Current therapy of the failing heart.
Myocardial dysfunction eventuating in systolic and diastolic pump function abnormalities is a consequence of a wide variety of cardiac diseases. The symptoms that develop in this syndrome appear to be related as much to peripheral and neurohormonal mechanisms as to the underlying pathological and cardiac functional abnormality. Relief of symptoms, slowing of the progression of the cardiac functional abnormality, and prolongation of life provide the major agenda for the physician faced with the management of these patients. Judicious use of vasodilators, diuretics, digoxin, dietary therapy, and exercise therapy can relieve symptoms and improve the quality of life in most patients suffering from this syndrome. Recent evidence that vasodilator drugs can prolong life now provides the physician with further justification for routine use of this class of compounds. The eventual solution to the high mortality in this common disease process may be prevention of the development of overt heart failure by more prompt recognition and early treatment of the signs of ventricular dysfunction. This possibility must await the completion of current and proposed clinical trials.


The role of noninvasive methods in assessing airway inflammation and structural changes in asthma and COPD.
The aim of our study was to assess the role of non-invasive methods in assessing airway inflammation and structural changes in asthma and COPD. The study was conducted on patients attending outpatient and inpatient department of TB and Chest Diseases and Department of Pathology at our hospital from January 2006 to August 2007. 50 asthmatic and 46 COPD patients were selected. A detailed history and clinical examination, routine laboratory investigations, pulmonary function testing, Chest X-ray PA and lateral view, HRCT Thorax, biochemical and cellular analysis of sputum was carried out in all cases. Quality control and procedures of pulmomary function test were performed according to the European Respiratory Society guidelines. Bronchial wall thickening, bronchiectasis and air trapping correlated well with disease severity in asthmatics while all abnormal HRCT finding correlate well with disease severity in COPD patients. The levels of MMP-9 and TIMP-1 increased significantly with increasing disease severity in both asthmatic and COPD groups. The MMP-9/TIMP-1 ratio decreased with increasing disease severity in both groups. The major source of MMP-9 in human lungs is macrophages, neutrophils and eosinophils. Macrophages and neutrophils were also the source of TIMP-1. Asthma and COPD are characterised by an imbalance between MMP-9 and TIMP-1. COPD patients showed a higher prevalence of HRCT findings which correlate with their lower MMP-1/TIMP-1 ratio than asthmatics supporting fact that the destruction and fibrosis of alveolar walls are more prominent in COPD. MMP-9/TIMP-1 ratio is associated with magnitude of HRCT findings in asthma and COPD and suggests that level of these markers reflect the extent of structural changes of airway.


Rapid-scan acousto-optical delay line with 34 kHz scan rate and 15 as precision.
An optical fast scan delay exploiting the near-collinear interaction between a train of ultrashort optical pulses and an acoustic wave propagating in a birefringent crystal is introduced. In combination with a femtosecond Er:fiber laser, the scheme is shown to delay few femtosecond pulses by up to 6 ps with a precision of 15 as. A resolution of 5 fs is obtained for a single sweep at a repetition rate of 34 kHz. This value can be improved to 39 as for multiple scans at a total rate of 0.3 kHz.


Psychosocial adjustment of poor Mexican mothers of disabled and nondisabled children.
A comparison of 50 low-income Mexican mothers, 38 of whom had disabled and 22 nondisabled children, found significant differences in the areas of social support, child adjustment, perceived stress, and family functioning. Study findings point up the need for community-based education and support services.


Early results of the "clamp and sew" Fontan procedure without the use of circulatory support.
A modification of the Fontan operation was recently applied, which includes anastomoses of the extracardiac conduit to the right pulmonary artery and inferior vena cava using simple clamping with no additional circulatory support, venous shunting, pulmonary artery preparation, or prior maintenance of azygos vein patency. The objective of this study is to assess the outcomes of this novel off-pump "clamp and sew" Fontan procedure. This is a retrospective review of all patients having a Fontan procedure between January 2009 and October 2010 at a single institution. Twelve patients had a Fontan procedure with the use of cardiopulmonary bypass (CPB group), and 12 had an off-pump Fontan procedure (off-pump group). Preoperative demographic and hemodynamic data were similar except for higher mean pulmonary artery pressure in the CPB group (12.2±1.6 mm Hg versus 9.9±2.4 mm Hg; p=0.02). No patients in the off-pump group required conversion to CPB. The mean inferior vena cava clamp time in the off-pump group patients was 10±3 minutes. There were no early or midterm deaths. No patients exhibited postoperative hepatic or renal dysfunction. Postoperative maximal serum creatinine and aspartate transaminase were significantly lower in the off-pump group compared with the CPB group (0.59±0.12 versus 0.77±0.22 mg/dL; p=0.03 and 35.5±8.3 versus 53.1±19.0 U/L; p=0.02, respectively). At median follow-up of 13 months (range, 1 to 20 months), all but 1 patient in the CPB group are in New York Heart Association class I with unobstructed Fontan circulation. The clamp and sew technique for completion of an extracardiac conduit Fontan procedure appears safe and feasible for selected patients.


"Spinning Their Wheels … "-Influences That Shape How Nurse Educators Teach Social Justice.
Despite institutional claims that social justice is a core professional nursing value, efforts to fulfill this claim remain uneven. The purpose of this study was to examine the circumstances that shape nursing educators' approaches to social justice. In-depth semi-structured interviews with 28 educators teaching theory courses in baccalaureate nursing programs shed light upon the influences that shape how educators integrate social justice. These include formative experiences, institutional factors, and curricular opportunities. Formative experiences include upbringing, educational background, and preparation to teach. Institutional factors consist of the type of institution, geographic location, and the specter of retention, promotion, and tenure. Finally, curricular opportunities and fit include the positioning of Community Health Nursing, fragmentation and tension between "content and context," and the "driving force" of the National Council Licensure Examination for Registered Nurses (NCLEX). Findings indicate that the capacity to uphold the value of social justice is shaped by experiences across the lifespan, institutional policies, and practices related to faculty hiring, development, career advancement, as well as curricular vision. This study calls for a concerted effort to enact social justice nursing education.


Toward the fourth dimension of membrane protein structure: insight into dynamics from spin-labeling EPR spectroscopy.
Trapping membrane proteins in the confines of a crystal lattice obscures dynamic modes essential for interconversion between multiple conformations in the functional cycle. Moreover, lattice forces could conspire with detergent solubilization to stabilize a minor conformer in an ensemble thus confounding mechanistic interpretation. Spin labeling in conjunction with electron paramagnetic resonance (EPR) spectroscopy offers an exquisite window into membrane protein dynamics in the native-like environment of a lipid bilayer. Systematic application of spin labeling and EPR identifies sequence-specific secondary structures, defines their topology and their packing in the tertiary fold. Long range distance measurements (60 Å-80 Å) between pairs of spin labels enable quantitative analysis of equilibrium dynamics and triggered conformational changes. This review highlights the contribution of spin labeling to bridging structure and mechanism. Efforts to develop methods for determining structures from EPR restraints and to increase sensitivity and throughput promise to expand spin labeling applications in membrane protein structural biology.


NOD2: Activation During Bacterial and Viral Infections, Polymorphisms and Potential as Therapeutic Target.
Nucleotide-binding domain (NBD) leucine-rich repeat (LRR)-containing receptors or NLRs are a family of receptors that detect both, molecules associated to pathogens and alarmins, and are located mainly in the cytoplasm. NOD2 belongs to the NLR family and is a dynamic receptor capable of interacting with multiple proteins and modulate immune responses in a stimuli-dependent manner. The experimental evidence shows that interaction between NOD2 structural domains and the effector proteins shape the overall response against bacterial or viral infections. Other reports have focused on the importance of NOD2 not only in infection but also in maintaining tissue homeostasis. However, not only protein interactions relate to function but also certain polymorphisms in the gene that encodes NOD2 have been associated with inflammatory diseases, such as Crohn's disease. Here, we review the importance and general characteristics of NOD2, discussing its participation in infections caused by bacteria and viruses as well as its interaction with other pathogen recognition receptors or effectors to induce antibacterial and antiviral responses. Finally, the role of NOD2 in chronic inflammatory conditions and its potential to be targeted therapeutically are examined.


Opioid-Related Outcomes in West Virginia, 2008-2016.
To examine opioid-related outcomes by using hospitalization and mortality data as an indicator of the current opioid crisis in West Virginia. We used data from the West Virginia University Medicine health care system to examine the trend in opioid overdoses and percentage of patients with a repeat overdose from 2008 to 2016. We obtained the opioid overdose death rate for the state from Centers for Disease Control and Prevention WONDER (Wide-ranging ONline Data for Epidemiologic Research) mortality data for 2008 to 2016. The hospitalization rate for opioid overdoses increased (13%) on average each year in a similar fashion to the opioid overdose death rate for the state (12%) between 2008 and 2016. During the same time, the percentage of patients with a repeat opioid overdose increased annually by 13% on average. There continues to be a surge of opioid overdoses in West Virginia. These findings suggest a need to amplify comprehensive prevention and treatment efforts throughout the state. Public health initiatives to reduce the morbidity and mortality associated with overdoses should consider how the changes in potency may be influencing these outcomes.


Complications of mechanical thrombectomy for acute ischemic stroke: Incidence, risk factors, and clinical relevance in the Italian Registry of Endovascular Treatment in acute stroke.
There are limited data concerning procedure-related complications of endovascular thrombectomy for large vessel occlusion strokes. We evaluated the cumulative incidence, the clinical relevance in terms of increased disability and mortality, and risk factors for complications. From January 2011 to December 2017, 4799 patients were enrolled by 36 centers in the Italian Registry of Endovascular Stroke Treatment. Data on demographic and procedural characteristics, complications, and clinical outcome at three months were prospectively collected. The complications cumulative incidence was 201 per 1000 patients undergoing endovascular thrombectomy. Ongoing antiplatelet therapy (p < 0.01; OR 1.82, 95% CI: 1.21-2.73) and large vessel occlusion site (carotid-T, p < 0.03; OR 3.05, 95% CI: 1.13-8.19; M2-segment-MCA, p < 0.01; OR 4.54, 95% CI: 1.66-12.44) were associated with a higher risk of subarachnoid hemorrhage/arterial perforation. Thrombectomy alone (p < 0.01; OR 0.50, 95% CI: 0.31-0.83) and younger age (p < 0.04; OR 0.98, 95% CI: 0.97-0.99) revealed a lower risk of developing dissection. M2-segment-MCA occlusion (p < 0.01; OR 0.35, 95% CI: 0.19-0.64) and hypertension (p < 0.04; OR 0.77, 95% CI: 0.6-0.98) were less related to clot embolization. Higher NIHSS at onset (p < 0.01; OR 1.04, 95% CI: 1.02-1.06), longer groin-to-reperfusion time (p < 0.01; OR 1.05, 95% CI: 1.02-1.07), diabetes (p < 0.01; OR 1.67, 95% CI: 1.25-2.23), and LVO site (carotid-T, p < 0.01; OR 1.96, 95% CI: 1.26-3.05; M2-segment-MCA, p < 0.02; OR 1.62, 95% CI: 1.08-2.42) were associated with a higher risk of developing symptomatic intracerebral hemorrhage compared to no/asymptomatic intracerebral hemorrhage. The subgroup of patients treated with thrombectomy alone presented a lower risk of symptomatic intracerebral hemorrhage (p < 0.01; OR 0.70; 95% CI: 0.55-0.90). Subarachnoid hemorrhage/arterial perforation and symptomatic intracerebral hemorrhage after endovascular thrombectomy worsen both functional independence and mortality at three-month follow-up (p < 0.01). Distal embolization is associated with neurological deterioration (p < 0.01), while arterial dissection did not affect clinical outcome at follow-up. Complications globally considered are not uncommon and may result in poor clinical outcome. Early recognition of risk factors might help to prevent complications and manage them appropriately in order to maximize endovascular thrombectomy benefits.


Dopamine agonists in the treatment of Parkinson's disease.
Clinical responses to bromocriptine and three new ergoline derivatives, CM 29-712, CQ 32-084, and CU 32-085, in the treatment of Parkinson's disease were studied in new, non-levodopa-treated parkinsonian patients. All compounds elicited a significant but mostly only mild or moderate antiparkinsonian efficacy which seems to be less than that of levodopa. The therapeutic profile of the dopaminergic agonists studied was similar, and the improvement in tremor was considerably better than that in rigidity and hypokinesia. All of the compounds elicited clinical side effects typical of dopaminergic agonists but differed both quantitatively and qualitatively in certain respects. Fewer side effects, especially reduced blood pressure or the occurrence of postural hypotension, developed during treatment with CU 32-085. It is evident that more effective, specific, and tolerable dopaminergic agonists are needed before they can be considered a primary treatment of Parkinson's disease. At present, the main indications for dopaminergic agonists seem to be a deteriorating response to levodopa and daily fluctuations in performance.


Sibling influences on gender development in middle childhood and early adolescence: a longitudinal study.
The development of gender role qualities (attitudes, personality, leisure activities) from middle childhood to early adolescence was studied to determine whether siblings' gender role qualities predicted those of their sisters and brothers. Participants were 198 firstborn and second-born siblings (Ms = 10 years 9 months and 8 years 3 months, respectively, in Year 1) and their parents. Families were interviewed annually for 3 years. Firstborn siblings' qualities in Year 1 predicted second-born children's qualities in Year 3 when both parent and child qualities in Year 1 were controlled, a pattern consistent with a social learning model of sibling influence. Parental influence was more evident and sibling influence less evident in predicting firstborns' qualities; for firstborns, sibling influences suggested a de-identification process.


Prevention of Legionnaires' disease in hospitals.
The first instance of Legionella infection in a Norwegian hospital was confirmed in 2005. We describe the best-known methods of eradicating Legionella in hospitals. The article is based on the authors' experience of measures to prevent Legionnaires' disease in hospitals and on a non-systematic search in PubMed. There are several methods of combating Legionella in hospitals. These include chlorination, heat treatment, and the use of filters. However, recontamination easily re-occurs after eradication. The silver and copper ionisation treatment of water is a well-documented method for the systematic and long-term eradication of Legionella in water. The disadvantages of this method are that it is expensive, that there is a risk of discolouring the water, and that there is a possibility of developing resistance in environmental bacteria. This resistance mechanism can theoretically be transferred to bacteria that cause illness. We recommend the silver and copper ionisation treatment of water as a method of preventing nosocomial Legionnaires' disease when standard methods fail and there is a high prevalence of Legionella in the water. The discolouration of operation instruments that occurs as a result of high silver concentrations can be avoided by using a separate water supply for operation units.


Tissue Engineering of Axially Vascularized Soft-Tissue Flaps with a Poly-(ɛ-Caprolactone) Nanofiber-Hydrogel Composite.
Objective: To develop a novel approach for tissue engineering of soft-tissue flaps suitable for free microsurgical transfer, using an injectable nanofiber hydrogel composite (NHC) vascularized by an arteriovenous (AV) loop. Approach: A rat AV loop model was used for tissue engineering of vascularized soft-tissue flaps. NHC or collagen-elastin (CE) scaffolds were implanted into isolation chambers together with an AV loop and explanted after 15 days. Saphenous veins were implanted into the scaffolds as controls. Neoangiogenesis, ultrastructure, and protein expression of SYNJ2BP, EPHA2, and FOXC1 were analyzed by immunohistochemistry and compared between the groups. Rheological properties were compared between the two scaffolds and native human adipose tissue. Results: A functional neovascularization was evident in NHC flaps with its amount being comparable with CE flaps. Scanning electron microscopy revealed a strong mononuclear cell infiltration along the nanofibers in NHC flaps and a trend toward higher fiber alignment compared with CE flaps. SYNJ2BP and EPHA2 expression in endothelial cells (ECs) was lower in NHC flaps compared with CE flaps, whereas FOXC1 expression was increased in NHC flaps. Compared with the stiffer CE flaps, the NHC flaps showed similar rheological properties to native human adipose tissue. Innovation: This is the first study to demonstrate the feasibility of tissue engineering of soft-tissue flaps with similar rheological properties as human fat, suitable for microsurgical transfer using an injectable nanofiber hydrogel composite. Conclusions: The injectable NHC scaffold is suitable for tissue engineering of axially vascularized soft-tissue flaps with a solid neovascularization, strong cellular infiltration, and biomechanical properties similar to human fat. Our data indicate that SYNJ2BP, EPHA2, and FOXC1 are involved in AV loop-associated angiogenesis and that the scaffold material has an impact on protein expression in ECs.


Acidic and basic hair/nail ("hard") keratins: their colocalization in upper cortical and cuticle cells of the human hair follicle and their relationship to "soft" keratins.
Although numerous hair proteins have been studied biochemically and many have been sequenced, relatively little is known about their in situ distribution and differential expression in the hair follicle. To study this problem, we have prepared several mouse monoclonal antibodies that recognize different classes of human hair proteins. Our AE14 antibody recognizes a group of 10-25K hair proteins which most likely corresponds to the high sulfur proteins, our AE12 and AE13 antibodies define a doublet of 44K/46K proteins which are relatively acidic and correspond to the type I low sulfur keratins, and our previously described AE3 antibody recognizes a triplet of 56K/59K/60K proteins which are relatively basic and correspond to the type II low sulfur keratins. Using these and other immunological probes, we demonstrate the following. The acidic 44K/46K and basic 56-60K hair keratins appear coordinately in upper corticle and cuticle cells. The 10-25K, AE14-reactive antigens are expressed only later in more matured corticle cells that are in the upper elongation zone, but these antigens are absent from cuticle cells. The 10-nm filaments of the inner root sheath cells fail to react with any of our monoclonal antibodies and are therefore immunologically distinguishable from the cortex and cuticle filaments. Nail plate contains 10-20% soft keratins in addition to large amounts of hair keratins; these soft keratins have been identified as the 50K/58K and 48K/56K keratin pairs. Taken together, these results suggest that the precursor cells of hair cortex and nail plate share a major pathway of epithelial differentiation, and that the acidic 44K/46K and basic 56-60K hard keratins represent a co-expressed keratin pair which can serve as a marker for hair/nail-type epithelial differentiation.


Independent regulation of M-CSF and G-CSF gene expression in human monocytes.
The macrophage and granulocyte colony-stimulating factors, M-CSF and G-CSF, act in vitro to induce proliferation and differentiation of monocyte and granulocyte progenitor cells, respectively. We show here that both of these CSFs can be produced by stimulated human blood monocytes, but the M-CSF and G-CSF genes are independently regulated. Recombinant human interleukin-3 (IL-3) and GM-CSF primarily induce expression of the M-CSF gene and secretion of M-CSF, whereas bacterial lipopolysaccharide primarily induces expression of the G-CSF gene and secretion of G-CSF. These results suggest that under different conditions of in vitro stimulation the monocyte secretes factors that could lead selectively to either granulocyte or monocyte production.


A new anatomical insight into the aetiology of lateral trunk of suprascapular nerve neuropathy: isolated infraspinatus atrophy.
Although the pathomechanism of isolated infraspinatus atrophy (ISA) in throwing sports is known to be traction, it is unclear why only some players are affected. One likely explanation is that the infraspinatus pulling force exerted by its contracture generate the compressive resultant component force (Fn) compressing the lateral trunk of the suprascapular nerve (LTSN) against the edge of scapular spine. This paper makes two key assumptions (1) the course of LTSN in relation to the scapular spine, defined as the suprascapular-scapular spine angle (SSSA) is the key individual anatomical feature influencing the Fn magnitude, and thus potentially ISA development (2) SSSA is correlated with scapular notch type. The bone landmarks of the LTSN course were identified in 18 formalin-fixed cadaveric shoulders, and the SSSA was measured in 101 dry scapulae. The correlation between the SSSA and suprascapular notch type was evaluated. The Fn value was simulated mathematically based on the values of the SSSA of 101 dry scapulae and the prevalence of ISA in chosen throwing sports, as given in the literature: i.e., beach volleyball - 34% (group A1 - 34%; group A2-remaining 66% of scapulae) and tennis - 52% (group B1 - 52%; group B2-remaining 48% of scapulae). The mean SSSA value was 44.57° (± 7.9) and Fn 79 N (± 13.1). No statistically significant correlation was revealed between suprascapular notch type and SSSA. Groups A1 and B1 possessed significantly lower SSSA values (p < 0.000) and significantly higher Fn magnitude (p < 0.000) than groups A2 and B2 respectively. The average difference of Fn was 28.1% between group A1 and A2 and 31% between group B1 and B2. The SSSA has a wide range of values depending on the individual: the angle influencing the magnitude of the compressive resultant force Fn on the LTSN at the lateral edge of the scapular spine via contraction of the infraspinatus muscle. The prevalence of ISA in throwing sports may be correlated with the SSSA of the LTSN. However, further combined clinical, MRI or/and CT studies are needed to confirm this.


Limitations of high urgency listing--ventricular assist device support in a neonate for 452 days.
The Eurotransplant International Foundation in Leiden, the Netherlands, is responsible for mediation and allocation of organ donation procedures to its member countries Austria, Belgium, Croatia, Germany, Luxembourg, the Netherlands and Slovenia. To provide organs for the patients who require urgent transplantation, the "high urgent (HU)" status was introduced in 2001 in Germany . This new HU allocation system is applicable to neonates as well as adults. However, waiting times on HU status exceed several weeks to months. Therefore an increasing number of pediatric patients has to undergo implantation of a ventricular assist device (VAD). In the present report we discuss the current Eurotransplant heart allocation system for pediatric heart transplantation in the light of a neonate with 452 days on mechanical support. We compare the average waiting time of patients on HU status at our center and their outcome in 2007 and 2008 (Data obtained from Eurotransplant International Foundation). Waiting time on HU status in our center increased significantly from 2007 to 2008. Therefore more patients require VAD support as bridging to transplantation. The case of a neonate under long-term VAD support is an outstanding example of the negative effects of this development.


High-Performance Near-Infrared Photodetectors Based on p-Type SnX (X = S, Se) Nanowires Grown via Chemical Vapor Deposition.
Because of the distinct electronic properties and strong interaction with light, quasi-one-dimensional nanowires (NWs) with semiconducting property have been demonstrated with tremendous potential for various technological applications, especially electronics and optoelectronics. However, until now, most of the state-of-the-art NW photodetectors are predominantly based on the n-type NW channel. Here, we successfully synthesized p-type SnSe and SnS NWs via the chemical vapor deposition method and fabricated high-performance single SnSe and SnS NW photodetectors. Importantly, these two NW devices exhibit an impressive photodetection performance with a high photoconductive gain of 1.5 × 104 (2.8 × 104), good responsivity of 1.0 × 104 A W-1 (1.6 × 104 A W-1), and excellent detectivity of 3.3 × 1012 Jones (2.4 × 1012 Jones) under near-infrared illumination at a bias of 3 V for the SnSe NW (SnS NW) channel. The rise and fall times can be as efficient as 460 and 520 μs (1.2 and 15.1 ms), respectively, for the SnSe NW (SnS NW) device. Moreover, the spatially resolved photocurrent mapping of the devices further reveals the bias-dependent photocurrent generation. All these results evidently demonstrate that the p-type SnSe and SnS NWs have great potential to be applied in next-generation high-performance optoelectronic devices.


Overview of research progress and application of experimental models of colorectal cancer.
Colorectal cancer (CRC) is the third most common malignancy in terms of global tumor incidence, and the rates of morbidity and mortality due to CRC are rising. Experimental models of CRC play a vital role in CRC research. Clinical studies aimed at investigating the evolution and mechanism underlying the formation of CRC are based on cellular and animal models with broad applications. The present review classifies the different experimental models used in CRC research, and describes the characteristics and limitations of these models by comparing the research models with the clinical symptoms. The review also discusses the future prospects of developing new experimental models of CRC.


Management of NAFLD in primary care settings.
Non-alcoholic fatty liver disease (NAFLD) affects at least 25% of the general population and is an increasingly important cause of cirrhosis and hepatocellular carcinoma. Although it is the research focus of the hepatology field, it is clear that primary care physicians are seeing the majority of NAFLD patients and are in a pivotal position to provide quality care. In this article, we review the role of primary care in the management of NAFLD. NAFLD is common in patients with diabetes, obesity and other metabolic risk factors. Abdominal ultrasonography is the most commonly used method to diagnose fatty liver. Simple fibrosis scores have high negative predictive values in excluding advanced liver fibrosis and future liver-related events and can be used in primary care as initial evaluation. An abnormal result should be followed by subsequent workup or specialist referral. Primary care is the ideal setting to institute multidisciplinary care, especially the involvement of dietitians and physical activity trainers in lifestyle intervention, as well as initiating the discussion of bariatric surgery in patients with severe obesity. Although specific drug treatment for steatohepatitis would require a more precise diagnosis, metabolic drugs that improve both steatohepatitis and cardiovascular outcomes (e.g. glucagon-like peptide-1 receptor agonists) may be considered in patients with NAFLD.


HPV-Associated Benign Squamous Cell Papillomas in the Upper Aero-Digestive Tract and Their Malignant Potential.
Squamous cell papilloma (SCP) in the upper aero-digestive tract is a rare disease entity with bimodal age presentation both at childhood and in adults. It originates from stratified squamous and/or respiratory epithelium. Traditionally, SCPs have been linked to chemical or mechanical irritation but, since the 1980s, they have also been associated with human papillomavirus (HPV) infection. Approximately 30% of the head and neck SCPs are associated with HPV infection, with this association being highest for laryngeal papillomas (76-94%), followed by oral (27-48%), sinonasal (25-40%), and oropharyngeal papillomas (6-7%). There is, however, a wide variation in HPV prevalence, the highest being in esophageal SCPs (11-57%). HPV6 and HPV11 are the two main HPV genotypes present, but these are also high-risk HPVs as they are infrequently detected. Some 20% of the oral and oropharyngeal papillomas also contain cutaneous HPV genotypes. Despite their benign morphology, some SCPs tend to recur and even undergo malignant transformation. The highest malignant potential is associated with sinonasal inverted papillomas (7-11%). This review discusses the evidence regarding HPV etiology of benign SCPs in the upper aero-digestive tract and their HPV-related malignant transformation. In addition, studies on HPV exposure at an early age are discussed, as are the animal models shedding light on HPV transmission, viral latency, and its reactivation.


The Complex Transcriptional Landscape of Magnetosome Gene Clusters in Magnetospirillum gryphiswaldense.
Magnetosomes are complex membrane organelles synthesized by magnetotactic bacteria (MTB) for navigation in the Earth's magnetic field. In the alphaproteobacterium Magnetospirillum gryphiswaldense, all steps of magnetosome formation are tightly controlled by >30 specific genes arranged in several gene clusters. However, the transcriptional organization of the magnetosome gene clusters has remained poorly understood. Here, by applying Cappable-seq and whole-transcriptome shotgun RNA sequencing, we show that mamGFDCop and feoAB1op are transcribed as single transcriptional units, whereas multiple transcription start sites (TSS) are present in mms6op, mamXYop, and the long (>16 kb) mamABop. Using a bioluminescence reporter assay and promoter knockouts, we demonstrate that most of the identified TSS originate from biologically meaningful promoters which mediate production of multiple transcripts and are functionally relevant for proper magnetosome biosynthesis. In addition, we identified a strong promoter in a large intergenic region within mamXYop, which likely drives transcription of a noncoding RNA important for gene expression in this operon. In summary, our data suggest a more complex transcriptional architecture of the magnetosome operons than previously recognized, which is largely conserved in other magnetotactic Magnetospirillum species and, thus, is likely fundamental for magnetosome biosynthesis in these organisms. IMPORTANCE Magnetosomes have emerged as a model system to study prokaryotic organelles and a source of biocompatible magnetic nanoparticles for various biomedical applications. However, the lack of knowledge about the transcriptional organization of magnetosome gene clusters has severely impeded the engineering, manipulation, and transfer of this highly complex biosynthetic pathway into other organisms. Here, we provide a high-resolution image of the previously unappreciated transcriptional landscape of the magnetosome operons. Our findings are important for further unraveling the complex genetic framework of magnetosome biosynthesis. In addition, they will facilitate the rational reengineering of magnetic bacteria for improved bioproduction of tunable magnetic nanoparticles, as well as transplantation of magnetosome biosynthesis into foreign hosts by synthetic biology approaches. Overall, our study exemplifies how a genetically complex pathway is orchestrated at the transcriptional level to ensure the balanced expression of the numerous constituents required for the proper assembly of one of the most intricate prokaryotic organelles.


Myelin-oligodendrocyte glycoprotein antibody-associated disease.
Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.


Analysis of the inhibitors of apoptosis identifies BIRC3 as a facilitator of malignant progression in glioma.
Gliomas, the most common primary brain tumor in humans, include a spectrum of disease. High-grade gliomas (HGG), such as glioblastoma, may arise from low-grade gliomas (LGG) that have a more indolent course. The process of malignant transformation (MT) of LGG to HGG is poorly understood but likely involves the activation of signaling programs that suppress apoptosis. We previously showed that Survivin (BIRC5) plays a role in malignant progression of glioma. Here, we investigated the role of the remaining members of the Inhibitors of Apoptosis (IAP) family on promoting MT in glioma. Utilizing expression data from the cancer genome atlas (TCGA), we identified BIRC3 as a key facilitator of MT from LGG to HGG. TCGA HGGs with high expression of BIRC 3 demonstrated a survival disadvantage and expression levels of BIRC3 were also significantly higher in TCGA HGG compared to TCGA LGG cases. We validated our findings from TCGA by using matched human specimens to show that BIRC expression is increased in HGG compared to their precursor LGG lesions. Using a unique murine model of glioma, we show that overexpression of BIRC3 promotes higher grade glioma and significantly reduces tumor-free survival in mice.


Conducting a high-stakes OSCE in a COVID-19 environment.
This article was migrated. The article was marked as recommended. The COVID-19 pandemic has presented significant challenges for medical schools. It is critical to ensure final year medical school students are not delayed in their entry to the clinical workforce in times of healthcare crisis. However, proceeding with assessment to determine competency for graduation from medical school, and maintaining performance standards for graduating doctors is an unprecedented challenge under pandemic conditions. This challenge is hitherto uncharted territory for medical schools and there is scant guidance for medical educators. In early March 2020, Duke-National University Singapore Medical School embraced the challenge for ensuring competent final year medical students could complete their final year of studies and graduate on time, to enter the medical workforce in Singapore without delay. This paper provides details of how the final year clinical performance examinations were planned and conducted during the COVID-19 pandemic. The aim of the paper is to provide guidance to other medical schools in similar circumstances who need to plan and make suitable adjustments to clinical skills examinations under current pandemic conditions. The paper illustrates how it is possible to design and implement clinical skills examinations (OSCEs) to ensure the validity and reliability of high-stakes performance assessments whilst protecting the safety of all participants, minimising risk and maintaining defensibility to key stakeholders.


Three dimensions, two microscopes, one code: Automatic differentiation for x-ray nanotomography beyond the depth of focus limit.
Conventional tomographic reconstruction algorithms assume that one has obtained pure projection images, involving no within-specimen diffraction effects nor multiple scattering. Advances in x-ray nanotomography are leading toward the violation of these assumptions, by combining the high penetration power of x-rays, which enables thick specimens to be imaged, with improved spatial resolution that decreases the depth of focus of the imaging system. We describe a reconstruction method where multiple scattering and diffraction effects in thick samples are modeled by multislice propagation and the 3D object function is retrieved through iterative optimization. We show that the same proposed method works for both full-field microscopy and for coherent scanning techniques like ptychography. Our implementation uses the optimization toolbox and the automatic differentiation capability of the open-source deep learning package TensorFlow, demonstrating a straightforward way to solve optimization problems in computational imaging with flexibility and portability.


Key considerations for the success of Medical Education Research and Innovation units in Canada: unit director perceptions.
Growth in the field of medical education is evidenced by the proliferation of units dedicated to advancing Medical Education Research and Innovation (MERI). While a review of the literature discovered narrative accounts of MERI unit development, we found no systematic examinations of the dimensions of and structures that facilitate the success of these units. We conducted qualitative interviews with the directors of 12 MERI units across Canada. Data were analyzed using qualitative description (Sandelowski in Res Nurs Health 23:334-340, 2000). Final analysis drew on Bourdieu's (Outline of a theory of practice. Cambridge University Press, Cambridge, 1977; Media, culture and society: a critical reader. Sage, London, 1986; Language and symbolic power. Harvard University Press, Cambridge, 1991) concepts of field, habitus, and capital, and more recent research investigating the field of MERI (Albert in Acad Med 79:948-954, 2004; Albert et al. in Adv Health Sci Educ 12:103-115, 2007). When asked about the metrics by which they define their success, directors cited: teaching, faculty mentoring, building collaborations, delivering conference presentations, winning grant funding, and disseminating publications. Analyzed using Bourdieu's concepts, these metrics are discussed as forms of capital that have been legitimized in the MERI field. All directors, with the exception of one, described success as being comprised of elements (capital) at both ends of the service-research spectrum (i.e., Albert's PP-PU structure). Our analysis highlights the forms of habitus (i.e., behaviors, attitudes, demeanors) directors use to negotiate, strategize and position the unit within their local context. These findings may assist institutions in developing a new-or reorganizing an existing-MERI unit. We posit that a better understanding of these complex social structures can help units become savvy participants in the MERI field. With such insight, units can improve their academic output and their status in the MERI context-locally, nationally, and internationally.


Age-Induced Alterations in Hippocampal Function and Metabolism.
As the nervous system ages, a variety of changes occur in metabolism supporting glial and neuronal function, resulting in greater susceptibility to disease conditions. Changes with aging in the metabolic unit (i.e., neurons, glial cells and blood vessels) have been reported to include alterations of vascular reactivity, impaired transport of critical substrates underlying metabolism, enhanced reactive oxygen species production and alterations in calcium signaling. Some diseases are focused on the elderly, particularly cerebral ischemia, cognitive limitations, iatrogenic hypoglycemia, malignant brain tumors (i.e., glioblastoma), and Alzheimer's disease, partly due to metabolic alterations with aging. These metabolic changes with aging are discussed in light of primary theories of aging of the brain, which include mitochondrial, calcium dysfunction and enhanced oxidative damage. Here we focus on metabolic changes with aging which can influence the susceptibility of the brain to ischemia and cognitive function. Lastly, we describe treatment possibilities for these abnormal responses to aging, particularly the topic of caloric/dietary restriction, and possible mechanisms underlying this treatment direction.


Retirement and Healthy Lifestyle: A National Health and Nutrition Examination Survey (NHANES) Data Report.
The objective of this study was to compare the rates of healthy lifestyle adherence among retired late-middle-aged adults with rates among those who are still working. A national cross-sectional study using data from the National Health and Nutrition Examination survey (NHANES). The main outcome was the proportion of retires versus nonretirees who were adherent to ideal or intermediate goals of the American Heart Association's Life's Simple 7, cardiovascular factors including physical activity, healthy diet, healthy weight, smoking status, total cholesterol, glucose, and blood pressure. Retirees were more likely than nonretirees to have poorly controlled blood pressure (23.9% vs 15.1%; P = .05). However, there were no differences in healthy weight, smoking rates, healthy diet, or glucose or cholesterol control (P > .05). In controlled logistic regression analyses, retirees were more likely to be physically active than nonretirees (odds ratio, 1.85; 95% confidence interval, 1.11-3.09), but were not more likely to be following any other Life's Simple 7 factors. Retired adults were more likely to be physically active but were not more likely to be adhering to most of the Life's Simple 7 lifestyle and cardiovascular risk factors. More public health attention to encouraging healthy lifestyles during the transition into retirement may be warranted.


"There Is a Lot of Community Spirit Going On." Middle Managers' Stories of Innovation in Home Care Services.
Background: There is a need for qualitative studies on imposed innovation in home care services in welfare societies. The municipalities are key actors in the field of innovation in the public sector. As innovations often are interpreted to be in conflict with values in health care, we need knowledge on how policy changes and imposed innovations are understood and handled by middle managers working in the sector. Aim: We aim to explore how middle managers react to imposed innovation in health services through their storytelling. The research question was "What can middle managers' stories of imposed innovation tell us about their role in, and some important prerequisites for, innovation processes in municipal health-care services?" Methods: A narrative study of experiences with municipal innovation among middle managers in Norway. In this article, we do a thematic analysis of interviews with seven female middle managers who work in a home care service department. Findings: The study develops an understanding of which frameworks are required within a home care service to meet constant demands for innovation. Innovations are understood by the managers as results of policy changes and new public management demands and as a troublesome burden. We find the prerequisites for implementing innovations to be (1) trust-based management, (2) flexibility and dynamics, (3) continuity of care, and (4) emphasis on competence. These prerequisites are further interpreted in relation to dominant discourses on innovation at the macro, meso, and micro levels within the storytelling contexts. Conclusion: Imposed innovations require a negotiating practice in cross-disciplinary environments at all levels in the organization.


A population-based approach to integrated healthcare delivery: a scoping review of clinical care and public health collaboration.
A population-based approach to healthcare goes beyond the traditional biomedical model and addresses the importance of cross-sectoral collaboration in promoting health of communities. By establishing partnerships across primary care (PC) and public health (PH) sectors in particular, healthcare organizations can address local health needs of populations and improve health outcomes. The purpose of this study was to map a series of interventions from the empirical literature that facilitate PC-PH collaboration and develop a resource for healthcare organizations to self-evaluate their clinical practices and identify opportunities for collaboration with PH. A scoping review was designed and studies from relevant peer-reviewed literature and reports between 1990 and 2017 were included if they met the following criteria: empirical study methodology (quantitative, qualitative, or mixed methods), based in US, Canada, Western Europe, Australia or New Zealand, describing an intervention involving PC-PH collaboration, and reporting on structures, processes, outcomes or markers of a PC-PH collaboration intervention. Out of 2962 reviewed articles, 45 studies with interventions leading to collaboration were classified into the following four synergy groups developed by Lasker's Committee on Medicine and Public Health: Coordinating healthcare services (n = 13); Applying a population perspective to clinical practice (n = 21); Identifying and addressing community health problems (n = 19), and Strengthening health promotion and health protection (n = 21). Furthermore, select empirical examples of interventions and their key features were highlighted to illustrate various approaches to implementing collaboration interventions in the field. The findings of our review can be utilized by a range of organizations in healthcare settings across the included countries. Furthermore, we developed a self-evaluation tool that can serve as a resource for clinical practices to identify opportunities for cross-sectoral collaboration and develop a range of interventions to address unmet health needs in communities; however, the generalizability of the findings depends on the evaluations conducted in individual studies in our review. From a health equity perspective, our findings also highlight interventions from the empirical literature that address inequities in care by targeting underserved, high-risk populations groups. Further research is needed to develop outcome measures for successful collaboration and determine which interventions are sustainable in the long term.


[Pluripotent stem cells on cell therapy].
Induced pluripotent stem (iPS) cells are a novel stem cell population derived from human somatic cells through reprogramming using a set of transcription factors. These iPS cells were shown to share the characteristics of embryonic stem cells, including the ability to give rise to differentiated cells of every tissue type of the body. In the shorter term, iPS cells will be useful for creating patient-identical disease model cells in which the pathological process can be studied and drugs can be tested. Despite critical attitudes, accumulating preclinical evidence supports the effectiveness of iPSC-based cell therapy on the selection of appropriate iPSC clones. The production of iPS cells has also spurred the development of other techniques, for example, transdifferentiation by researchers can now convert heart fibroblasts directly in vivo into myocytes by similar methods. This pluripotent cells is indeed of great value in medical research and it is opening new possibilities in cell therapy.


RE-MIND: Comparing Tafasitamab + Lenalidomide (L-MIND) with a Real-world Lenalidomide Monotherapy Cohort in Relapsed or Refractory Diffuse Large B-cell Lymphoma.
Tafasitamab, an Fc-modified, humanized, anti-CD19 monoclonal antibody, in combination with lenalidomide, demonstrated efficacy in transplant-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), in the single-arm, phase II L-MIND study (NCT02399085). RE-MIND, a retrospective observational study, generated a historic control for L-MIND to delineate the contribution of tafasitamab to the efficacy of the combination. Data were retrospectively collected from patients with R/R DLBCL treated with lenalidomide monotherapy for comparison with tafasitamab + lenalidomide-treated patients (L-MIND). Key eligibility criteria were aligned with L-MIND. Estimated propensity score-based Nearest Neighbor 1:1 Matching methodology balanced the cohorts for nine prespecified prognostic baseline covariates. The primary endpoint was investigator-assessed best overall response rate (ORR). Secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Data from 490 patients going through lenalidomide monotherapy were collected; 140 qualified for matching with the L-MIND cohort. The primary analysis included 76 patients from each cohort who received a lenalidomide starting dose of 25 mg/day. Cohort baseline covariates were comparable. A significantly better ORR of 67.1% (95% confidence interval, 55.4-77.5) was observed for the combination therapy versus 34.2% (23.7-46.0) for lenalidomide monotherapy [odds ratio, 3.89 (1.90-8.14); P < 0.0001]. Higher CR rates were achieved with combination therapy compared with lenalidomide monotherapy [39.5% (28.4-51.4) vs. 13.2% (6.5-22.9)]. Survival endpoints favored combination therapy. Lenalidomide monotherapy outcomes were similar to previously published data. RE-MIND enabled the estimation of the additional treatment effect achieved by combining tafasitamab with lenalidomide in patients with R/R DLBCL.


Relationship of insulin resistance to vitamin d status in children with nondiabetic chronic kidney disease.
Insulin Resistance is common in patients with mild-to-moderate stage chronic kidney disease (CKD), even when the glomerular filtration rate is within the normal range. This study aimed to investigate the association of IR and 25-hydroxyvitamin D levels. In this study, we evaluated the frequency of IR in predialysis patients and the association with 25-hydroxyvitamin (OH)D levels. A total of 32 non-diabetic patients with predialysis were included in the study. Homeostasis model assessment for insulin resistance (HOMA-IR) index was calculated to show presence of IR. Data were analyzed with the Statistical Package for the Social Sciences (SPSS) program version 13.0 (SPSS Inc, Chicago, Ill, USA) using the Chi-square, Student t-test, and logistic regression analysis. Nineteen of 32 subjects (59.4%) were detected to have IR. There was no consistent relationship was detected between IR and glomerular filtration rate, body mass index, and blood pressure in chronic kidney disease (CKD). However; significant difference was detected in 25(OH)D levels with IR in CKD (P = 0.49). The regression analysis showed that 25(OH)D was an independent predictor of IR with an odds ratio of 1.2. In our study, we demonstrated that IR was high in different stages of CKD. Insulin-resistance in non-diabetic CKD was correlated with 25(OH)D levels. 25(OH) vitamin D levels can play a significant role in the development of IR in pediatric patients with CKD. This is important for the early detection and intervention of vitamin D deficiency thereby preventing potentially future complications related to IR.


MRI and proton spectroscopy in Lowe syndrome.
The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by major abnormalities of eyes, nervous system, and kidneys. We report two patients with typical intracranial lesions on MRI. The proton spectroscopy study of the periventricular white matter showed a moderate elevation of the signal at 3.56 ppm in the patient with cystic lesions. This resonance is usually assigned to myo-inositol and interpreted as a glial marker. In our patient it could also represent a true accumulation inside the cysts of phosphatidylinositol 4,5-biphosphate which is not degraded in patients with Lowe syndrome.


Improved efficacy and reduced toxicity of doxorubicin encapsulated in sulfatide-containing nanoliposome in a glioma model.
As a glycosphingolipid that can bind to several extracellular matrix proteins, sulfatide has the potential to become an effective targeting agent for tumors overexpressing tenasin-C in their microenvironment. To overcome the dose-limiting toxicity of doxorubicin (DOX), a sulfatide-containing nanoliposome (SCN) encapsulation approach was employed to improve treatment efficacy and reduce side effects of free DOX. This study analysed in vitro characteristics of sulfatide-containing nanoliposomal DOX (SCN-DOX) and assessed its cytotoxicity in vitro, as well as biodistribution, therapeutic efficacy, and systemic toxicity in a human glioblastoma U-118MG xenograft model. SCN-DOX was shown to achieve highest drug to lipid ratio (0.5∶1) and a remarkable in vitro stability. Moreover, DOX encapsulated in SCN was shown to be delivered into the nuclei and displayed prolonged retention over free DOX in U-118MG cells. This simple two-lipid SCN-DOX nanodrug has favourable pharmacokinetic attributes in terms of prolonged circulation time, reduced volume of distribution and enhanced bioavailability in healthy rats. As a result of the improved biodistribution, an enhanced treatment efficacy of SCN-DOX was found in glioma-bearing mice compared to the free drug. Finally, a reduction in the accumulation of DOX in the drug's principal toxicity organs achieved by SCN-DOX led to the diminished systemic toxicity as evident from the plasma biochemical analyses. Thus, SCN has the potential to be an effective and safer nano-carrier for targeted delivery of therapeutic agents to tumors with elevated expression of tenascin-C in their microenvironment.


Short telomeres result in chromosomal instability in hematopoietic cells and precede malignant evolution in human aplastic anemia.
In cell and animal models, telomere erosion promotes chromosomal instability via breakage-fusion-bridge cycles, contributing to the early stages of tumorigenesis. However, evidence involving short telomeres in cancer development in humans is scarce, epidemiological and indirect. Here we directly implicate telomere shortening as a critical molecular event for malignant evolution in aplastic anemia (AA). Patients' telomere lengths at diagnosis of AA, while comparable to age-matched controls, inversely correlated with the probability of developing a cytogenetically abnormal clone. A significantly increased number of telomere signal-free chromosomal ends and chromosomal numerical and structural abnormalities were observed in bone marrow cells of patients with shorter telomeres in comparison with patients with longer telomeres and healthy subjects. The proportion of monosomy-7 cells in the bone marrow at diagnosis of AA inversely correlated with telomere length, years before the emergence of an autonomous and clinically detectable abnormal clone. Marrow cells of clinically healthy individuals carrying loss-of-function telomerase mutations and with extremely short telomeres also showed chromosomal instability in vitro. These results provide the first clinical direct evidence in humans that short telomeres in hematopoietic cells are dysfunctional, mediate chromosomal instability and predispose to malignant transformation in a human disease.


Ratings of patient-provider communication among veterans: serious mental illnesses, substance use disorders, and the moderating role of trust.
Many individuals with a mental illness are not satisfied with their communication with their primary provider. The present study examined the relationship of serious mental illness (SMI), substance use disorder (SUD), and trust for the provider with provider communication. The sample included Veterans Administration (VA) patients throughout the United States who either had a SMI diagnosis (schizophrenia or bipolar disorder) or were in a random sample of non-SMI patients (total N=8,089). Latent class (LC) modeling identified three classes of provider communication ratings in the sample: very good, good, and poor. In LC regression, poor trust for the provider was associated with a decrease in the likelihood of being in the "very good" or "good" compared to the "poor" provider communication ratings group, and the decrease was significantly greater for VA patients with a SMI or SUD diagnosis than those without. Training providers on creating trust is particularly important for those who serve patients with SMI and SUD diagnoses.


Prevention of tetanus in the wounded.
Recommendations for the prevention of tetanus in the wounded have been revised to incorporate the use of human tetanus immunoglobulin, which is now available in the United Kingdom. Surgical toilet is of prime importance for all wounds, and is usually sufficient for tetanus prophylaxis in patients with wounds that are less than six hours old, clean, non-penetrating, and with negligible tissue damage. Human tetanus immunoglobulin should be given to patients with more serious wounds sho have had toxoid injections over 10 years earlier, had an incomplete course, or do not know their immunity status. The importance of active immunization is emphasized. The recommendations should be regarded as guidelines as the circumstances in individual cases will differ.


Do immunological, endocrine and metabolic traits fall on a single Pace-of-Life axis? Covariation and constraints among physiological systems.
Variation in demographic and physiological attributes of life history is thought to fall on one single axis, a phenomenon termed the Pace-of-Life. A slow Pace-of-Life is characterized by low annual reproduction, long life span and low metabolic rate, a fast Pace-of-Life by the opposite characteristics. The existence of a single axis has been attributed to constraints among physiological mechanisms that are thought to restrict evolutionary potential. In that case, physiological traits should covary in the same fashion at the levels of individual organisms and species. We examined covariation at the levels of individual and subspecies in three physiological systems (metabolic, endocrine and immune) using four stonechat subspecies with distinct life-history strategies in a common-garden set-up. We measured basal metabolic rate, corticosterone as endocrine measure and six measures of constitutive immunity. Metabolic rate covaried with two indices of immunity at the individual level, and with corticosterone concentrations and one index of immunity at the subspecies level, but not with other measures. The different patterns of covariation among individuals and among subspecies demonstrate that links among physiological traits are loose and suggest that these traits can evolve independent of each other.


Theoretical study on the mechanochemical reactivity in Diels-Alder reactions.
Mechanochemical reactions sometimes give different yields from those under solvent conditions, and such mechanochemical reactivities depend on the reactions. This study theoretically elucidates what governs mechanochemical reactivities, taking the Diels-Alder reactions as an example. Applying mechanical force can be regarded as the deformation of molecules, and the deformation in an orthogonal direction to a reaction mode can lower the reaction barrier. Here, we introduce a dimensionless cubic force constant, a mechanochemical reaction constant. It tells us how easily the deformation can lower a reaction barrier and enables us to compare the mechanochemical reactivities of different reactions. The constants correlate positively with the yields of the mechanochemical Diels-Alder reactions.


Unhealthy habits persist: The ongoing presence of modifiable risk factors for disease in women.
Vascular disease remains a leading cause of death. There are several vascular risk factors identified that can mitigate development of disease in ageing. We examine reported rates of modifiable risk factors in women responding to an online health questionnaire advertised by popular media. A sample of 26 620 women aged over 18 was examined in 2015 with a cross-sectional health questionnaire. The questionnaire included self-reported health, mood, lifestyle and vascular risk factors. There remains high rates of modifiable risk factors present in women. The vast majority of women (80%) reported not eating enough fruit and vegetables. Compared to the guidelines for health, the majority did not perform enough weekly physical activity (70%) and more than half the participants were overweight (54%). Sufficient fruit, vegetables, fish, legumes and physical activity were reported in less than 30% of women! Women continue to report low rates of physical activity, fruit and vegetable intake and higher BMI than recommended for good health, despite worldwide health promotion activities aimed at changing these lifestyle factors. Programs to support healthy living need to be reviewed and revised to reduce the burden of vascular disease and dementia in women. Previous guidelines are not having the important impact they should, particularly in women.


Multiple origins for Mediterranean olive (Olea europaea L. ssp. europaea) based upon mitochondrial DNA polymorphisms.
A study of nuclear and cytoplasmic genetic diversity of cultivated olive, oleaster and other taxa belonging to the complex O. europaea was performed. Nuclear DNA polymorphism (RAPDs) in oleaster displays a gradient between the east and west of the Mediterranean Basin. In cultivars, the gradient is less visible owing to their diffusion and selection. Furthermore, three mitotypes (ME1, MOM and MCK) were detected in both cultivated olive and oleaster. A fourth mitotype, ME2, was unique to some cultivars. The preponderant mitotype, ME1, marks the Near Eastern origin of olive in oleaster. In the west of the Mediterranean, another mitotype, MOM, was found in most oleaster. and a few cultivars. The third, MCK, was found in a few oleaster from the west and in cultivars originating in Kabylie and Languedoc. We argue that MCK marks an ancestral Mediterranean population. The mitotypes mark independent cultivated olive origins which were not detected with DNA nuclear diversity.


Is risk of diabetic retinopathy lower in Australia's Greek-born migrants?
The standardized cardiovascular disease death rate for the Greek population in Crete has increased since the 1960s, unlike the all-cause and cardiovascular disease death rate for Australia's Greek migrant population, which has remained paradoxically low. A small window of opportunity remains in which the vascular profile of this interesting atypical migrant population can be characterized. This study assessed whether ethnicity modulates the risk of diabetic retinopathy in Greek-born migrants to Australia. The study design was a community-based cross-sectional study of diabetic retinopathy in 107 Greek-born and Australian-born men with Type 2 diabetes, aged 44-83 years. Diabetic retinopathy was assessed by mydriatic three-field retinal photography. Prevalence of diabetic retinopathy was lower in Greek-born than in Australian-born participants (22 and 37%, respectively). Despite having a higher mean systolic blood pressure level (148 vs. 137 mmHg), Greek-born men had a significantly lower risk of diabetic retinopathy than Australian-born men, after adjusting for age, duration of diabetes, glycated haemoglobin, systolic blood pressure, diastolic blood pressure, albumin to creatinine ratio, and total cholesterol and triglyceride levels [odds ratio 0.32 (0.10-0.99); r(2) = 0.41, P = 0.047]. Greek ethnicity may confer some protection against diabetic retinopathy to Australia's Greek-born migrants, an effect not explained by established risk factors for diabetic retinopathy. A small window of opportunity remains in which to elucidate the ethnicity-related exposures that modulate vascular risk in this older migrant population.


Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV.
People living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.


Rapid Determination of Wine Grape Maturity Level from pH, Titratable Acidity, and Sugar Content Using Non-Destructive In Situ Infrared Spectroscopy and Multi-Head Attention Convolutional Neural Networks.
In the pursuit of enhancing the wine production process through the utilization of new technologies in viticulture, this study presents a novel approach for the rapid assessment of wine grape maturity levels using non-destructive, in situ infrared spectroscopy and artificial intelligence techniques. Building upon our previous work focused on estimating sugar content (∘Brix) from the visible and near-infrared (VNIR) and short-wave infrared (SWIR) regions, this research expands its scope to encompass pH and titratable acidity, critical parameters determining the grape maturity degree, and in turn, wine quality, offering a more representative estimation pathway. Data were collected from four grape varieties-Chardonnay, Malagouzia, Sauvignon Blanc, and Syrah-during the 2023 harvest and pre-harvest phenological stages in the vineyards of Ktima Gerovassiliou, northern Greece. A comprehensive spectral library was developed, covering the VNIR-SWIR spectrum (350-2500 nm), with measurements performed in situ. Ground truth data for pH, titratable acidity, and sugar content were obtained using conventional laboratory methods: total soluble solids (TSS) (∘Brix) by refractometry, titratable acidity by titration (expressed as mg tartaric acid per liter of must) and pH by a pH meter, analyzed at different maturation stages in the must samples. The maturity indicators were predicted from the point hyperspectral data by employing machine learning algorithms, including Partial Least Squares regression (PLS), Random Forest regression (RF), Support Vector Regression (SVR), and Convolutional Neural Networks (CNN), in conjunction with various pre-processing techniques. Multi-output models were also considered to simultaneously predict all three indicators to exploit their intercorrelations. A novel multi-input-multi-output CNN model was also proposed, incorporating a multi-head attention mechanism and enabling the identification of the spectral regions it focuses on, and thus having a higher interpretability degree. Our results indicate high accuracy in the estimation of sugar content, pH, and titratable acidity, with the best models yielding mean R2 values of 0.84, 0.76, and 0.79, respectively, across all properties. The multi-output models did not improve the prediction results compared to the best single-output models, and the proposed CNN model was on par with the next best model. The interpretability analysis highlighted that the CNN model focused on spectral regions associated with the presence of sugars (i.e., glucose and fructose) and of the carboxylic acid group. This study underscores the potential of portable spectrometry for real-time, non-destructive assessments of wine grape maturity, thereby providing valuable tools for informed decision making in the wine production industry. By integrating pH and titratable acidity into the analysis, our approach offers a holistic view of grape quality, facilitating more comprehensive and efficient viticultural practices.


Child eating behavior outcomes of an early feeding intervention to reduce risk indicators for child obesity: the NOURISH RCT.
The objective was to describe parent-reported child eating behavior and maternal parenting impact outcomes of an infant feeding intervention to reduce child obesity risk. An assessor masked Randomized Controlled Trial (RCT) with concealed allocation of individual mother-infant dyads. The NOURISH RCT enrolled 698 first-time mothers (mean age 30.1 years, SD = 5.3) with healthy term infants (51% female) aged 4.3 months (SD = 1.0) at baseline. Outcomes were assessed 6 months post-intervention when the children were 2 years old. Mothers reported on child eating behaviors using the Children's Eating Behavior Questionnaire (CEBQ), food preferences, and dietary intake using a 24-hour telephone recall. Parenting was assessed using five scales validated for use in Australia. Intervention effects were evident on the CEBQ overall (MANOVA P = 0.002) and 4/8 subscales: child satiety responsiveness (P = 0.03), fussiness (P = 0.01), emotional overeating (P < 0.01), and food responsiveness (P = 0.06). Intervention children "liked" more fruits (P < 0.01) and fewer non-core foods and beverages (P = 0.06, 0.03). The intervention mothers reported greater "autonomy encouragement" (P = 0.002). Anticipatory guidance on protective feeding practices appears to have modest positive impacts on child eating behaviors that are postulated to reduce future obesity risk.


Insulin-egg yolk dispersions in self microemulsifying system.
Formulation of insulin into a microemulsion very often presents a physicochemical instability during their preparation and storage. In order to overcome this lack of stability and facilitate the handling of these colloidal systems, stabilization of insulin in presence of hydrophobic components of a microemulsion appears as the most promising strategy. The present paper reports the use of egg yolk for stabilization of insulin in self microemulsifying dispersions. Insulin loaded egg yolk self microemulsifying dispersions were prepared by lyophilization followed by dispersion into self microemulsifying vehicle. The physicochemical characterization of selfmicroemulsifying dispersions includes such as insulin encapsulation efficiency, in vitro stability of insulin in presence of proteolytic enzymes and in vitro release. The biological activity of insulin from the dispersion was estimated by enzyme-linked immunosorbant assay and in vivo using Wistar diabetic rats. The particle size ranged 1.023±0.316 μm in diameter and insulin encapsulation efficiency was 98.2±0.9 %. Insulin hydrophobic self microemulsifying dispersions suppressed insulin release in pH 7.4 phosphate buffer and shown to protect insulin from enzymatic degradation in vitro in presence of chymotripsin. Egg yolk encapsulated insulin was bioactive, demonstrated through both in vivo and in vitro.


Predicting pKa for proteins using COSMO-RS.
We have used the COSMO-RS implicit solvation method to calculate the equilibrium constants, pKa, for deprotonation of the acidic residues of the ovomucoid inhibitor protein, OMTKY3. The root mean square error for comparison with experimental data is only 0.5 pH units and the maximum error 0.8 pH units. The results show that the accuracy of pKa prediction using COSMO-RS is as good for large biomolecules as it is for smaller inorganic and organic acids and that the method compares very well to previous pKa predictions of the OMTKY3 protein using Quantum Mechanics/Molecular Mechanics. Our approach works well for systems of about 1000 atoms or less, which makes it useful for small proteins as well as for investigating portions of larger proteins such as active sites in enzymes.


The Bacteroides by-product succinic acid inhibits neutrophil respiratory burst by reducing intracellular pH.
Short-chain fatty acids, particularly succinic acid, are major metabolic by-products of Bacteroides species. To determine their role as potential virulence factors in infections containing Bacteroides species, short-chain fatty acids were examined for their effect on the neutrophil respiratory burst. Succinate (30 to 50 mM) irreversibly impaired superoxide and hydrogen peroxide production in response to opsonized zymosan and phorbol myristate acetate when neutrophils were treated at pH 5.5 but not pH 6.0 or greater. Several other short-chain fatty acids tested produced similar inhibition. Reversible inhibition of oxygen consumption was found when neutrophils were incubated in succinate-containing medium (pH 6.0) as well as control medium (pH 6.0 and 5.5). Neutrophil cytoplasmic pH was measured by fluorimetric techniques to determine whether the inhibition was mediated via a reduction in intracellular pH. The intracellular pH of cells in control medium (pH 6.5 or less) was significantly reduced compared with pH 7.4. The addition of succinate (30 mM) to these media caused a further significant reduction in cytoplasmic pH at each pH level. The reduction in intracellular pH was sufficient to account for both the irreversible and reversible impairment of the neutrophil respiratory burst. Thus, short-chain fatty acids appear to exert their inhibition, at least in part, by reducing intracellular pH. These data also demonstrate the potential for interactions between Bacteroides species and their microenvironment to increase the virulence of an infection.


Readability of Written Materials for CKD Patients: A Systematic Review.
The "average" patient has a literacy level of US grade 8 (age 13-14 years), but this may be lower for people with chronic kidney disease (CKD). Current guidelines suggest that patient education materials should be pitched at a literacy level of around 5th grade (age 10-11 years). This study aims to evaluate the readability of written materials targeted at patients with CKD. Systematic review. Patient information materials aimed at adults with CKD and written in English. Patient education materials designed to be printed and read, sourced from practices in Australia and online at all known websites run by relevant international CKD organizations during March 2014. Quantitative analysis of readability using Lexile Analyzer and Flesch-Kincaid tools. We analyzed 80 materials. Both Lexile Analyzer and Flesch-Kincaid analyses suggested that most materials required a minimum of grade 9 (age 14-15 years) schooling to read them. Only 5% of materials were pitched at the recommended level (grade 5). Readability formulas have inherent limitations and do not account for visual information. We did not consider other media through which patients with CKD may access information. Although the study covered materials from the United States, United Kingdom, and Australia, all non-Internet materials were sourced locally, and it is possible that some international paper-based materials were missed. Generalizability may be limited due to exclusion of non-English materials. These findings suggest that patient information materials aimed at patients with CKD are pitched above the average patient's literacy level. This issue is compounded by cognitive decline in patients with CKD, who may have lower literacy than the average patient. It suggests that information providers need to consider their audience more carefully when preparing patient information materials, including user testing with a low-literacy patient population.


Prevalence of blindness and visual impairment among Jordanian diabetics.
To investigate the prevalence of blindness and visual impairment among a population of Jordanian diabetics. A total of 986 diabetic patients were fully assessed, including complete history, examination, and laboratory tests. All patients underwent detailed eye examination, which included visual acuity, slit-lamp examination, tonometry, funduscopy, and fundus fluorescein angiography (FFA). Of all patients examined, 53.2% were male and 46.8% were female. The mean age and duration of diabetes were 55.3 and 11.9 years. Of all patients, 93.3% had type 2 while 6.7% had type 1 diabetes mellitus (DM). Over half (50.3%) were on oral hypoglycemic agents, 34% on insulin, and 14.5% on both types of treatment, whereas only 1.2% were on diet alone. The mean value for HbA1c was 7.7%. The prevalence of blindness among participants was found to be 7.4%, while 10.1% were visually impaired. Diabetic retinopathy (DR) was present in 64.1%, 37.8% had cataract, and 8.7% had undergone cataract surgery. Using multivariate logistic regression analysis, visual impairment was significantly associated with age, treatment of diabetes, and DR, while only age and retinopathy were significantly related to blindness. DM is a common disease in Jordan and DR is highly prevalent among Jordanian diabetics. National screening and educational programs are highly needed to reduce the risk of blindness and visual impairment among diabetic patients.


Factors related to hydrocephalus after aneurysmal subarachnoid hemorrhage.
The purpose of this study was to identify factors predictive of shunt-dependent hydrocephalus among patients with aneurysmal subarachnoid hemorrhage. The data can be used to predict which patients in this group have a high probability of requiring permanent cerebrospinal fluid diversion. Seven hundred eighteen patients with aneurysmal subarachnoid hemorrhage who were treated between 1990 and 1999 were retrospectively studied, to identify factors contributing to shunt-dependent hydrocephalus. With these data, a stepwise logistic regression procedure was used to determine the effect of each variable on the development of hydrocephalus and to create a scoring system. Overall, 152 of the 718 patients (21.2%) underwent shunting procedures for treatment of hydrocephalus. Four hundred seventy-nine of the patients (66.7%) were female. Of the factors investigated, the following were associated with shunt-dependent hydrocephalus, as determined with a variety of statistical methods: 1) increasing age (P < 0.001), 2) female sex (P = 0.015), 3) poor admission Hunt and Hess grade (P < 0.001), 4) thick subarachnoid hemorrhage on admission computed tomographic scans (P < 0.001), 5) intraventricular hemorrhage (P < 0.001), 6) radiological hydrocephalus at the time of admission (P < 0.001), 7) distal posterior circulation location of the ruptured aneurysm (P = 0.046), 8) clinical vasospasm (P < 0.001), and 9) endovascular treatment (P = 0.013). The presence of intracerebral hematomas, giant aneurysms, or multiple aneurysms did not influence the development of shunt-dependent hydrocephalus. The results of this study can help identify patients with a high risk of developing shunt-dependent hydrocephalus. This may help neurosurgeons expedite treatment, may decrease the cost and length of hospital stays, and may result in improved outcomes.


Intervention to improve quality of sleep of palliative patient carers in the community: protocol for a multicentre randomised controlled trial.
Sleep disorders are commonly experienced by community caregivers for persons with cancer, with at least 72% reporting moderate to severe disorders. A consequence of this condition, which is associated with the presence of overload in the caregiver, is the increased risk of clinical depression. The aim of this study is to evaluate the effects of music on the sleep quality achieved by informal caregivers for cancer patients receiving home palliative care. In addition, we will assess the influence of specific variables that could modify these effects, analyse the correlates related to nocturnal wakefulness and consider the diurnal consequences according to the sleep characteristics identified. This single-blind, multicentre, randomised clinical trial will focus on informal providers of care for cancer patients. Two samples of 40 caregivers will be recruited. The first, intervention, group will receive seven music-based sessions. The control group will be masked with seven sessions of therapeutic education (reinforcing previous sessions). Outcomes will be evaluated using the Pittsburgh Sleep Quality Index, a triaxial accelerometer, EuroQol-5D-5L, the Caregiver Strain Index, the Epworth Sleepiness Scale and the Client Satisfaction Questionnaire. The caregivers' satisfaction with the intervention performed will also be examined. This study is expected to extend our understanding of the efficacy of music therapy in enhancing the sleep quality of caregivers for patients receiving home palliative care. To our knowledge, no reliable scientific investigations of this subject have previously been undertaken. Music is believed to benefit certain aspects of sleep, but this has yet to be proven and, according to a Cochrane review, high-quality research in this field is necessary. One of the main strengths of our study, which heightens the quality of the randomised clinical trial design, is the objective assessment of physical activity by accelerometry and the use of both objective and subjective measures of sleep in caregivers. Music therapy for the caregivers addressed in this study is complementary, readily applicable, provokes no harmful side effects and may produce significant benefits. The IMECA study is registered at Clinical Trials.gov, ClinicalTrials.gov Identifier: NCT04491110 . Registered 29 July, 2020.


Re-imagining metastatic breast cancer care delivery: a patient-partnered qualitative study.
While significant progress in metastatic breast cancer (MBC) treatment has prolonged survival and improved prognosis, there remain substantial gaps in providing patient-centered supportive care. The specific care delivery needs for metastatic cancer differ from that of early-stage cancer due to the incurable nature and lifelong duration of the condition. The objective of this study was to assess how patients living with MBC would re-imagine cancer care delivery. This qualitative study was conducted in partnership with patient-led organizations Guiding Researchers and Advocates to Scientific Partnerships (GRASP) and Project Life, a nonprofit, online wellness community founded by patients with MBC for patients living with MBC. Virtual semi-structured interviews (n = 36) were conducted with Project Life members purposively sampled from the groups' overall membership. The interview guide contained items surrounding patients' lived experiences of MBC, greatest unmet needs related to care, and perspectives on virtual wellness community involvement. Interviews were coded using two-stage deductive and inductive analysis. Three major themes for re-imagining cancer care delivery were identified, including holistic care, information needs, and conceptual shifts. Within these several subthemes emerged with patients re-imagining referrals to non-oncological services, caregiver support, acceptance of integrative medicine, streamlined clinical trial enrollment, curated quality patient resources, MBC-specific terminology and approaches, long-term life and goal-of-care planning, and patient-centered voice throughout. People living with metastatic cancers have specific supportive care needs. These findings highlight patient-driven areas for re-imagination that are most salient for individuals with MBC.


Cyclic stretch up-regulates proliferation and heat shock protein 90 expression in human melanocytes.
Human skin is repeatedly exposed to mechanical stretching in vivo, but in an ordinary culture of skin cells this prominent feature has been neglected. In order to study whether mechanical stretching plays a role for human melanocytes, we have established a culture technique to mimic this physical stretching: primary cultures of human melanocytes were plated on silicon supports, which undergo a stretching of about 10% of the initial length. After application of repeated stretching and relaxation for 4 days, cell count was significantly (about 40%) enhanced. In addition, we found approximately 2-fold increase in heat shock protein (HSP) 90, both at the protein and mRNA level. HSP 90 is known to bind to Raf-1 and, therefore, may contribute to the Raf-1-MEK (mitogen-activated protein-kinase kinase)-MAPK (mitogen-activated protein-kinase) signaling pathway. Disruption of the Raf-1-HSP 90 multimolecular complex by geldanamycin lead to a considerable decrease in melanocyte cell count. However, geldanamycin did not reverse the stretch-induced growth stimulation. Therefore, the stretch-mediated up-regulation of HSP 90 expression in melanocytes appears to be independent of stretch-mediated growth stimulation. These findings have strong implications for the in vitro cultivation of melanocytes for transplantation purposes.


Ab interno trabecular bypass surgery with Schlemm´s canal microstent (Hydrus) for open angle glaucoma.
Glaucoma is a leading cause of irreversible blindness. A number of minimally-invasive surgical techniques have been introduced as a treatment to prevent glaucoma from progressing; ab interno trabecular bypass surgery with the Schlemm's canal Hydrus microstent is one of them. To evaluate the efficacy and safety of ab interno trabecular bypass surgery with the Hydrus microstent in treating people with open angle glaucoma (OAG). On 7 May 2019, we searched CENTRAL (2019, Issue 5), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. We searched for randomised controlled trials (RCTs) of the Hydrus microstent, alone or with cataract surgery, compared to other surgical treatments (cataract surgery alone, other minimally-invasive glaucoma device techniques, trabeculectomy), laser treatment, or medical treatment. A minimum of three authors independently extracted data from reports of included studies, using a data collection form and analysed data, based on standard Cochrane methods. We included three published studies, with 808 people randomised. Two studies had multiple international recruitment centres in the USA and other countries. The third study had several sites based in Europe. All three studies were sponsored by the Hydrus manufacturer Ivantis Inc. All studies included participants with mainly mild or moderate OAG (mean deviation between -3.6 dB (decibel) and -8.4 dB in all study arms), which was controlled with medication in many participants (mean medicated intraocular pressure (IOP) 17.9 mmHg to 19.1 mmHg). There were no concerns regarding allocation concealment bias, but masking of outcome assessors was high or unclear risk in all studies; masking of participants was achieved, and losses to follow-up were not a concern. Two studies compared the Hydrus microstent combined with cataract surgery to cataract surgery alone, in participants with visually significant cataracts and OAG. We found moderate-certainty evidence that adding the Hydrus microstent to cataract surgery increased the proportion of participants who were medication-free from about half to more than three quarters at 12-month, short-term follow-up (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.39 to 1.83; 2 studies, 639 participants; I² = 0%; and 24-month, medium-term follow-up (RR 1.63, 95% CI 1.40 to 1.88; 2 studies, 619 participants; I² = 0%). The Hydrus microstent combined with cataract surgery reduced the medium-term mean change in unmedicated IOP (after washout) by 2 mmHg more compared to cataract surgery alone (mean difference (MD) -2.00, 95% CI -2.69 to -1.31; 2 studies, 619 participants; I² = 0%; moderate-certainty evidence), and the mean change in IOP-lowering drops (MD -0.41, 95% CI -0.56 to -0.27; 2 studies, 619 participants; I² = 0%; low-certainty evidence). We also found low-certainty evidence that adding a Hydrus microstent to cataract surgery reduced the need for secondary glaucoma surgery from about 2.5% to less than 1% (RR 0.17, 95% CI 0.03 to 0.86; 2 studies, 653 participants; I² = 27%; low-certainty evidence). Intraocular bleeding, loss of 2 or more visual acuity (VA) lines, and IOP spikes of 10 mmHg or more were rare in both groups; estimates were imprecise, and included both beneficial and harmful effects. There were no cases of endophthalmitis in either group. No data were available on the proportion of participants achieving IOP less than 21 mmHg, 17 mmHg, or 14 mmHg; health-related quality of life (HRQOL), or visual field progression. One study provided short-term data for the Hydrus microstent compared with the iStent trabecular micro-bypass stent (iStent: implantation of two devices in a single procedure) in 152 participants with OAG (148 in analyses). Use of the Hydrus increased the proportion of medication-free participants from about a quarter to about half compared to those who received iStent, but this estimate was imprecise (RR 1.94, 95% CI 1.21 to 3.11; low-certainty evidence). Use of the Hydrus microstent reduced unmedicated IOP (after washout) by about 3 mmHg more than the iStent (MD -3.10, 95% CI -4.17 to -2.03; moderate-certainty evidence), and the use of IOP-lowering medication (MD -0.60, 95% CI -0.99 to -0.21; low-certainty evidence). Both devices achieved a final IOP < 21 mmHg in most participants (Hydrus microstent: 91.8%; iStent: 84%; RR 1.09, 95% CI 0.97 to 1.23; low-certainty evidence). None of the participants who received the Hydrus microstent (N = 74) required additional glaucoma surgery; two participants who received the iStent (N = 76) did. Few adverse events were found in either group. No data were available on the proportion of participants achieving IOP less than 17 mmHg or 14 mmHg, or on HRQOL. In people with cataracts and generally mild to moderate OAG, there is moderate-certainty evidence that the Hydrus microstent with cataract surgery compared to cataract surgery alone, likely increases the proportion of participants who do not require IOP lowering medication, and may further reduce IOP at short- and medium-term follow-up. There is moderate-certainty evidence that the Hydrus microstent is probably more effective than the iStent in lowering IOP of people with OAG in the short-term. Few studies were available on the effects of the Hydrus microstent, therefore the results of this review may not be applicable to all people with OAG, particularly in selected people with medically uncontrolled glaucoma, since IOP was controlled with medication in many participants in the included studies. Complications may be rare using the Hydrus microstent, as well as the comparator iStent, but larger studies are needed to investigate its safety.


Menopause, hormone therapy and cognition: maximizing translation from preclinical research.
Menopause-associated and hormone-associated cognitive research has a rich history built from varied disciplines and species. This review discusses landmark rodent and human work addressing cognitive outcomes associated with varied experiences of menopause and hormone therapy. Critical variables in menopause and cognitive aging research are considered, including menopause etiology, background hormone milieu and parameters of exposure to estrogens and progestogens. Recent preclinical research has identified that menopause and ovarian hormone fluctuations across many neurobiological systems affect cognitive aging, mapping novel avenues for future research. Preclinical models provide insight into complex interdisciplinary relationships in a systematic and highly controlled fashion. We highlight that acknowledging the strengths and weaknesses for both preclinical and clinical research approaches is vital to accurate interpretation, optimal translation and the direction of future research. There is great value in collaboration and communication across preclinical and clinical realms, especially regarding reciprocal feedback of findings to advance preclinical models, improve experimental designs and enrich basic science translation to the clinic. In searching for biological mechanisms underlying the cognitive consequences of menopause and hormone therapies, it is noteworthy that clinical and preclinical scientists are grounded in the same fundamental goal of optimizing health outcomes for women across the lifespan.


Survival among patients with lung cancer. An epidemiologic study.
A series of 446 patients with lung cancer, comprising all cases diagnosed in a defined population of approximately 300,000 persons during a period of 4 yr, were studied prospectively and followed for 5 yr or until death. Histologic or cytologic confirmation of the diagnosis was achieved in 431 cases (97%). Only 140 patients (31%) were alive 1 yr after diagnosis, and only 19 patients (4%) were alive after 5 yr, with no significant difference between the men and women. The 5-yr. survival rates among patients with epidermoid. small-cell anaplastic, and adenocarcinoma were 6, 2, and 4%, respectively. The patients could also be divided into prognostically meaningful groups according to the symptomatic staging proposed by Feinstein. Of the 427 patients who had died within 5 yr, 410 (96%) had died of lung cancer and only 17 (4%) had died of other diseases.


Borrelia burgdorferi bba74 is expressed exclusively during tick feeding and is regulated by both arthropod- and mammalian host-specific signals.
Although BBA74 initially was described as a 28-kDa virulence-associated outer-membrane-spanning protein with porin-like function, subsequent studies revealed that it is periplasmic and downregulated in mammalian host-adapted spirochetes. To further elucidate the role of this protein in the Borrelia burgdorferi tick-mammal cycle, we conducted a thorough examination of its expression profile in comparison with the profiles of three well-characterized, differentially expressed borrelial genes (ospA, ospC, and ospE) and their proteins. In vitro, transcripts for bba74 were expressed at 23 degrees C and further enhanced by a temperature shift (37 degrees C), whereas BBA74 protein diminished at elevated temperatures; in contrast, neither transcript nor protein was expressed by spirochetes grown in dialysis membrane chambers (DMCs). Primer extension of wild-type B. burgdorferi grown in vitro, in conjunction with expression analysis of DMC-cultivated wild-type and rpoS mutant spirochetes, revealed that, like ospA, bba74 is transcribed by sigma(70) and is subject to RpoS-mediated repression within the mammalian host. A series of experiments utilizing wild-type and rpoS mutant spirochetes was conducted to determine the transcriptional and translational profiles of bba74 during the tick-mouse cycle. Results from these studies revealed (i) that bba74 is transcribed by sigma(70) exclusively during the larval and nymphal blood meals and (ii) that transcription of bba74 is bracketed by RpoS-independent and -dependent forms of repression that are induced by arthropod- and mammalian host-specific signals, respectively. Although loss of BBA74 does not impair the ability of B. burgdorferi to complete its infectious life cycle, the temporal compartmentalization of this gene's transcription suggests that BBA74 facilitates fitness of the spirochete within a narrow window of its tick phase. A reexamination of the paradigm for reciprocal regulation of ospA and ospC, performed herein, revealed that the heterogeneous expression of OspA and OspC displayed by spirochete populations during the nymphal blood meal results from the intricate sequence of transcriptional and translational changes that ensue as B. burgdorferi transitions between its arthropod vector and mammalian host.


Encoding of Arousal and Physical Characteristics in Audible and Ultrasonic Vocalizations of Mongolian Gerbil Pups Testing Common Rules for Mammals.
In mammals, common rules for the encoding of arousal and physical characteristics of the sender are suggested based on a similar vocal production apparatus. In this study, we want to investigate to what extent vocalizations of developing Mongolian gerbil pups fulfill these rules. We recorded vocalizations of 28 Mongolian gerbil pups in four developmental stages using a separation paradigm, suggested to induce different arousal levels. For low arousal, a pup was placed in an arena isolated from its siblings and parents; for high arousal, the pup was additionally stressed through the simulation of a predator. An unsupervised cluster analysis revealed three call types: ultrasonic (USV), audible vocalizations (ADV), and transitions between both (USV-ADV). The USV and USV-ADV rate showed an age-dependent decrease, contrasting an age-dependent increase for ADVs. Vocal correlates for the encoding of arousal were found for USVs and of physical characteristics for USVs and ADVs. However, the pattern of encoding these cues differed between call types and only partly confirmed the common rules suggested for mammals. Our results show that divergent encoding patterns do not only differ between species but also between call types within a species, indicating that coding rules can be shaped by socio-ecological factors or call type specific production mechanisms.