturation pathway in anammox bacteria by comparative genomics.
Anaerobic ammonium oxidizing (anammox) bacteria may contribute up to 50% to the global nitrogen production, and are, thus, key players of the global nitrogen cycle. The molecular mechanism of anammox was recently elucidated and is suggested to proceed through a branched respiratory chain. This chain involves an exceptionally high number of c-type cytochrome proteins which are localized within the anammoxosome, a unique subcellular organelle. During transport into the organelle the c-type cytochrome apoproteins need to be post-translationally processed so that heme groups become covalently attached to them, resulting in mature c-type cytochrome proteins. In this study, a comparative genome analysis was performed to identify the cytochrome c maturation system employed by anammox bacteria. Our results show that all available anammox genome assemblies contain a complete type II cytochrome c maturation system. Our working model suggests that this machinery is localized at the anammoxosome membrane which is assumed to be the locus of anammox catabolism. These findings will stimulate further studies in dissecting the molecular and cellular basis of cytochrome c biogenesis in anammox bacteria.


Cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and norepinephrine levels in alcohol withdrawal. Correlations with clinical signs.
Cerebrospinal fluid (CSF) and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were significantly elevated in patients during the alcohol withdrawal syndrome. When CSF MHPG was corrected using a formula proposed to determine CSF MHPG levels of central origin, these values were still significantly elevated when compared with control values. The MHPG concentrations in CSF also showed significant positive correlations with heart rate, systolic and diastolic blood pressures, tremor, anorexia, and sweating. The results of this study indicate increased presynaptic release of norepinephrine during alcohol withdrawal.


Intravenous transplantation of bone marrow-derived mesenchymal stem cells improved behavioral deficits and altered fecal microbiota composition of BTBR mice.
It is recognized that autism spectrum disorder (ASD) is a highly complex neurodevelopmental disorder with communication deficits as well as multiple social barriers. The core symptoms of ASD are not treatable with current therapeutics. Therefore, finding new treatment strategies for ASD is urgently needed. Mesenchymal stem cells (MSC) have been shown to be a promising therapeutic approach in previous studies. However, the underlying mechanisms of MSC treatment for ASD through gut microbiota remain unclear and require further investigation. BTBR mice were used as ASD model and then randomly assigned to the human bone marrow-derived mesenchymal stem cell (hBMMSC) intravenous treatment group or vehicle treatment group. C57BL/6J (C57) mice served as control. Multiple social behavioral tests were performed during the 6-week period and fecal samples were collected at different time points for 16 s rRNA sequencing analysis. The administration of hBMMSC improved social deficits of BTBR mice in the open field test (OFT), light-dark box test (LBT), novel object recognition (NOR), and free social test (FST), while also significantly reducing stereotypic behaviors. Additionally, hBMMSC administration notably reversed the alterations of microbiota abundance in BTBR mice, particularly the Firmicutes/Bacteroidetes ratio. Several specific differential taxa were further selected and showed a correlation with the prognosis and behavioral scores of ASD. Overall, intravenous treatment with hBMMSC had a beneficial impact on ASD by ameliorating social deficits and modifying microbiota compositions. This outcome indicates that hBMMSC intravenous transplantation could be a promising therapeutic strategy for enhancing ASD symptoms improvements.


Pediatric emergency care capabilities of Indian Health Service emergency medical service agencies serving American Indians/Alaska Natives in rural and frontier areas.
In the USA, the emergency medical services (EMS) system is vital for American Indians and Alaska Natives, who are disproportionately burdened by injuries and diseases and often live in rural areas geographically far from hospitals. In rural areas, where significant health disparities exist, EMS is often a primary source of healthcare providing a safety net for uninsured individuals or families who otherwise lack access to health-related services. EMS is frequently the first entry point for children and their families into the healthcare system. The Indian Health Service (IHS) supports the federally funded, tribally operated EMS agencies to help meet the affiliated American Indian and Alaska Natives' pre-hospital needs. While periodic assessments of state EMS agencies capabilities to care for children occur, it appears a systematic assessment of IHS EMS agencies in regards to children had not been previously conducted. A consensus process, involving stakeholders, was used to identify topic areas for a survey for assessing the pediatric capabilities of IHS EMS. The survey was sent to 75 of 88 IHS EMS agency contacts. Sixty-one agencies (81%) responded. Nine agencies (15%) did not have a medical director. Agencies without a medical director were less likely to report the availability of online (p=0.1) or offline (p<0.01) pediatric medical direction. Half (51%) of the agencies had a mass casualties plan; however, 29% reported responding to a mass casualty incident, involving a large number of pediatric patients, that overwhelmed their service. Most agencies were well integrated with their state EMS system with almost all (95%) collecting EMS patient care data and 47% using national standard data elements. In some areas, IHS EMS agencies did not have the infrastructure to treat pediatric patients during day-to-day operations as well as disasters. Similar to operational challenges faced by rural EMS agencies, the IHS agencies lacked a medical director, were unable to provide pediatric continuing education, and were overwhelmed during mass casualty incidents. Moreover, the overall ratio of IHS EMS to service population is almost double that for other EMS agencies. In other areas, agencies were well integrated with their state EMS system. One possible solution to increase capabilities to care for pediatric patients is combining and sharing of common resources including medical directors with their state EMS systems and authorities.


[Correlation between amniotic fluid glucose concentration and amniotic fluid volume and neonatal birth weight in pregnancy complicated by gestational diabetes mellitus].
To investigate the relationship between amniotic fluid glucose concentration, amniotic fluid volume and neonatal birth weight in gestational diabetes mellitus (GDM). Two hundred and fifty-five singleton, normal term pregnant women were divided into three groups: GDM, gestational impaired glucose tolerance (GIGT) and normal pregnancy according to the results of a 50 g, 1 hour glucose challenge test (GCT) or of a 75 g oral glucose tolerance test (OGTT). There were 85 study subjects in each group. All women had GCT at 24 - 28 gestational weeks. When they had a positive GCT, in which glucose level was > or = 7.8 mmol/L, and < 10.6 mmol/L at 1 hour after oral 50 g glucose, they were required to have a 75 g OGTT. Amniotic fluid glucose concentration (AFG), amniotic fluid index (AFI), neonatal birth weight (NBW), maternal fasting glucose level (MFG) and umbilical venous glucose level (UvG) were compared in three groups. Statistical analysis of linear regression was done on these indices. (1) The mean AFG in group GDM was (1.30 +/- 0.71) mmol/L, which was significantly greater than that in group GIGT, (1.02 +/- 0.57) mmol/L and that in normal group, (0.90 +/- 0.58) mmol/L. There were significant differences among three groups (P < 0.01). (2) In group GDM, the mean AFI was (16.1 +/- 4.6) cm, which was slightly greater than that in group GIGT, (14.8 +/- 4.3) cm (P > 0.05), but was significantly higher than that in normal group, (12.7 +/- 3.2) cm (P < 0.01). (3) The NBW of group GDM was (3612 +/- 510) g, which was lower than that of group GIGT, (3694 +/- 490) g, and higher than that of normal group, (3487 +/- 458) g, but there were no significant differences among three groups (P > 0.05). (4) Among women with GDM, AFG was significantly correlated with AFI (r = 0.330, P = 0.002), NBW (r = 0.347, P = 0.001), MFG (r = 0.589, P < 0.01), and with UvG (r = 0.218, P = 0.045). But in group GIGT and normal group, AFG was only correlated with AFI. (5) In GDM group, the AFG, (1.02 +/- 0.50) mmol/L; AFI, (13.9 +/- 4.2) cm; and NBW, (3497 +/- 475) g in women who had ideal blood glucose level were significantly lower than that in women whose blood glucose levels were not well-controlled [AFG, (1.92 +/- 0.76) mmol/L, AFI, (16.4 +/- 4.4) cm, NBW, (3869 +/- 481) g (P < 0.01, P < 0.05, P < 0.01)], and the mean values of these three indices were close to those of the control group. In the cohort with GDM, there were correlations between AFG, AFI, and NBW. The results show that an active management could significantly improve the prognoses of the diabetes mothers and their fetuses.


Natural history of patients with venous thromboembolism and hereditary hemorrhagic telangiectasia. Findings from the RIETE registry.
Limited data exist about the clinical presentation, ideal therapy and outcomes of patients with hereditary hemorrhagic telangiectasia (HHT) who develop venous thromboembolism (VTE). We used the data in the RIETE Registry to assess the clinical characteristics, therapeutic approaches and clinical outcomes during the course of anticoagulant therapy in patients with HHT according to initial presentation as pulmonary embolism (PE) or deep venous thrombosis (DVT). Of 51,375 patients with acute VTE enrolled in RIETE from February 2009 to January 2019, 23 (0.04%) had HHT: 14 (61%) initially presented with PE and 9 (39%) with DVT alone. Almost half (47.8%) of the patients with VTE had a risk factor for VTE. Most PE and DVT patients received low-molecular-weight heparin for initial (71 and 100%, respectively) and long-term therapy (54 and 67%, respectively). During anticoagulation for VTE, the rate of bleeding events (major 2, non-major 6) far outweighed the rate of VTE recurrences (recurrent DVT 1): 50.1 bleeds per 100 patient-years (95%CI: 21.6-98.7) vs. 6.26 recurrences (95%CI: 0.31-30.9; p = 0.020). One major and three non-major bleeding were epistaxis. No patient died of bleeding. One patient died shortly after being diagnosed with acute PE. During anticoagulation for VTE in HHT patients, there were more bleeding events than VTE recurrences. Most bleeding episodes were non-major epistaxis.


The search for better prognostic models in myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are a group of heterogeneous bone marrow disorders characterized by a failure of hematopoiesis and an increased propensity for transformation to acute myeloid leukemia. Determining the prognosis of patients with MDS is essential for discerning the best therapy, which can vary from supportive care to allogeneic stem cell transplantation. The most widely used prognostic model in MDS is the International Prognostic Scoring System (IPSS), which estimates survival and risk of transformation to acute myeloid leukemia based on the percentage of blasts, karyotype, and number of cytopenias, but the IPSS has several limitations that preclude more widespread application. Over the past decade, several studies have reported on new prognostic factors for MDS, including transfusion dependency and DNA methylation abnormalities. More recently, two prognostic models for MDS that aim to overcome the limitations of the IPSS have been published. This review focuses on the most recent advances in this field, detailing current prognostic models and the more important risk factors in MDS.


Responding to COVID-19: The UW Medicine Information Technology Services Experience.
UW Medicine was one of the first health systems to encounter and treat COVID-19 patients in the United States, starting in late February 2020. Here we describe the rapid rollout of capabilities by UW Medicine Information Technology Services (ITS) to support our clinical response to the COVID-19 pandemic and provide recommendations for health systems to urgently consider, as they plan their own response to this and potentially other future pandemics. Our recommendations include establishing a hospital incident command structure that includes tight integration with IT, creating automated dashboards for incident command, optimizing emergency communication to staff and patients, and preparing human resources, security, other policies, and equipment to support the transition of all nonessential staff to telework.We describe how UW Medicine quickly expanded telemedicine capabilities to include most primary care providers and increasing numbers of specialty providers. We look at how we managed expedited change control processes to quickly update electronic health records (EHR) with new COVID-19 laboratory and clinical workflows. We also examine the integration of new technology such as tele-intensive care (ICU) equipment and improved integration with teleconferencing software into our EHR. To support the rapid preparation for COVID-19 at other health systems, we include samples of the UW Medicine's COVID-19 order set, COVID-19 documentation template, dashboard metric categories, and a list of the top 10 things your health care IT organization can do now to prepare. The COVID-19 response requires new and expedited ways of approaching ITS support to clinical needs. UW Medicine ITS leadership hope that by quickly sharing our nimble response to clinical and operational requests, we can help other systems prepare to respond to this public health emergency.


Is Carbon Dioxide Insufflation During Endoscopy in Children as Safe and as Effective as We Think?
Distension of the gastrointestinal lumen is crucial for visualization and advancement during endoscopic procedures. An increasing number of pediatric centers now use carbon dioxide (CO2) preferentially over air as many adult studies and a few pediatric studies have concluded that CO2 is better tolerated than air, especially for colonoscopy. The aim of the study was to determine if CO2 is as safe and as effective as air and if it reduces abdominal discomfort and distension in children undergoing upper endoscopy and colonoscopy. Double blinded, prospective, randomized clinical study. Patient- and nursing-reported outcomes of pain and distension were recorded. End tidal CO2 (EtCO2) was monitored continuously with a CO2-sampling nasal cannula for patients undergoing procedural sedation and via the endotracheal tube for those who were intubated. One hundred seventy-eight patients with 180 procedures were enrolled, 91 procedures were randomized to receive CO2, and 89 to air. Groups did not differ significantly with respect to nursing-assessed abdominal discomfort, change in girth from baseline, or endoscopist-perceived ease of inflation. Use of CO2 was associated with transient spikes in the EtCO2 (≥60 mmHg) in a significant number of patients during sedated upper endoscopy without endotracheal intubation. There was a reduction of bloating and flatulence for all procedures in the CO2 group. The benefits of using CO2 for insufflation were minimal in our patients. The observed transient elevations of EtCO2 during sedated upper endoscopy raise concerns of possible systemic hypercarbia. The wisdom of its routine use for all pediatric endoscopic procedures is questioned.


The High Rate CIS Auditory Brainstem Implant for Restoration of Hearing in NF-2 Patients.
Hearing preservation is one of the major goals of acoustic neuroma surgery. In NF-2 patients, bilateral hearing loss is frequently caused by the disease or results from its treatment. Several implant devices for electrical stimulation of the cochlear nucleus have been developed to restore serviceable hearing in these patients. We report our experience and results using a high rate continuous interleaved sampling (CIS) auditory brainstem implant (ABI). Between June 1997 and May 2004, 24 NF-2 patients were managed by our group. In 20 patients an ABI was implanted successfully. The cochlear nucleus was located using anatomical landmarks and E-ABR recordings after resection of the neuroma via a retrosigmoid approach in the semi-sitting position. The 12-channel stimulating electrode array was inserted and fixed in the lateral recess. There were no surgical complications related to implantation apart from pseudomeningo that were managed by lumbar drainage. In one patient the electrode array became dislocated and this necessitated revision surgery which was successful. One patient failed to gain benefit from the implant. Overall, 70% of electrodes were found to be serviceable for auditory stimulation, 5.3% of electrodes were primarily nonauditory, and in 7.8% side effects during stimulation were observed. Lip reading was improved by more than 100% as a result of the additional auditory input. For many patients, comprehension of open speech was restored to a useful level. Almost all patients were able to perceive environmental sounds and tinnitus was masked. Restoration of hearing using ABIs in NF-2 patients is a safe and promising procedure for those who would otherwise be totally deaf. The high rate CIS speech processing strategy has proven to be very useful and effective in direct cochlear nucleus stimulation.


Iberian wolf as a reservoir of extended-spectrum β-lactamase-producing Escherichia coli of the TEM, SHV, and CTX-M groups.
The intensive use of antibiotics in human and veterinary medicine, associated with mechanisms of bacterial genetic transfer, caused a selective pressure that contributed to the dissemination of antimicrobial resistance in different bacteria groups and throughout different ecosystems. Iberian wolf, due to his predatory and wild nature, may serve as an important indicator of environmental contamination with antimicrobial resistant bacteria. The aim of this study was to characterize the diversity of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli isolates within the fecal microbiota of Iberian wolf. Additionally, the identification of other associated resistance genes, phylogenetic groups, and the detection of virulence determinants were also focused on in this study. From 2008 to 2009, 237 fecal samples from Iberian wolf were collected in Portugal. E. coli isolates with TEM-52, SHV-12, CTX-M-1, and CTX-M-14-type ESBLs were detected in 13 of these samples (5.5%). This study reveals the presence of ESBL-producing E. coli isolates, in a wild ecosystem, which could be disseminated through the environment. Moreover, the presence of resistant genes in integrons and the existence of virulence determinants were shown. The association between antibiotic resistance and virulence determinants should be monitored, as it constitutes a serious public health problem.


Optimizing mental health services in low-income and middle-income countries.
Against the backdrop of a large burden and treatment gap for mental disorders in low-income and middle-income countries (LMICs), recently published articles were reviewed to assess strategies and actions for optimizing mental health services in LMICs. Key strategies and actions are as follows: (i) the adoption of a decentralized stepped care approach embracing task shifting to nonspecialists for those disorders for which it has been shown to be effective; (ii) ensuring adequate numbers of mental health specialists to provide a supportive supervisory framework and referral pathways; (iii) ensuring adequate infrastructure to support decentralized care; (iv) promoting mental health literacy; (v) adoption of a social inclusion and developmental model of disability in caring for people with chronic mental illness; and (vi) embracing a multisectoral community collaborative approach. Optimizing mental health services in LMICs requires legislation, policies and plans that are enabling of the above strategies and actions. Studies demonstrating the cost-effectiveness of integrated stepped packages of care embracing a task-shifting approach, and best practices for strengthening mental health literacy and collaborative arrangements with community caregivers and other sectors, can assist this process. Specialist mental health training programmes in LMICs also need to be responsive to the changing demands on service providers, incorporating a public health approach and equipping specialists for diversification of their roles within the task shifting model.


Social resources and disordered living conditions: evidence from a national sample of community-residing older adults.
For older adults aging in the community, living conditions can promote health, enhance coping, and reduce disablement--but they can also create stress and increase risks of illness, accidents, and decline. Although socioeconomic disparities in housing likely contribute to inequalities in interior conditions, I argue that living conditions are also shaped by social resources such as coresidential relationships, social network ties, and social support. In this article, I examine the distribution of a set of risky or stressful physical and ambient living conditions including structural disrepair, clutter, lack of cleanliness, noise, and odor. Using data from the National Social Life, Health, and Aging Project (NSHAP), I find that low-income and African American older adults have more disordered living conditions as do those with poorer physical and mental health. In addition, older adults who have a coresident partner, more nonresidential network ties, and more sources of instrumental support are exposed to fewer risky or harmful living conditions. This suggests that living conditions are an important, though overlooked, mechanism through which household composition, social networks, and social support affect health and well-being in later life.


Drosophila's contribution to stem cell research.
The discovery of Drosophila stem cells with striking similarities to mammalian stem cells has brought new hope for stem cell research. Recent developments in Drosophila stem cell research is bringing wider opportunities for contemporary stem cell biologists. In this regard, Drosophila germ cells are becoming a popular model of stem cell research. In several cases, genes that controlled Drosophila stem cells were later discovered to have functional homologs in mammalian stem cells. Like mammals, Drosophila germline stem cells (GSCs) are controlled by both intrinsic as well as external signals. Inside the Drosophila testes, germline and somatic stem cells form a cluster of cells (the hub). Hub cells depend on JAK-STAT signaling, and, in absence of this signal, they do not self-renew. In Drosophila, significant changes occur within the stem cell niche that contributes to a decline in stem cell number over time. In case of aging Drosophila, somatic niche cells show reduced DE-cadherin and unpaired (Upd) proteins. Unpaired proteins are known to directly decrease stem cell number within the niches, and, overexpression of upd within niche cells restored GSCs in older males also . Stem cells in the midgut of Drosophila are also very promising. Reduced Notch signaling was found to increase the number of midgut progenitor cells. On the other hand, activation of the Notch pathway decreased proliferation of these cells. Further research in this area should lead to the discovery of additional factors that regulate stem and progenitor cells in Drosophila.


[Diversity of beta-proteobacterial ammonia-oxidizing bacteria and ammonia-oxidizing archaea in shrimp farm sediment].
In order to study the diversity of ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) in shrimp farm sediment. Total microbial DNA was directly extracted from the shrimp farm sediment. The clone library of amoA genes were constructed with beta-Proteobacterial-AOB and AOA specific primers. The library was screened by PCR-restriction fragment length polymorphism (RFLP) analysis and clones with unique RFLP patterns were sequenced. Phylogenetic analyses of the amoA gene fragments showed that all AOB sequences from shrimp farm sediment were affiliated with Nitrosomonas (61.54%) or Nitrosomonas-like (38. 46%) species and grouped into Nitrosomonas communis cluster, Nitrosomonas sp. Nm148 cluster, Nitrosomonas oligotropha cluster. All AOA sequences belonged to the kingdom Crenarchaeote except that one Operational Taxa Unit (OTU) sequence was Unclassified-Archaea and fell within cluster S (soil origin). AOB and AOA species composition included 13 OTUs and 9 OTUs. The clone coverage of bacterial and archaeal amoA genes was 73.47% and 90.43%. The Shannon-Wiener index, Evenness index, Simpson index and Richness index of AOB were higher than those of AOA. These findings represent the first detailed examination of archaeal amoA diversity in shrimp farm sediment and demonstrate that diverse communities of Crenarchaeote capable of ammonia oxidation are present within shrimp farm sediment, where they may be actively involved in nitrification.


Maternal prepregnancy overweight and offspring fatness and blood pressure: role of physical activity.
The purpose of this study was to examine if offspring physical activity may affect the relationship between maternal overweight and offspring fatness and blood pressure (BP). Subjects included 144 maternal-child pairs (n = 74 boys and 70 girls, mean age = 7.3 yrs). Maternal prepregnancy BMI was determined by self-report. Offspring characteristics included resting systolic and diastolic BP, body fatness by dual energy x-ray absorbtiometry, and moderate-to-vigorous physical activity (MVPA) using the Actigraph accelerometer. Children whose mothers were overweight or obese prepregnancy (Prepreg OW) were significantly larger and fatter than children from mothers with a normal prepregnancy BMI (Prepreg NORM). Prepreg OW children also had higher mean arterial pressure than Prepreg NORM children. BP values were not different across maternal Prepreg BMI/ MVPA groups. Percent fat was significantly different across Prepreg BMI/MVPA groups. Prepreg OW children that did not meet the daily recommended value of MVPA were the fattest. Prepreg OW children that attained (3)60 min of MVPA/ day had a mean percent body fat that was similar to Prepreg NORM children of either MVPA group.


Delayed Auditory Feedback and Transcranial Direct Current Stimulation Treatment for the Enhancement of Speech Fluency in Adults Who Stutter: Protocol for a Randomized Controlled Trial.
Stuttering is a complex speech disorder that affects speech fluency. Recently, it has been shown that noninvasive brain stimulation may be useful to enhance the results of fluency interventions in adults who stutter. Delayed auditory feedback (DAF) is a method to enhance speech fluency in individuals who stutter. Adjunctive interventions are warranted to enhance the efficacy of this intervention. Individuals who stutter have pathological activation patterns in the primary and secondary auditory areas. Consequently, in this study, we hypothesize that stimulation of these areas might be promising as an adjunctive method to fluency training via DAF to enhance speech therapy success in individuals with a stutter. We will systematically test this hypothesis in this study. This study is designed as a randomized, double-blind, sham-controlled clinical trial. All participants will receive DAF. The intervention group will additionally receive real transcranial direct current stimulation, while the control group will be exposed to sham stimulation. The assignment of the participants to one of these groups will be randomized. Before starting the treatment program, 2 preintervention assessments will be conducted to determine the severity of stuttering. Once these assessments are completed, each subject will participate in 6 intervention sessions. Postintervention assessments will be carried out immediately and 1 week after the last intervention session. Subsequently, to explore the long-term stability of the treatment results, the outcome parameters will be obtained in follow-up assessments 6 weeks after the treatment. The primary outcome measurement-the percentage of stuttered syllables-will be calculated in pre-, post-, and follow-up assessments; the secondary outcomes will be the scores of the following questionnaires: the Stuttering Severity Instrument-Fourth Edition and the Overall Assessment of the Speaker's Experience of Stuttering. This protocol was funded in 2019 and approved by the Research Ethics Committee of the Iran University of Medical Sciences in June 2019. Data collection started in October 2019. As of February 2020, we have enrolled 30 participants. We expect data analysis to be completed in April 2020, and results will be published in summer 2020. We anticipate that this study will show an adjunctive effect of transcranial direct current stimulation, when combined with DAF, on stuttering. This should include not only a reduction in the percentage of stuttered syllables but also improved physical behavior and quality of life in adults who stutter. ClinicalTrial.gov NCT03990168; https://clinicaltrials.gov/ct2/show/NCT03990168. DERR1-10.2196/16646.


Liposomal formulation of retinoids designed for enzyme triggered release.
The design of retinoid phospholipid prodrugs is described based on molecular dynamics simulations and cytotoxicity studies of synthetic retinoid esters. The prodrugs are degradable by secretory phospholipase A(2) IIA and have potential in liposomal drug delivery targeting tumors. We have synthesized four different retinoid phospholipid prodrugs and shown that they form particles in the liposome size region with average diameters of 94-118 nm. Upon subjection to phospholipase A(2), the lipid prodrugs were hydrolyzed, releasing cytotoxic retinoids and lysolipids. The formulated lipid prodrugs displayed IC(50) values in the range of 3-19 microM toward HT-29 and Colo205 colon cancer cells in the presence of phospholipase A(2), while no significant cell death was observed in the absence of the enzyme.


Influence of Cedar Essential Oil on Physical and Biological Properties of Hemostatic, Antibacterial, and Antioxidant Polyvinyl Alcohol/Cedar Oil/Kaolin Composite Hydrogels.
Polyvinyl alcohol (PVA) is a safe and biodegradable polymer. Given the unique physical and chemical properties of PVA, we physically cross-linked PVA with kaolin (K) and cedar essential oil (Ced) using the freeze-thawing approach to fabricate PVA/Ced/K sponge hydrogels as hemostatic, antibacterial, and antioxidant wound healing materials. The physicochemical characteristics of PVA/Ced/K hydrogels, including water swelling profiles and gel fractions, were surveyed. Additionally, the functional groups of hydrogels were explored by Fourier transform infrared spectroscopy (FTIR), while their microstructures were studied using scanning electron microscopy (SEM). Furthermore, the thermal features of the hydrogels were probed by thermal gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Evidently, alterations in cedar concentrations resulted in significant variations in size, water uptake profiles, and hydrolytic degradation of the hydrogels. The incorporation of cedar into the PVA/K endowed the hydrogels with significantly improved antibacterial competency against Bacillus cereus (B. cereus) and Escherichia coli (E. coli). Moreover, PVA/Ced/K exhibited high scavenging capacities toward ABTS•+ and DPPH free radicals. Beyond that, PVA/Ced/K hydrogels demonstrated hemocompatibility and fast blood clotting performance in addition to biocompatibility toward fibroblasts. These findings accentuate the prospective implementation of PVA/Ced/K composite hydrogel as a wound dressing.


Telomere length, family history, and paternal age in schizophrenia.
Leukocyte telomere length (LTL) is longer in association with advanced paternal age, but this association has not been examined along with family history (FH) in schizophrenia. LTL was measured by PCR and compared across cases and controls as part of a study to examine the characteristics of paternal age related schizophrenia. The 53 schizophrenia cases had similar mean LTL as 20 controls, although cases were significantly older than controls and overwhelmingly smoked cigarettes. Multivariate analyses showed that a FH of schizophrenia was associated with longer LTL in both male and female cases. Later paternal age was also related to longer LTL in male cases, but with shorter LTL in female cases. Male cases with older fathers and a FH had the longest LTL. The genetic architecture associated with a familial risk for schizophrenia may include pathways that lengthen LTL. Paternal aging conferred an additional increase in LTL lengthening in male cases, but reduced LTL in female cases. The gender difference in LTL for paternal aging is consistent with the severe illness features reported for female cases with older fathers and could implicate epigenetic alterations in the paternal X chromosomal region with advanced paternal age in association with the risk for schizophrenia.


Measuring community-oriented attitudes towards medical practice.
The measurement of attitude and attitudinal changes regarding community-oriented primary care (COPC) and the community-oriented principles of family medicine from the College of Family Physicians of Canada was a key component of this study involving family medicine residents. The Department of Family and Community Medicine at the Toronto Hospital initiated a new COPC curriculum in July 1997 for its first-year residents which was designed to teach the principles of family medicine which are community oriented. This study was developed to provide an analysis and summary of the attitude and attitudinal changes of residents exposed to the programme and those of two cohort groups who were not exposed. A quasi-experimental design was used. A 20-item questionnaire was administered pre- and post-intervention. Qualitative data were also collected from focus group sessions with the residents exposed to the programme. The questionnaire was found to have good reliability, with an alpha coefficient of 0.8. No significant differences were observed between the study and control groups pre- and post-intervention. Within the study group, two items from the questionnaire yielded significant differences (P < 0.05). These items dealt with lack of funding and impracticality issues of applying COPC in medical practice. They were also the prevalent themes generated from the focus group session analysis. The qualitative data corroborated the findings of the survey. These findings have helped in the evolution of the curriculum. Longitudinal studies to measure attitudes and the practice of COPC and community-oriented principles of family medicine after residency are recommended.


PALEOANTHROPOLOGY. Comment on "Early Homo at 2.8 Ma from Ledi-Geraru, Afar, Ethiopia".
Villmoare et al. (Reports, 20 March 2015, p. 1352) report on a hominin mandible from the Ledi-Geraru research area, Ethiopia, which they claim to be the earliest known representative of the genus Homo. However, certain measurements and observations for Australopithecus sediba mandibles presented are incorrect or are not included in critical aspects of the study. When correctly used, these data demonstrate that specimen LD 350-1 cannot be unequivocally assigned to the genus Homo.


Immunologic studies in patients with sarcoidosis and cryptococcosis.
Immunologic studies were performed in two patients with sarcoidosis, who developed cryptococcosis. Polymorphonuclear leukocyte function, complement, and serum antibodies were normal. Both patients had depressed cell-mediated immunity (cmi) to Cryptococcus neoformans and other antigens that persisted after therapy for their infection. These findings suggest that the patients' impaired CMI predisposed them to cryptococcal infection, which complicated their sarcoidosis. Evaluation of sarcoidosis cases should include studies of immune function, and the possibility of a secondary infection should be considered in patients with long-standing sarcoidosis, who develop unexpected changes in their clinical status.


Social inequalities in trajectories of contacts with the healthcare system in adolescence and young adulthood.
Understanding of healthcare utilization of different populations is useful for prevention and prioritization of healthcare resources. This study aims to identify populations following different trajectories of contacts with the healthcare system and to describe social inequalities between the groups. Individuals born 1980-2000 in Denmark were linked to national registers. Contacts with somatic hospitals, psychiatric hospitals, general practitioners, and redeemed prescriptions were counted for each year between 16 and 37 years of age. Trajectories of contacts with the four dimensions of healthcare use were identified using group-based multi-trajectory modeling. Five trajectory groups were identified. One group had low healthcare utilization over time (12% in women; 27% in men). The largest group had low healthcare utilization but more contacts with especially GP (39% in women; 43% in men). A third group had more contacts with most dimensions of the healthcare system (33% in women; 21% in men). The fourth group had many contacts with especially somatic hospitals and GP (7% in women; 4% in men). The fifth group had many contacts especially to psychiatric hospitals (8% in women; 5% in men). Shorter parental education, parental unemployment, family income below the poverty line, and cohabitation with one or no parent was more frequent in the two high utilization groups compared to the lower utilization groups. The observed trajectories of health service use and the social inequalities between trajectory groups highlight that prevention and treatment targeting the entire population will benefit from a complementary focus on social inequalities in health.


Curcumin Stimulates Proliferation of Spinal Cord Neural Progenitor Cells via a Mitogen-Activated Protein Kinase Signaling Pathway.
The aims of our study are to evaluate the effect of curcumin on spinal cord neural progenitor cell (SC-NPC) proliferation and to clarify the mechanisms of mitogen-activated protein (MAP) kinase signaling pathways in SC-NPCs. We established cultures of SC-NPCs, extracted from the spinal cord of Sprague-Dawley rats weighing 250 g to 350 g. We measured proliferation rates of SC-NPCs after curcumin treatment at different dosage. The immuno-blotting method was used to evaluate the MAP kinase signaling protein that contains extracellular signal-regulated kinases (ERKs), p38, c-Jun NH2-terminal kinases (JNKs) and β-actin as the control group. Curcumin has a biphasic effect on SC-NPC proliferation. Lower dosage (0.1, 0.5, 1 µM) of curcumin increased SC-NPC proliferation. However, higher dosage decreased SC-NPC proliferation. Also, curcumin stimulates proliferation of SC-NPCs via the MAP kinase signaling pathway, especially involving the p-ERK and p-38 protein. The p-ERK protein and p38 protein levels varied depending on curcumin dosage (0.5 and 1 µM, p<0.05). Curcumin can stimulate proliferation of SC-NPCs via ERKs and the p38 signaling pathway in low concentrations.


Predictors of increased cumulative serum levels of the N-terminal prohormone of brain natriuretic peptide 4 days after acute spontaneous subarachnoid hemorrhage.
The rupture of an intracranial aneurysm is followed by increased intracranial pressure and decreased cerebral blood flow. A major systemic stress reaction follows, presumably to restore cerebral blood flow. However, this reaction can also cause adverse effects, including myocardial abnormalities, which are common and can be serious, and increased levels of natriuretic peptides, especially brain natriuretic peptide (BNP). The association of BNP with fluid and salt balance, vasospasm, brain ischemia, and cardiac injury has been studied but almost exclusively regarding events after admission. Brain natriuretic peptide has also been measured at various time points and analyzed in different ways statistically. The authors approached BNP measurement in a new way; they used the calculated area under the curve (AUC) for the first 4 days to quantitatively measure the BNP load during the first critical part of the disease state. Their rationale was a suspicion that early BNP load is a marker of the severity of the ictus and will influence the subsequent course of the disease by disturbing the fluid and salt balance. The study included 156 patients with acute spontaneous subarachnoid hemorrhage (SAH). Mean patient age was 59.8 ± 11.2 years, and 105 (67%) of the patients were female. An aneurysm was found in 138 patients. A total of 82 aneurysms were treated by endovascular coiling, 50 were treated by surgery, and 6 were untreated. At the time of admission, serum samples were collected for troponin-I analysis and for the N-terminal prohormone of BNP (NT-proBNP); daily thereafter, samples were collected for the NT-proBNP analysis. The cumulative BNP load was calculated as the AUC for NT-proBNP during the first 4 days. The following variables were studied in terms of their influence on the AUC for NT-proBNP: sex, age, World Federation of Neurosurgical Societies grade of SAH, Fisher grade, angiographic result, treatment of aneurysm, clinical neurological deterioration, verified infections, vasospasm treatment, and 6-month outcome. The AUC for NT-proBNP was larger when variables indicated a more severe SAH. These variables were higher Fisher and World Federation of Neurosurgical Societies grades, high levels of troponin-I at admission, an aneurysm, neurological deficits, and infections. The AUC for NT-proBNP was also larger among women, older patients, and patients with poor outcomes. Linear regression showed that the best predicting model for large AUC for NT-proBNP was the combination of the following: female sex, high levels of troponin-I, an aneurysm, neurological deficits, and advanced age. The cumulative BNP load during the first days after SAH can be predicted by variables describing the severity of the disease already known at the time of admission. This information can be used to identify patients at risk for an adverse course of the disease.


[The significance of elevated troponin levels in the absence of acute cardiac ischaemia].
Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are valuable heart markers in patients presenting with symptoms of ischaemic heart disease. A number of categories of patients frequently have raised concentrations of cardiac troponin (cTn) without having ischaemic heart disease. These include patients with heart diseases such as heart failure, myocarditis and valvular disease but also those with lung emboli, renal failure and sepsis. Possible underlying mechanisms are diffuse necrosis, cTn proteolysis or leakage of cytoplasmatic cTn with no irreversible damage to the contraction complex of heart-muscle cells. It is possible that cTn-measurement in patients with non-cardiac conditions is of prognostic value but so far this has only been demonstrated in dialysis patients and patients with pulmonary embolism.


miR-335 Restrains the Aggressive Phenotypes of Ovarian Cancer Cells by Inhibiting COL11A1.
High collagen type XI alpha 1 (COL11A1) levels are associated with tumor progression, chemoresistance, and poor patient survival in several cancer types. MicroRNAs (miRNAs) are dysregulated in multiple cancers, including epithelial ovarian carcinoma (EOC); however, the regulation of COL11A1 by miRNAs in EOC remains unclear. We examined the role of miRNAs in regulating COL11A1 expression. We identified miR-509 and miR-335 as the candidate miRNAs through an online database search. EOC cell treatment with miR-335 mimics abrogated COL11A1 expression and suppressed cell proliferation and invasion, besides increasing the sensitivity of EOC cells to cisplatin. Conversely, treatment with miR-335 inhibitors prompted cell growth/invasiveness and chemoresistance of EOC cells. miR-335 inhibited COL11A1 transcription, thus reducing the invasiveness and chemoresistance of EOC cells via the Ets-1/MMP3 and Akt/c/EBPβ/PDK1 axes, respectively. Furthermore, it did not directly regulate PDK1 but increased PDK1 ubiquitination and degradation through COL11A1 inhibition. In vivo findings highlighted significantly decreased miR-335 mRNA expressions in EOC samples. Furthermore, patients with low miR335 levels were susceptible to advanced-stage cancer, poor response to chemotherapy, and early relapse. This study highlighted the importance of miR-335 in downregulating COL11A1-mediated ovarian tumor progression, chemoresistance, and poor survival and suggested its potential application as a therapeutic target.


The molecular basis of lung cancer: molecular abnormalities and therapeutic implications.
Lung cancer is the number one cause of cancer-related death in the western world. Its incidence is highly correlated with cigarette smoking, and about 10% of long-term smokers will eventually be diagnosed with lung cancer, underscoring the need for strengthened anti-tobacco policies. Among the 10% of patients who develop lung cancer without a smoking history, the environmental or inherited causes of lung cancer are usually unclear. There is no validated screening method for lung cancer even in high-risk populations and the overall five-year survival has not changed significantly in the last 20 years. However, major progress has been made in the understanding of the disease and we are beginning to see this knowledge translated into the clinic. In this review, we will summarize the current state of knowledge regarding the cascade of events associated with lung cancer development. From subclinical DNA damage to overt invasive disease, the mechanisms leading to clinically and molecularly heterogeneous tumors are being unraveled. These lesions allow cells to escape the normal regulation of cell division, apoptosis and invasion. While all subtypes of non-small cell lung cancer have historically been treated the same, stage-for-stage, recent technological advances have allowed a better understanding of the molecular classification of the disease and provide hypotheses for molecular early detection and targeted therapeutic strategies.


GnRH analogs induce a LH peak and increase pregnancy per timed-AI in ewes.
To date, there have been no studies testing the capacity of GnRH analogs and respective doses to induce a LH peak in sheep. In this sense, the present study aimed to evaluate the capacity of different synthetic forms and doses of GnRH in inducing LH release in sheep, and the effect of GnRH administration at timed artificial insemination (TAI) on pregnancy per timed-AI. In experiment 1, ewes (n = 40) received an intravaginal device (IVD) of medroxyprogesterone acetate (MPA; 60 mg) for 7 d and prostaglandin F2α analog on Day 5. On Day 7, the ewes were allocated randomly into one of eight groups (n = 5/group), which received a GnRH analog at a specific dose, as follows: lecirelin (12.5 or 25 μg), gonadorelin (50 or 100 μg), buserelin acetate (4.2 or 8.4 μg), or deslorelin (375 or 750 μg). Blood samples for LH determination were obtained at 0, 2, 4, and 6 h after GnRH and the IVDs were removed after the last blood collection. The maximal LH concentration induced by gonadorelin at doses of 50 μg and 100 μg (12.0 ± 2.4 ng/mL and 28.6 ± 7.1 ng/mL, respectively) was lower (P < 0.05) than serum LH induced by 8.4 μg of buserelin (78.9 ± 12.9 ng/mL), 375 μg and 750 μg of deslorelin (75.6 ± 7.4 ng/mL and 72.1 ± 10.6 ng/mL, respectively) and 12.5 μg and 25 μg of lecirelin (73.3 ± 17.8 ng/mL and 61.6 ± 5.9 ng/mL, respectively). However, the maximal LH concentration induced by 4.2 μg of buserelin (49.4 ± 5.9 ng/mL) was similar (P > 0.05) to the 100 μg of gonadorelin. The total release of LH (area under the curve - AUC) after treatment with 50 μg of gonadorelin (31.7 ± 5.9 ng h/mL) was lower (P < 0.05) than after other agonists. In a second experiment, 330 ewes were treated with IVD containing MPA for 7 d. Simultaneously with IVD removal, 250 μg of cloprostenol and 200 IU of eCG were administered. Then, ewes were assigned randomly to either no further treatment (control); or to receive 4.2 μg of buserelin acetate (GnRH group) at cervical TAI, which was performed with fresh semen 54 h after IVD withdrawal in all the animals. Higher pregnancy per timed-AI was observed for GnRH (50.3 %) compared to control (40.7 %). We conclude that buserelin acetate (8.4 μg), lecirelin (12.5 and 25 μg) and deslorelin (375 and 750 μg) induced a greater stimulatory effect on LH secretion than gonadorelin treatment. Furthermore, buserelin acetate treatment at TAI increased pregnancy per timed-AI in ewes previously treated with MPA and eCG.


Ocular Inflammatory Events Following COVID-19 Vaccination in the Paediatric Population: A Multinational Case Series.
Ocular inflammatory events following COVID-19 vaccination have been reported in the adult population. Multinational case series of patients under the age of 18 diagnosed with ocular inflammatory events within 28 days of COVID-19 vaccination. Twenty individuals were included. The most common event was anterior uveitis (n = 8, 40.0%), followed by intermediate uveitis (7 patients, 35%), panuveitis (4 patients, 20%), and posterior uveitis (1 patient, 5%). The event was noticed in the first week after vaccination in 11 patients (55.0%). Twelve patients (60.0%) had a previous history of intraocular inflammatory event. Patients were managed with topical corticosteroids (n = 19, 95.0%), oral corticosteroids (n = 10, 50.0%), or increased dose of immunosuppressive treatment (n = 6, 30.0%). Thirteen patients (65.0%) had a complete resolution of the ocular event without complications. All patients had a final visual acuity unaffected or less than three lines of loss. Ocular inflammatory events may happen in the paediatric population following COVID-19 vaccination. Most events were successfully treated, and all showed a good visual outcome.


Predicting Response to an Internet-Delivered Parenting Program for Anxiety in Early Childhood.
Previous research has identified factors related to outcome in child anxiety treatment and parent training programs for child behavior problems. However, it is unclear what factors predict outcomes in interventions delivered online to parents of young children at risk of anxiety. This study investigated predictors of child anxiety outcomes among 433 families with young children (3-6 years) who participated in a randomized controlled trial of Cool Little Kids Online, an eight-module early intervention program for child anxiety based on cognitive-behavioral therapy (CBT). Potential predictors included baseline demographic factors, child and parent mental health factors, and indicators of program use, including number of online modules completed and frequency of homework practice. Results showed that only access to a printer moderated intervention effectiveness. Printer access predicted lower child anxiety in the Cool Little Kids Online group, but had no effect on outcomes in the wait-list group. In both groups, higher levels of child anxiety symptoms, child-inhibited temperament, and poorer parent mental health at baseline predicted higher levels of child anxiety symptoms at 6-month follow-up. The amount of online program use was not related to improvements in child anxiety symptoms. However, parents who reported practicing the program skills more frequently showed greater reductions in child anxiety, and access to a printer was related to frequency of program skills practice. These findings provide empirical support for the important role of skills practice in online CBT interventions, and suggest that practicing program skills may be more important than completing the online modules.


Extra-spinal sciatica and sciatica mimics: a scoping review.
Not all sciatica-like manifestations are of lumbar spine origin. Some of them are caused at points along the extra-spinal course of the sciatic nerve, making diagnosis difficult for the treating physician and delaying adequate treatment. While evaluating a patient with sciatica, straightforward diagnostic conclusions are impossible without first excluding sciatica mimics. Examples of benign extra-spinal sciatica are: piriformis syndrome, walletosis, quadratus lumborum myofascial pain syndrome, cluneal nerve disorder, and osteitis condensans ilii. In some cases, extra-spinal sciatica may have a catastrophic course when the sciatic nerve is involved in cyclical sciatica, or the piriformis muscle in piriformis pyomyositis. In addition to cases of sciatica with clear spinal or extra-spinal origin, some cases can be a product of both origins; the same could be true for pseudo-sciatica or sciatica mimics, we simply don't know how prevalent extra-spinal sciatica is among total sciatica cases. As treatment regimens differ for spinal, extra-spinal sciatica, and sciatica-mimics, their precise diagnosis will help physicians to make a targeted treatment plan. As published works regarding extra-spinal sciatica and sciatica mimics include only a few case reports and case series, and systematic reviews addressing them are hardly feasible at this stage, a scoping review in the field can be an eye-opener for the scientific community to do larger-scale prospective research.


The heterogeneous nuclear ribonucleoprotein-R is necessary for axonal beta-actin mRNA translocation in spinal motor neurons.
Axonal transport and translation of beta-actin mRNA plays an important role for axonal growth and presynaptic differentiation in many neurons including hippocampal, cortical and spinal motor neurons. Several beta-actin mRNA-binding and transport proteins have been identified, including ZBP1, ZBP2 and hnRNP-R. hnRNP-R has been found as an interaction partner of the survival motor neuron protein that is deficient in spinal muscular atrophy. Little is known about the function of hnRNP-R in axonal beta-actin translocation. hnRNP-R and beta-actin mRNA are colocalized in axons. Recombinant hnRNP-R interacts directly with the 3'-UTR of beta-actin mRNA. We studied the role of hnRNP-R in motor neurons by knockdown in zebrafish embryos and isolated mouse motor neurons. Suppression of hnRNP-R in developing zebrafish embryos results in reduced axon growth in spinal motor neurons, without any alteration in motor neuron survival. ShRNA-mediated knockdown in isolated embryonic mouse motor neurons reduces beta-actin mRNA translocation to the axonal growth cone, which is paralleled by reduced axon elongation. Dendrite growth and neuronal survival were not affected by hnRNP-R depletion in these neurons. The loss of beta-actin mRNA in axonal growth cones of hnRNP-R-depleted motor neurons resembles that observed in Smn-deficient motor neurons, a model for the human disease spinal muscular atrophy. In particular, hnRNP-R-depleted motor neurons also exhibit defects in presynaptic clustering of voltage-gated calcium channels. Our data suggest that hnRNP-R-mediated axonal beta-actin mRNA translocation plays an essential physiological role for axon growth and presynaptic differentiation.


A revised strategy for the monitoring and management of the galapagos sea cucumber Isostichopus fuscus (Aspidochirotida: Stichopodidae).
The brown sea cucumber fishery is active in the Galapagos Islands since the year 1991 after its collapse in mainland Ecuador. This paper analyzes the Galapagos Sea cucumber fishery over the past decade and the reasons for its management pitfalls and chronic over fishing, and proposes an improved strategy for estimating stock size and harvest potential. Based on the historical distribution of the fishing fleet and past fishery surveys, 15 macrozones were defined; their areas were estimated from the coastline to the 30m isobaths and the numbers of sample replicates per macrozone were calculated for a density estimate precision of +/-25%. Overall stock size was calculated by summing over all macrozones and was multiplied by 0.122 to obtain the annual quota. This multiplier was derived by inserting an exploitation rate of E=0.3 and a published natural mortality value of M=0.17 into Cadimas formula, thereby obtaining a more conservative precautionary quota estimate. Pre-fishery stock densities in 2009 were below the legal threshold value and the fishery remained closed. Mean densities were significantly lower in the deeper (>15m) than in the shallower (<15m) stratum, contrary to fishermen expectations. Through an empirical regression of (log) pre-fishery density versus subsequent annual catch for the period 1998-2008 we found that catches of most years greatly exceeded the here proposed quota explaining the collapsed nature of the stock.


A smoker with cyanosis and hypotension.
Involvement of the pericardium and pericardial effusion at postmortem is common in advanced malignant disease. However, cardiac tamponade presenting as the first manifestation of malignancy is uncommon. We present the case of a patient who presented with malignant pericardial effusion who had advanced lung cancer with metastasis and paraneoplastic features.


Magnetic resonance fingerprinting.
Magnetic resonance is an exceptionally powerful and versatile measurement technique. The basic structure of a magnetic resonance experiment has remained largely unchanged for almost 50 years, being mainly restricted to the qualitative probing of only a limited set of the properties that can in principle be accessed by this technique. Here we introduce an approach to data acquisition, post-processing and visualization--which we term 'magnetic resonance fingerprinting' (MRF)--that permits the simultaneous non-invasive quantification of multiple important properties of a material or tissue. MRF thus provides an alternative way to quantitatively detect and analyse complex changes that can represent physical alterations of a substance or early indicators of disease. MRF can also be used to identify the presence of a specific target material or tissue, which will increase the sensitivity, specificity and speed of a magnetic resonance study, and potentially lead to new diagnostic testing methodologies. When paired with an appropriate pattern-recognition algorithm, MRF inherently suppresses measurement errors and can thus improve measurement accuracy.


Effect of vasoactive intestinal peptide on isolated perfused rat kidney.
Vasoactive intestinal peptide, a polypeptide neurotransmitter, stimulates salt secretion by the mammalian intestine and the rectal gland of the dogfish shark. Because of the recent identification of vasoactive intestinal peptide in renal nerves, the present study was undertaken to investigate its effects on the isolated perfused rat kidney. The addition of vasoactive intestinal peptide to the recirculating perfusate produced a significant increase in urine volume, fractional excretion of sodium, chloride, and potassium, as well as osmolar clearance when compared with control kidneys. These changes associated with addition of vasoactive intestinal peptide occurred without any significant changes in perfusion flow, renal vascular resistance, or inulin clearance. These experiments strongly suggest an action of vasoactive intestinal peptide on renal tubular reabsorption.


Nomogram to predict cycle-one serious drug-related toxicity in phase I oncology trials.
All patients in phase I trials do not have equivalent susceptibility to serious drug-related toxicity (SDRT). Our goal was to develop a nomogram to predict the risk of cycle-one SDRT to better select appropriate patients for phase I trials. The prospectively maintained database of patients with solid tumor enrolled onto Cancer Therapeutics Evaluation Program-sponsored phase I trials activated between 2000 and 2010 was used. SDRT was defined as a grade ≥ 4 hematologic or grade ≥ 3 nonhematologic toxicity attributed, at least possibly, to study drug(s). Logistic regression was used to test the association of candidate factors to cycle-one SDRT. A final model, or nomogram, was chosen based on both clinical and statistical significance and validated internally using a bootstrapping technique and externally in an independent data set. Data from 3,104 patients enrolled onto 127 trials were analyzed to build the nomogram. In a model with multiple covariates, Eastern Cooperative Oncology Group performance status, WBC count, creatinine clearance, albumin, AST, number of study drugs, biologic study drug (yes v no), and dose (relative to maximum administered) were significant predictors of cycle-one SDRT. All significant factors except dose were included in the final nomogram. The model was validated both internally (bootstrap-adjusted concordance index, 0.60) and externally (concordance index, 0.64). This nomogram can be used to accurately predict a patient's risk for SDRT at the time of enrollment. Excluding patients at high risk for SDRT should improve the safety and efficiency of phase I trials.


A cluster-randomized controlled trial of a combination HIV risk reduction and microfinance intervention for female sex workers who use drugs in Kazakhstan.
Female sex workers (FSW) who use drugs are a key population at risk of HIV in Kazakhstan, and face multiple structural barriers to HIV prevention. More research is needed on the role of structural interventions such as microfinance (MF) in reducing HIV risk. This paper describes the results of a cluster-randomized controlled trial to test the efficacy of a combination HIVRR + MF intervention in reducing biologically confirmed STIs and HIV risk behaviours. This study took place from May 2015 to October 2018 in two cities in Kazakhstan. We screened 763 participants for eligibility and enrolled 354 FSW who use drugs. Participants were randomized in cohorts to receive either a four-session HIVRR intervention, or that same intervention plus 30 additional sessions of financial literacy training, vocational training and asset-building through a matched-savings programme. Repeated behavioural and biological assessments were conducted at baseline, 3-, 6- and 12-months post-intervention. Biological and behavioural primary outcomes included HIV/STI incidence, sexual risk behaviours and drug use risk behaviours, evaluated over the 12-month period. Over the 12-month follow-up period, few differences in study outcomes were noted between arms. There was only one newly-detected HIV case, and study arms did not significantly differ on any STI incidence. At post-intervention assessments compared to baseline, both HIVRR and HIVRR + MF participants significantly reduced sexual and drug use risk behaviours, and showed improvements in financial outcomes, condom use attitudes and self-efficacy, social support, and access to medical care. In addition, HIVRR + MF participants showed a 72% greater reduction in the number of unprotected sex acts with paying partners at the six-month assessment (IRR = IRR = 0.28, 95% CI = 0.08, 0.92), and a 10% greater reduction in the proportion of income from sex work at the three-month assessment (b = -0.10, 95% CI = -0.17, -0.02) than HIVRR participants did. HIVRR + MF participants also showed significantly improved performance on financial self-efficacy compared to HIVRR over the 12-month follow-up period. Compared to a combination HIVRR + MF intervention, a robust HIVRR intervention alone may be sufficient to reduce sexual and drug risk behaviours among FSW who use drugs. There may be structural limitations to the promise of microfinance for HIV risk reduction among this population.


Towards interoperability in infection control: a standard data model for microbiology.
The COVID-19 pandemic has made it clear: sharing and exchanging data among research institutions is crucial in order to efficiently respond to global health threats. This can be facilitated by defining health data models based on interoperability standards. In Germany, a national effort is in progress to create common data models using international healthcare IT standards. In this context, collaborative work on a data set module for microbiology is of particular importance as the WHO has declared antimicrobial resistance one of the top global public health threats that humanity is facing. In this article, we describe how we developed a common model for microbiology data in an interdisciplinary collaborative effort and how we make use of the standard HL7 FHIR and terminologies such as SNOMED CT or LOINC to ensure syntactic and semantic interoperability. The use of international healthcare standards qualifies our data model to be adopted beyond the environment where it was first developed and used at an international level.


Thermal conductivity of glassy GeTe4 by first-principles molecular dynamics.
A transient thermal regime is achieved in glassy GeTe4 by first-principles molecular dynamics following the recently proposed "approach-to-equilibrium" methodology. The temporal and spatial evolution of the temperature do comply with the time-dependent solution of the heat equation. We demonstrate that the time scales required to create the hot and the cold parts of the system and observe the resulting approach to equilibrium are accessible to first-principles molecular dynamics. Such a strategy provides the thermal conductivity from the characteristic decay time. We rationalize in detail the impact on the thermal conductivity of the initial temperature difference, the equilibration duration, and the main simulation features.


Extremely low-coverage whole genome sequencing in South Asians captures population genomics information.
The cost of Whole Genome Sequencing (WGS) has decreased tremendously in recent years due to advances in next-generation sequencing technologies. Nevertheless, the cost of carrying out large-scale cohort studies using WGS is still daunting. Past simulation studies with coverage at ~2x have shown promise for using low coverage WGS in studies focused on variant discovery, association study replications, and population genomics characterization. However, the performance of low coverage WGS in populations with a complex history and no reference panel remains to be determined. South Indian populations are known to have a complex population structure and are an example of a major population group that lacks adequate reference panels. To test the performance of extremely low-coverage WGS (EXL-WGS) in populations with a complex history and to provide a reference resource for South Indian populations, we performed EXL-WGS on 185 South Indian individuals from eight populations to ~1.6x coverage. Using two variant discovery pipelines, SNPTools and GATK, we generated a consensus call set that has ~90% sensitivity for identifying common variants (minor allele frequency ≥ 10%). Imputation further improves the sensitivity of our call set. In addition, we obtained high-coverage for the whole mitochondrial genome to infer the maternal lineage evolutionary history of the Indian samples. Overall, we demonstrate that EXL-WGS with imputation can be a valuable study design for variant discovery with a dramatically lower cost than standard WGS, even in populations with a complex history and without available reference data. In addition, the South Indian EXL-WGS data generated in this study will provide a valuable resource for future Indian genomic studies.


Development of the Vision Impairment in Low Luminance Questionnaire.
The purpose of this study was to design and evaluate an instrument for assessing vision-related quality of life appropriate for the specific visual impairment characteristic for all stages of age-related macular degeneration (AMD), with a focus on the low luminance deficit in early/intermediate stages. A standardized questionnaire was developed in three steps with participants with early, intermediate, and late AMD: (1) based on in-depth interviews (n = 19) and two focus group discussions (n = 5 each), content was developed followed by 2. (2) The questionnaire development using cognitive debriefing interviews (n = 3) and leading to a preliminary version of the questionnaire. (3) This version was then administered to 127 participants with early, intermediate, and late AMD. Psychometric properties, such as response category functioning (floor and ceiling effects) and targeting of item difficulty to patient ability of the pilot Vision Impairment in Low Luminance (VILL) questionnaire were evaluated using Rasch analysis. The preliminary VILL questionnaire consisted of 68 items with a 5-step response scale. Several items were removed based on floor/ceiling effects or misfit and a final pool of 37 items remained. The response scale was collapsed to four categories as one category was underutilized. The targeting of the instrument was good with minimal difference in person and item means (0.52 logits). Precision was also good with a person separation index of 3.55 and reliability of 0.93. There was evidence of multidimensionality (eigenvalue of the first contrast = 5.95) in the scale, which could be resolved by splitting the items into subscales including a reading, mobility, and emotional well-being subscale. Individuals with AMD report difficulties with vision-related activities and functioning under visually challenging conditions at all stages of the disease. These aspects were considered when developing the 37-item VILL, which demonstrates promising psychometric characteristics. Further assessments of reliability and validity are warranted. The VILL questionnaire is a new patient-reported outcome (PRO) measure developed for future use in AMD studies.


Sublaminar wire migration into the medulla oblongata: a case report.
Atlantoaxial procedures have been developed in an effort to ensure solid C1-C2 fusion. However, techniques that involve sublaminar wiring have the potential for neural structure injury. We present the management of a patient who previously underwent Gallie fusion 10 years ago and is presenting with a dislodged titanium wire that has migrated into the medulla oblongata. A 52-year-old female patient known with rheumatoid arthritis presented with truncal ataxia and food regurgitation 10 years after undergoing a C1-C2 Gallie fusion. A computerized tomography (CT) scan revealed that a wire from her Gallie fusion procedure migrated into the medulla oblongata. The patient underwent foramen magnum decompression with C1 bilateral laminectomy, instrumentation, and removal of a migrated wire. Six months later, a CT scan showed that all occipital screws were pulled out. In the revision surgery, new occipital screws were placed with a resultant significant improvement in patient's gait postoperatively. Wire migration as a differential diagnosis should be considered in patients presenting with neurological dysfunction who underwent surgical treatment with sublaminar wire fusion techniques.


Spectral dependence of nanocrystal photoionization probability: the role of hot-carrier transfer.
We conduct measurements of photocharging of PbSe and PbS nanocrystal quantum dots (NQDs) as a function of excitation energy (ℏω). We observe a rapid growth of the degree of photocharging with increasing ℏω, which indicates an important role of hot-carrier transfer in the photoionization process. The corresponding spectral dependence exhibits two thresholds that mark the onsets of weak and strong photocharging. Interestingly, both thresholds are linked to the NQD band gap energy (E(g)) and scale as ∼1.5E(g) and ∼3E(g), indicating that the onsets of photoionization are associated with specific nanocrystal states (tentatively, 1P and 2P, respectively) and are not significantly dependent on the energy of external acceptor sites. For all samples, the hot-electron transfer probability increases by nearly 2 orders of magnitude as photon energy increases from 1.5 to 3.5 eV, although at any given wavelength the photoionization probability shows significant sample-to-sample variations (∼10(-6) to 10(-3) for 1.5 eV and ∼10(-4) to 10(-1) for 3.5 eV). In addition to the effect of the NQD size, these variations are likely due to differences in the properties of the NQD surface and/or the number and identity of external acceptor trap sites. The charge-separated states produced by photoionization are characterized by extremely long lifetimes (20 to 85 s) that become longer with increasing NQD size.


Effects of testosterone on erectile function: implications for the therapy of erectile dysfunction.
Sexual potency declines with age, as does the efficiency of erection. Many studies show that different patterns of erectile dysfunction (ED), varying from occasional inability to obtain a full erection, impairment throughout intercourse and total absence of erectile response, might not be triggered by psychological factors only. Recent research indicates that ED relies on organic causes, and has challenged the development of new therapies. One therapeutic approach in patients who have testosterone deficiency is based on androgen therapy. Thus, we reviewed data on testosterone-induced effects relative to erectile function, summarizing the results from studies reported in 1991-2006 on testosterone therapy in patients with ED and hypogonadism, with a special focus on men not responding to phosphodiesterase-5 (PDE-5) inhibitors. We searched several computerized databases parallel with printed bibliographic references. Many studies have established animal models, which confirm that testosterone is important in modulating the central and peripheral regulation of ED. Testosterone deprivation has a strong negative impact on the structure of penile tissues and erectile nerves, which can be prevented by androgen administration. Combined therapy regimens with PDE-5 inhibitors and testosterone might improve ED in patients with hypogonadism of different causes. Thus, androgen treatment in hypogonadic patients, including those unresponsive to PDE-5 inhibitors, often results in an improvement of ED. Testosterone therapy is safe and convenient, while rapidly correcting low testosterone levels.


Interplay of viral and cellular proteins along the long control region of human papillomavirus type 18.
The long control region of human genital papillomavirus type 18 harbors transcription regulatory elements, such as the E6 promoter and a cell type-specific enhancer independent of the E2 protein. By performing DNase I footprint experiments in vitro with protein extracts from different cell lines and tissues we searched for cellular factors interacting with the totality of the control region. We detected a total of eight different protected sites; most of them were found with all the extracts. Two of these sites, one in the enhancer and the other in the sequences proximal to the E6 cap site, interact with a member of the activator protein 1 family. However, in the absence of fine mutational analysis, we cannot readily discern an exact functional role for the different binding sites. We also characterized two regions, which are protected only in the presence of E2, corresponding to the perfect palindromes ACCGN4CGGT and present either 500 nucleotides or tandemly repeated about 70 nucleotides upstream of the E6 cap site. This last protected area covers a large part of the putative TATA box of the E6 promoter and could explain its repression by bovine papilloma virus type 1 E2, which could interfere with binding of the TFII D ubiquitous transcription factor to the TATA sequence of the promoter.


The role of connexin 37 polymorphism in spontaneous abortion.
Among unique cardiovascular risk factors in women are complications during pregnancy, including miscarriage. Important risk factor is also genetic background. One of powerful candidate genes for cardiovascular disease of atherosclerotic origin (aCVD) is gene for connexin 37 (Cx37) with strong gene-environment interaction including smoking status, that is also strong risk factor for complications in pregnancy including spontaneous abortion (SA). We analyzed association between SA and Cx37 gene polymorphism (1019C>T; Pro319Ser) in 547 fetuses and its potential interaction with smoking status of mothers. Using genetic analyses from women from general population as controls, ORs for T allele, found in our previous studies to be protective against aCVD, were calculated. T allele carriers (fetuses), had OR 0.91 (95 % CI 0.72-1.14) and no interaction with smoking was observed. In conclusion, no significant association between Cx37 polymorphism and SA was observed and no modifying effect of smoking status on this association was detected.


Conivaptan: a step forward in the treatment of hyponatremia?
Hyponatremia is one of the most common electrolyte abnormalities linked to adverse outcomes and increased mortality in hospitalized patients. While the differential diagnosis for hyponatremia is diverse, most cases stem from arginine vasopressin (AVP) dysregulation, where hypoosmolality fails to suppress AVP synthesis and release. The physiological effects of AVP are currently known to depend on its interaction with any of 3 receptor subtypes V1A, V2, and V1B. Activation of V2 by AVP is the key in renal water regulation and maintenance of total body volume and plasma tonicity. Despite the long-recognized problem with excess AVP in euvolemic and hypervolemic hyponatremia, traditional therapeutic options have relied on nonspecific and potentially problematic strategies. More recently, a new class of drugs, introduced as "aquaretics," has gained great attention among clinicians because of its ability to correct hyponatremia via direct competitive inhibition of AVP at V2 receptors to induce renal electrolyte-free water excretion. In this paper, we aim to review available clinical data on the only FDA-approved aquaretic, dual V1A/V2 receptor antagonist conivaptan, discuss its clinical indications, efficacy, safety profile, and comment on its clinical limitations.


Spatially-explicit estimation of geographical representation in large-scale species distribution datasets.
Much ecological research relies on existing multispecies distribution datasets. Such datasets, however, can vary considerably in quality, extent, resolution or taxonomic coverage. We provide a framework for a spatially-explicit evaluation of geographical representation within large-scale species distribution datasets, using the comparison of an occurrence atlas with a range atlas dataset as a working example. Specifically, we compared occurrence maps for 3773 taxa from the widely-used Atlas Florae Europaeae (AFE) with digitised range maps for 2049 taxa of the lesser-known Atlas of North European Vascular Plants. We calculated the level of agreement at a 50-km spatial resolution using average latitudinal and longitudinal species range, and area of occupancy. Agreement in species distribution was calculated and mapped using Jaccard similarity index and a reduced major axis (RMA) regression analysis of species richness between the entire atlases (5221 taxa in total) and between co-occurring species (601 taxa). We found no difference in distribution ranges or in the area of occupancy frequency distribution, indicating that atlases were sufficiently overlapping for a valid comparison. The similarity index map showed high levels of agreement for central, western, and northern Europe. The RMA regression confirmed that geographical representation of AFE was low in areas with a sparse data recording history (e.g., Russia, Belarus and the Ukraine). For co-occurring species in south-eastern Europe, however, the Atlas of North European Vascular Plants showed remarkably higher richness estimations. Geographical representation of atlas data can be much more heterogeneous than often assumed. Level of agreement between datasets can be used to evaluate geographical representation within datasets. Merging atlases into a single dataset is worthwhile in spite of methodological differences, and helps to fill gaps in our knowledge of species distribution ranges. Species distribution dataset mergers, such as the one exemplified here, can serve as a baseline towards comprehensive species distribution datasets.


Head-to-head comparison of two loop-mediated isothermal amplification (LAMP) kits for diagnosis of malaria in a non-endemic setting.
Light microscopy and rapid diagnostic tests (RDT) have long been the recommended diagnostic methods for malaria. However, in recent years, loop-mediated isothermal amplification (LAMP) techniques have been shown to offer superior performance, in particular concerning low-grade parasitaemia, by delivering higher sensitivity and specificity with low laboratory capacity requirements in little more than an hour. In this study, the diagnostic performance of two LAMP kits were assessed head-to-head, compared to highly sensitive quantitative real time PCR (qPCR), in a non-endemic setting. In this retrospective validation study two LAMP kits; Alethia® Illumigene Malaria kit and HumaTurb Loopamp™ Malaria Pan Detection (PDT) kit, were evaluated head-to-head for detection of Plasmodium-DNA in 133 biobanked blood samples from suspected malaria cases at the Clinical Microbiology Laboratory of Region Skåne, Sweden to determine their diagnostic performance compared to qPCR. Of the 133 samples tested, qPCR detected Plasmodium DNA in 41 samples (defined as true positives), and the two LAMP methods detected 41 and 37 of those, respectively. The results from the HumaTurb Loopamp™ Malaria PDT kit were in complete congruence with the qPCR, with a sensitivity of 100% (95% CI 91.40-100%) and specificity of 100% (95% CI 96.07-100%). The Alethia® Illumigene Malaria kit had a sensitivity of 90.24% (95% CI 76.87-97.28) and a specificity of 95.65% (95% CI 89.24-98.80) as compared to qPCR. This head-to-head comparison showed higher performance indicators of the HumaTurb Loopamp™ Malaria PDT kit compared to the Alethia® illumigene Malaria kit for detection of malaria.


Antiandrogen or estradiol treatment or both during hormone therapy in transitioning transgender women.
Gender dysphoria is described as a mismatch between an individual's experienced or expressed gender and their assigned gender, based on primary or secondary sexual characteristics. Gender dysphoria can be associated with clinically significant psychological distress and may result in a desire to change sexual characteristics. The process of adapting a person's sexual characteristics to their desired sex is called 'transition.' Current guidelines suggest hormonal and, if needed, surgical intervention to aid transition in transgender women, i.e. persons who aim to transition from male to female. In adults, hormone therapy aims to reverse the body's male attributes and to support the development of female attributes. It usually includes estradiol, antiandrogens, or a combination of both. Many individuals first receive hormone therapy alone, without surgical interventions. However, this is not always sufficient to change such attributes as facial bone structure, breasts, and genitalia, as desired. For these transgender women, surgery may then be used to support transition. We aimed to assess the efficacy and safety of hormone therapy with antiandrogens, estradiol, or both, compared to each other or placebo, in transgender women in transition. We searched MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Biosis Preview, PsycINFO, and PSYNDEX. We carried out our final searches on 19 December 2019. We aimed to include randomised controlled trials (RCTs), quasi-RCTs, and cohort studies that enrolled transgender women, age 16 years and over, in transition from male to female. Eligible studies investigated antiandrogen and estradiol hormone therapies alone or in combination, in comparison to another form of the active intervention, or placebo control. We used standard methodological procedures expected by Cochrane to establish study eligibility. Our database searches identified 1057 references, and after removing duplicates we screened 787 of these. We checked 13 studies for eligibility at the full text screening stage. We excluded 12 studies and identified one as an ongoing study. We did not identify any completed studies that met our inclusion criteria. The single ongoing study is an RCT conducted in Thailand, comparing estradiol valerate plus cyproterone treatment with estradiol valerate plus spironolactone treatment. The primary outcome will be testosterone level at three month follow-up. We found insufficient evidence to determine the efficacy or safety of hormonal treatment approaches for transgender women in transition. This lack of studies shows a gap between current clinical practice and clinical research. Robust RCTs and controlled cohort studies are needed to assess the benefits and harms of hormone therapy (used alone or in combination) for transgender women in transition. Studies should specifically focus on short-, medium-, and long-term adverse effects, quality of life, and participant satisfaction with the change in male to female body characteristics of antiandrogen and estradiol therapy alone, and in combination. They should also focus on the relative effects of these hormones when administered orally, transdermally, and intramuscularly. We will include non-controlled cohort studies in the next iteration of this review, as our review has shown that such studies provide the highest quality evidence currently available in the field. We will take into account methodological limitations when doing so.


Statistical correlations between two-dimensional images and three-dimensional structures in natural scenes.
In spite of the recent surge in the popularity of statistical approaches to vision, the joint statistics of coregistered range and light-intensity images have gone relatively unexplored. We investigate statistical correlations between images and the surface shapes that produced them. We determine which linear properties of range images can be best predicted from simple computations on intensity information, and we determine those properties of intensity images that best predict range information. We find that significant (up to p = 0.45) and potentially exploitable correlations exist between linear properties of range and intensity images, and we explore the structure of these correlations.


Cerebrovascular events after transcatheter mitral valve interventions: a systematic review and meta-analysis.
Current guidelines support the use of transcatheter mitral valve interventions to treat some selected high-risk patients with significant mitral valvulopathy. As with any other interventional cardiac procedure, concerns have been raised about cerebrovascular event. The aim of this systematic review and meta-analysis was to determine the incidence of cerebrovascular events following (1) transcatheter mitral valve edge-to-edge repair with mitral valve clip and (2) transcatheter mitral valve replacement (TMVR). We conducted a systematic review of studies reporting the cerebrovascular adverse events after transcatheter mitral valve edge-to-edge repair and TMVR procedures. The primary endpoint was the incidence of cerebrovascular events as defined by the Mitral Valve Academic Research Consortium. An event that occurred within 30 days or during index hospitalisation was defined as periprocedural; otherwise it was defined as non-periprocedural. This study was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Aggregated study-level data were pooled using a random effect model. The quality of each study was appraised with the Hawker checklist, a method of systematically reviewing research from different paradigms. Sixty studies totalling 28 155 patients undergoing edge-to-edge repair with mitral valve clip were included in the analysis. Periprocedural stroke and non-periprocedural stroke rates were 0.9% (95% CI 0.6 to 1.1) and 2.4% (95% CI 1.6 to 3.2), respectively. For TMVR procedures, 26 studies including 1910 patients were analysed. The estimated periprocedural stroke incidence was 1% (95% CI 0.5 to 1.8) compared with 7% (95% CI 0.8 to 18.5) for non-periprocedural stroke. Transcatheter mitral valve interventions are associated with low rates of cerebrovascular events. The exact mechanisms of these complications are still poorly understood given the relative paucity of good quality data. CRD42019117257.


Dementia associated with periventricular and deep white matter alterations: a subtype of subcortical dementia.
This research examined the neuropsychological functioning of demented patients with periventricular and deep white matter alterations. Thirty-three outpatients with NINCDS-ADRDA probable Alzheimer's disease (AD) and 27 outpatients with probable/ possible ischaemic vascular dementia (IVD, Chui et al., 1992) associated with periventricular and deep white matter alterations matched for age, education, level of dementia, and functional disability were studied. White matter alterations were measured using a 40-point scale previously described by Junque et al. (1990). Subjects with cortical CVAs were excluded. On executive control tests, IVD subjects made more preservations on tests of mental control and response set, and produced fewer responses on phonemic controlled oral word association tests (letters: F,A,S). IVD subjects also made more preservations and graphomotor errors on clock drawings. On the California Verbal Learning Test the IVD group performed better than AD subjects on the short delay free recall test condition, the recognition discriminability index, and made fewer intrusion errors on both free and cued recall conditions. We conclude that neuropsychological assessment can differentiate AD from IVD associated with white matter alterations, and that the neuropsychological profile of demented subjects with significant periventricular and deep white matter alterations is similar to other subcortical dementing illnesses.


Whole Genome Sequencing of Field Isolates Reveals Extensive Genetic Diversity in Plasmodium vivax from Colombia.
Plasmodium vivax is the most prevalent malarial species in South America and exerts a substantial burden on the populations it affects. The control and eventual elimination of P. vivax are global health priorities. Genomic research contributes to this objective by improving our understanding of the biology of P. vivax and through the development of new genetic markers that can be used to monitor efforts to reduce malaria transmission. Here we analyze whole-genome data from eight field samples from a region in Cordóba, Colombia where malaria is endemic. We find considerable genetic diversity within this population, a result that contrasts with earlier studies suggesting that P. vivax had limited diversity in the Americas. We also identify a selective sweep around a substitution known to confer resistance to sulphadoxine-pyrimethamine (SP). This is the first observation of a selective sweep for SP resistance in this species. These results indicate that P. vivax has been exposed to SP pressure even when the drug is not in use as a first line treatment for patients afflicted by this parasite. We identify multiple non-synonymous substitutions in three other genes known to be involved with drug resistance in Plasmodium species. Finally, we found extensive microsatellite polymorphisms. Using this information we developed 18 polymorphic and easy to score microsatellite loci that can be used in epidemiological investigations in South America.


Human cartilage stiffness. In vivo studies.
Integrated structural properties of cartilage, the combined structural behavior of a material (which accounts for both of its elastic properties and geometry) were measured in 25 autopsies and 35 open operations. The intraoperative measurements were made at the time of total knee arthroplasties, synovectomies, amputations, and traumatic lesions of the knee. The results obtained through evaluation of force deformation curves have been computer analyzed. There were no statistically significant differences between the stiffness of autopsy cartilage and in vivo cartilage as obtained through measurements at surgery. There was significant age dependence of stiffness of joint cartilage. Stiffness of intraoperative as of autopsy cartilage, depends on the thickness of the material tested.


Treatment of chronic myelogenous leukemia in accelerated and blastic phases with daunorubicin, high-dose cytarabine, and granulocyte-macrophage colony-stimulating factor.
The study was undertaken to improve the results of intensive chemotherapy in chronic myelogenous leukemia (CML) in accelerated (CML-AP) and blastic phases (CML-BP) by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) as supportive therapy. Forty-eight patients were treated with daunorubicin 120 mg/m2 intravenously on day 1, cytarabine (ara-C) 1.5 g/m2/d by continuous infusion over 24 hours for 4 days, and Solu-Medrol (methylprednisolone; The Upjohn Co, Kalamazoo, MI) 100 mg/d for 5 days, followed on day 5 by GM-CSF 125 micrograms/m2/d over 6 hours until recovery of granulocyte count above 2.0 x 10(3)/microliters. Twenty-four patients had CML-BP, and 24 had CML-AP. During remission induction, 45 patients (94%) developed febrile episodes (fever of unknown origin, 23 patients [48%]; documented infections, 22 patients [46%]). The median time to recovery of granulocyte count above 0.5 x 10(3)/microliters was 29 days and to platelet count above 30 x 10(3)/microliters, 28 days. Overall, 14 of 48 patients (29%) achieved a complete hematologic remission (CHR), and seven (15%) reverted to a second chronic phase. CHR was noted in eight of 24 patients with CML-BP (33%), and in six of 24 patients with CML-AP (25%). Cytogenetic responses were observed in 11 patients (23%), but were transient. Sixteen patients developed either fluid retention, hypotension, pleuropericardial effusions, or pericarditis, or a combination of these side effects. These side effects were severe in four patients and are likely to be disease-associated, as a similar regimen of intensive chemotherapy and GM-CSF at the same dose and schedule in acute lymphocytic leukemia was not associated with these side effects. The results pertinent to remission rates, induction mortality, myelosuppression profile and related complications, and overall survival were not significantly improved compared with previous experience. In summary, the results of intensive chemotherapy in CML-transformed phases remain poor, despite the addition of GM-CSF as a supportive measure.