Transplant candidates with severe left ventricular dysfunction managed with medical treatment: characteristics and survival.
This study sought to assess the clinical characteristics and survival of patients with symptomatic heart failure who were referred as potential heart transplant candidates, but were selected for medical management. Patients with severe left ventricular dysfunction referred for heart transplantation may be considered too well to be placed immediately on an active waiting transplant list. The clinical characteristics of this patient group and their survival have not been well defined. These patients represent a unique group that are characterized by comparatively low age and freedom from significant comorbid conditions. We studied 116 consecutive patients with symptomatic heart failure, severe left ventricular dysfunction (left ventricular ejection fraction 20 +/- 7% [mean +/- SD]) and duration of symptoms >1 month referred for heart transplantation, who were acceptable candidates for the procedure but who were not listed for transplantation because of relative clinical stability. These patients were followed up closely on optimal medical therapy. A variety of baseline clinical, hemodynamic and exercise variables were assessed to define this patient group and used to predict cardiac death and requirement later for heart transplantation. During a mean follow-up period of 25.0 +/- 14.8 months (follow-up 99% complete), there were eight cardiac deaths (7%) (seven sudden, one acute myocardial infarction). Only nine patients (8%) were listed for heart transplantation. Actuarial 1- and 4-year cardiac survival rates were 98 +/- 1% and 84 +/- 7% (mean +/- SE), respectively, and freedom from listing for transplantation was 95 +/- 2% and 84 +/- 7% (mean +/- SE), respectively. Patients were mainly in New York Heart Association functional class II or III and had a preserved cardiac index (2.4 liters/min.m2), pulmonary capillary wedge pressure of 16 +/- 9 mm Hg (mean +/- SD) and maximal oxygen consumption of 17.4 +/- 4.3 ml/min per kg (mean +/- SD). By logistic regression analysis, there was no predictor for cardiac death. Longer duration of heart failure (p = 0.013) and mean pulmonary artery (p < 0.05) and pulmonary systolic (p = 0.014) and diastolic (p < 0.05) pressures correlated significantly with listing for heart transplantation by univariate logistic regression. By multivariate logistic regression, only pulmonary artery systolic pressure (p < 0.004) and duration of heart failure (p < 0.015) remained as predictors for need for later transplantation. In the current treatment era, prognosis is favorable in a definable group of transplant candidates despite severe left ventricular dysfunction. This patient group can be identified after intensive medical therapy by stable symptoms, a relatively high maximal oxygen uptake at peak exercise and a preserved cardiac output.


Evaluation of health alerts from an early illness warning system in independent living.
Passive sensor networks were deployed in independent living apartments to monitor older adults in their home environments to detect signs of impending illness and alert clinicians so they can intervene and prevent or delay significant changes in health or functional status. A retrospective qualitative deductive content analysis was undertaken to refine health alerts to improve clinical relevance to clinicians as they use alerts in their normal workflow of routine care delivery to older adults. Clinicians completed written free-text boxes to describe actions taken (or not) as a result of each alert; they also rated the clinical significance (relevance) of each health alert on a scale of 1 to 5. Two samples of the clinician's written responses to the health alerts were analyzed after alert algorithms had been adjusted based on results of a pilot study using health alerts to enhance clinical decision-making. In the first sample, a total of 663 comments were generated by seven clinicians in response to 385 unique alerts; there are more comments than alerts because more than one clinician rated the same alert. The second sample had a total of 142 comments produced by three clinicians in response to 88 distinct alerts. The overall clinical relevance of the alerts, as judged by the content of the qualitative comments by clinicians for each alert, improved from 33.3% of the alerts in the first sample classified as clinically relevant to 43.2% in the second. The goal is to produce clinically relevant alerts that clinicians find useful in daily practice. The evaluation methods used are described to assist others as they consider building and iteratively refining health alerts to enhance clinical decision making.


Retinal and cortical electrophysiological responses to instantaneous frequency shifts in light modulated above fusion.
Simultaneously recorded visual-evoked responses and electroretinograms are reported for a transient response produced by an abrupt change in the frequency of a light modulated above fusion. A principal components analysis was made of the recorded waveforms, and results of this analysis and their possible significance to clinical electrophysiology are discussed.


Addressing HIV stigma in healthcare, community, and legislative settings in Central and Eastern Europe.
Surging HIV prevalence across countries of Central and Eastern Europe (CEE) is largely a result of poor HIV care engagement and a lack of comprehensive support for key populations. This is fostered by widespread stigma across healthcare, community, and legislative settings. Throughout CEE, HIV stigma and intersectional stigma are serious obstacles to providing adequate medical care to people living with HIV. Anticipated and enacted (experienced) stigma from healthcare professionals, and fears of breaches in confidentiality, deter individuals from having an HIV test and engaging in HIV care. Furthermore, negative connotations surrounding HIV infection can lead to discrimination from family, friends, colleagues, and the public, leading to internalized stigma and depression. Key populations that have higher HIV prevalence, such as men who have sex with men, people who inject drugs, transgender individuals, and sex workers, experience additional stigma and discrimination based on their behaviour and identities. This contributes to the concentrated HIV epidemics seen in these populations in many CEE countries. The stigma is exacerbated by punitive legislation that criminalizes HIV transmission and penalizes sexual orientation, drug use, gender identities, and sex work. Despite high levels of HIV stigma and intersectional stigma, there are many evidence-based interventions that have reduced stigma in other parts of the world. Here, we discuss the interventions that are currently being enacted in various countries of CEE, and we suggest additional effective, evidence-based interventions that will tackle stigma and lead to increased HIV care engagement and higher rates of viral suppression. We cover the promotion of the undetectable = untransmittable (U = U) message, stigma-reduction education and training for healthcare professionals, patient-centric approaches for testing and treatment, and advocacy for non-discriminatory legislation, policies, and practices. We also consider targeted stigma-reduction interventions that acknowledge the wider challenges faced by marginalized populations. HIV stigma and intersectional stigma in CEE drive poor engagement with HIV testing services and care. Widespread adoption of evidence-based interventions to tackle stigma highlighted in this review will improve the quality of life of people living with HIV, improve HIV care engagement, and ultimately slow the surging HIV prevalence and concentrated epidemics occurring throughout CEE.


Early Cytokine Induction Upon Pseudomonas aeruginosa Infection in Murine Precision Cut Lung Slices Depends on Sensing of Bacterial Viability.
Breathing allows a multitude of airborne microbes and microbial compounds to access the lung. Constant exposure of the pulmonary microenvironment to immunogenic particles illustrates the need for proper control mechanisms ensuring the differentiation between threatening and harmless encounters. Discrimination between live and dead bacteria has been suggested to be such a mechanism. In this study, we performed infection studies of murine precision cut lung slices (PCLS) with live or heat-killed P. aeruginosa, in order to investigate the role of viability for induction of an innate immune response. We demonstrate that PCLS induce a robust transcriptomic rewiring upon infection with live but not heat-killed P. aeruginosa. Using mutants of the P. aeruginosa clinical isolate CHA, we show that the viability status of P. aeruginosa is assessed in PCLS by TLR5-independent sensing of flagellin and recognition of the type three secretion system. We further demonstrate that enhanced cytokine expression towards live P. aeruginosa is mediated by uptake of viable but not heat-killed bacteria. Finally, by using a combined approach of receptor blockage and genetically modified PCLS we report a redundant involvement of MARCO and CD200R1 in the uptake of live P. aeruginosa in PCLS. Altogether, our results show that PCLS adapt the extent of cytokine expression to the viability status of P. aeruginosa by specifically internalizing live bacteria.


Acute ptosis as a presentation of preseptal cellulitis leading to cerebral abscess in a patient with uncontrolled diabetes.
Acute ptosis due to preseptal cellulitis requires urgent medical attention, as the infection can extend posteriorly into the orbit, leading to significant visual and cerebral complications. We report a case of a 58-year-old woman with uncontrolled diabetes mellitus presenting with acute ptosis due to preseptal cellulitis. After initial resolution of fever with intravenous amoxicillin-clavulanate, she experienced a seizure due to cerebral abscess a week later and was treated with intravenous ceftriaxone. Preseptal cellulitis is usually treated on an outpatient basis with oral antibiotics, as it rarely extends posteriorly to cause cerebral complications. We wish to highlight the importance of admitting patients with preseptal cellulitis in patients with uncontrolled diabetes for intravenous antibiotics due to the potential for visual and cerebral complications.


Concrete Lessons: Policies and Practices Affecting the Impact of COVID-19 for Urban Indigenous Communities in the United States and Canada.
Throughout the Americas, most Indigenous people move through urban areas and make their homes in cities. Yet, the specific issues and concerns facing Indigenous people in cities, and the positive protective factors their vibrant urban communities generate are often overlooked and poorly understood. This has been particularly so under COVID-19 pandemic conditions. In the spring of 2020, the United Nations High Commissioner Special Rapporteur on the Rights of Indigenous Peoples called for information on the impacts of COVID-19 for Indigenous peoples. We took that opportunity to provide a response focused on urban Indigenous communities in the United States and Canada. Here, we expand on that response and Indigenous and human rights lens to review policies and practices impacting the experience of COVID-19 for urban Indigenous communities. Our analysis integrates a discussion of historical and ongoing settler colonialism, and the strengths of Indigenous community-building, as these shape the urban Indigenous experience with COVID-19. Mindful of the United Nations Declaration on the Rights of Indigenous Peoples, we highlight the perspectives of Indigenous organizations which are the lifeline of urban Indigenous communities, focusing on challenges that miscounting poses to data collection and information sharing, and the exacerbation of intersectional discrimination and human rights infringements specific to the urban context. We include Indigenous critiques of the implications of structural oppressions exposed by COVID-19, and the resulting recommendations which have emerged from Indigenous urban adaptations to lockdown isolation, the provision of safety, and delivery of services grounded in Indigenous initiatives and traditional practices.


Stable genetic integration of a red fluorescent protein in a virulent Group A Streptococcus strain.
There are several advantages, both in vitro and in vivo, in utilizing bacteria that express a fluorescent protein. Such a protein can be transiently incorporated into the bacteria or integrated within the bacterial genome. The most widely utilized fluorescent protein is green fluorescent protein (GFP), but limitations exist on its use. Additional fluorescent proteins have been designed that have many advantages over GFP and technologies for their incorporation into bacteria have been optimized. In the current study, we report the successful integration and expression of a stable fluorescent reporter, mCherry (red fluorescent protein, RFP), into the genome of a human pathogen, Group A Streptococcus pyogenes (GAS) isolate AP53(S-). RFP was targeted at the atg codon of the fcR pseudogene that is present in the mga regulon of AP53(S-). Transcription of critical bacterial genes was not functionally altered by the genomic integration of mCherry. Host virulence both in vitro (keratinocyte infection and cytotoxicity) and in vivo (skin infection) was maintained in AP53(S-)-RFP. Additionally, survival of mice infected with either AP53(S-) or AP53(S-)-RFP was similar, demonstrating that overall pathogenicity of the AP53(S-) strain was not altered by the expression of mCherry. These studies demonstrate the feasibility of integrating a fluorescent reporter into the bacterial genome of a naturally virulent isolate of Group A S. pyogenes for comparative experimental studies.


Inflammation and neuropathic attacks in hereditary brachial plexus neuropathy.
To study the role of mechanical, infectious, and inflammatory factors inducing neuropathic attacks in hereditary brachial plexus neuropathy (HBPN), an autosomal dominant disorder characterised by attacks of pain and weakness, atrophy, and sensory alterations of the shoulder girdle and upper limb muscles. Four patients from separate kindreds with HBPN were evaluated. Upper extremity nerve biopsies were obtained during attacks from a person of each kindred. In situ hybridisation for common viruses in nerve tissue and genetic testing for a hereditary tendency to pressure palsies (HNPP; tomaculous neuropathy) were undertaken. Two patients treated with intravenous methyl prednisolone had serial clinical and electrophysiological examinations. One patient was followed prospectively through pregnancy and during the development of a stereotypic attack after elective caesarean delivery. Upper extremity nerve biopsies in two patients showed prominent perivascular inflammatory infiltrates with vessel wall disruption. Nerve in situ hybridisation for viruses was negative. There were no tomaculous nerve changes. In two patients intravenous methyl prednisolone ameliorated symptoms (largely pain), but with tapering of steroid dose, signs and symptoms worsened. Elective caesarean delivery did not prevent a typical postpartum attack. Inflammation, probably immune, appears pathogenic for some if not all attacks of HBPN. Immune modulation may be useful in preventing or reducing the neuropathic attacks, although controlled trials are needed to establish efficacy, as correction of the mutant gene is still not possible. The genes involved in immune regulation may be candidates for causing HBPN disorders.


Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes.
The potential therapeutic value of cell-based therapy with mesenchymal stem cells (MSC) has been reported in mouse models of polymicrobial peritoneal sepsis. However, the mechanisms responsible for the beneficial effects of MSC have not been well defined. Therefore, we tested the therapeutic effect of intravenous bone marrow-derived human MSC in peritoneal sepsis induced by gram-negative bacteria. At 48 h, survival was significantly increased in mice treated with intravenous MSC compared with control mice treated with intravenous fibroblasts (3T3) or intravenous PBS. There were no significant differences in the levels of TNF-α, macrophage inflammatory protein 2, or IL-10 in the plasma. However, there was a marked reduction in the number of bacterial colony-forming units of Pseudomonas aeruginosa in the blood of MSC-treated mice compared with the 3T3 and PBS control groups. In addition, phagocytic activity was increased in blood monocytes isolated from mice treated with MSC compared with the 3T3 and PBS groups. Furthermore, levels of C5a anaphylotoxin were elevated in the blood of mice treated with MSC, a finding that was associated with upregulation of the phagocytosis receptor CD11b on monocytes. The phagocytic activity of neutrophils was not different among the groups. There was also an increase in alternately activated monocytes/macrophages (CD163- and CD206-positive) in the spleen of the MSC-treated mice compared with the two controls. Thus intravenous MSC increased survival from gram-negative peritoneal sepsis, in part by a monocyte-dependent increase in bacterial phagocytosis.


Sero-status of preschoolers and disclosure to schools.
Infants with HIV-infection have longevity due to improved Highly Active Antiretroviral Therapy (HAART), making many realise their developmental progression which includes access to schooling. However, there is scant information that focuses on disclosure of their positive sero-status to schools and how these children understand and communicate their illnesses. This paper reports on a study of experiences of children affected by HIV and AIDS in Kenya. Qualitative phenomenological data from children aged between 5 and 7 years and their teachers in Early Childhood Development and Education (ECDE) centres were collected using multiple methods. Thematic content analysis was utilised with several themes emerging from findings. Obstacles to disclosure, anticipation of exceptional care, accidental disclosures, lack of psychosocial structures, a need for specialised skills training for teachers, and lack of clear guidelines to assist in disclosure processes emerged as some of the challenges faced. The findings also provide insights into teachers' scaffolding efforts to educate children in understanding and communicating their illnesses, and forging support structures through relationships with their siblings and peers for care and management.


[Effects of metoclopramide on Vmax of action potentials in guinea pig papillary muscles].
The effects of metoclopramide (MCP) on Vmax of action potentials of guinea pig papillary muscles were studied with intracellular microelectrodes. MCP 10-550 mumol/L abbreviated the action potential duration at 90% repolarization (APD90) and decreased the maximal rate of rise of action potential (Vmax) dose-dependently. MCP caused rate-dependent and voltage-dependent reductions of Vmax and retardation of the recovery of Vmax. The results present the possible causes of depressant effect of MCP on Na channel.


Benefit of Targeting a LDL (Low-Density Lipoprotein) Cholesterol <70 mg/dL During 5 Years After Ischemic Stroke.
Background and Purpose- The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of <70 mg/dL to reduce the risk of cardiovascular events in 2860 patients with ischemic stroke with atherosclerotic stenosis of cerebral vasculature or aortic arch plaque >4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods- One thousand seventy-three French patients were assigned to <70 mg/dL (1.8 mmol/L) and 1075 to 100±10 mg/dL (90-110 mg/dL, 2.3-2.8 mmol/L). To achieve these goals, investigators used the statin and dosage of their choice and added ezetimibe on top if needed. The primary outcome was the composite of ischemic stroke, myocardial infarction, new symptoms requiring urgent coronary or carotid revascularization and vascular death. Results- After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57-0.94]; P=0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% (P=0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% (P=0.023). The primary outcome or intracranial hemorrhage was reduced by 25% (P=0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53-2.62]; P=0.70). Conclusions- After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of <70 mg/dL during 5.3 years avoided 1 subsequent major vascular event in 4 (number needed to treat of 30) and no increase in intracranial hemorrhage. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT01252875.


Design of Experiments to Study the Impact of Process Parameters on Droplet Size and Development of Non-Invasive Imaging Techniques in Tablet Coating.
Atomisation of an aqueous solution for tablet film coating is a complex process with multiple factors determining droplet formation and properties. The importance of droplet size for an efficient process and a high quality final product has been noted in the literature, with smaller droplets reported to produce smoother, more homogenous coatings whilst simultaneously avoiding the risk of damage through over-wetting of the tablet core. In this work the effect of droplet size on tablet film coat characteristics was investigated using X-ray microcomputed tomography (XμCT) and confocal laser scanning microscopy (CLSM). A quality by design approach utilising design of experiments (DOE) was used to optimise the conditions necessary for production of droplets at a small (20 μm) and large (70 μm) droplet size. Droplet size distribution was measured using real-time laser diffraction and the volume median diameter taken as a response. DOE yielded information on the relationship three critical process parameters: pump rate, atomisation pressure and coating-polymer concentration, had upon droplet size. The model generated was robust, scoring highly for model fit (R2 = 0.977), predictability (Q2 = 0.837), validity and reproducibility. Modelling confirmed that all parameters had either a linear or quadratic effect on droplet size and revealed an interaction between pump rate and atomisation pressure. Fluidised bed coating of tablet cores was performed with either small or large droplets followed by CLSM and XμCT imaging. Addition of commonly used contrast materials to the coating solution improved visualisation of the coating by XμCT, showing the coat as a discrete section of the overall tablet. Imaging provided qualitative and quantitative evidence revealing that smaller droplets formed thinner, more uniform and less porous film coats.


Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers.
Cancer cells can evade natural killer (NK) cell activity, thereby limiting anti-tumor immunity. To reveal genetic determinants of susceptibility to NK cell activity, we examined interacting NK cells and blood cancer cells using single-cell and genome-scale functional genomics screens. Interaction of NK and cancer cells induced distinct activation and type I interferon (IFN) states in both cell types depending on the cancer cell lineage and molecular phenotype, ranging from more sensitive myeloid to less sensitive B-lymphoid cancers. CRISPR screens in cancer cells uncovered genes regulating sensitivity and resistance to NK cell-mediated killing, including adhesion-related glycoproteins, protein fucosylation genes, and transcriptional regulators, in addition to confirming the importance of antigen presentation and death receptor signaling pathways. CRISPR screens with a single-cell transcriptomic readout provided insight into underlying mechanisms, including regulation of IFN-γ signaling in cancer cells and NK cell activation states. Our findings highlight the diversity of mechanisms influencing NK cell susceptibility across different cancers and provide a resource for NK cell-based therapies.


Incidence and prevalence of hepatitis B. A community-based survey in the Philippines.
In a rural village in the Philippines, sera were collected from 744 residents and tested for evidence of hepatitis B virus infection. In the subsequent year, every household was visited every other week for a period of three months in an attempt to identify clinically apparent cases. At the end of the year, sera were obtained from 78% of persons initially negative for hepatitis B virus and 97% of those initially positive for hepatitis B surface antigen (HBsAg). Overall, HBsAg was found in 8.8% of the population tested, of whom 86% were still HBsAg-positive at the end of the year. Susceptibility to hepatitis B virus infection declined significantly with age, to only 16% in the age group 50 years and older. No difference in the prevalence of markers by sex was observed. The risk of infection in children appeared to increase if one or both parents were infected, compared with both parents susceptible (odds ratio = 3.3 and 7.6, respectively); the risk increased if older siblings were infected, compared with all older siblings susceptible. The overall incidence rate of hepatitis B virus infection was 3.3% per year. For those aged five years or younger, the incidence rate was 9.2%. None of the seroconverters manifested acute symptoms of infection. Despite the evident clustering in families of persons with hepatitis B virus markers, which is suggested by the prevalence survey, only two of nine incident infections observed were in children with HBsAg-positive close relatives. The findings support the impression that in countries endemic for hepatitis B virus, most new cases occur in the young and are clinically inapparent. Furthermore, screening families of young children for chronic carriers in an effort to identify children at high risk for hepatitis B virus infection would have a low sensitivity in the Philippine setting.


Predicting Prostate Cancer Death with Different Pretreatment Risk Stratification Tools: A Head-to-head Comparison in a Nationwide Cohort Study.
Numerous pretreatment risk classification tools are available for prostate cancer. Which tool is best in predicting prostate cancer death is unclear. To systematically compare the prognostic performance of the most commonly used pretreatment risk stratification tools for prostate cancer. A nationwide cohort study was conducted, including 154 811 men in Prostate Cancer data Base Sweden (PCBaSe) 4.0 diagnosed with nonmetastatic prostate cancer during 1998-2016 and followed through 2016. We compared the D'Amico, National Institute for Health and Care Excellence (NICE), European Association of Urology (EAU), Genito-Urinary Radiation Oncologists of Canada (GUROC), American Urological Association (AUA), National Comprehensive Cancer Network (NCCN), and Cambridge Prognostic Groups (CPG) risk group systems; the Cancer of the Prostate Risk Assessment (CAPRA) score; and the Memorial Sloan Kettering Cancer Center (MSKCC) nomogram in predicting prostate cancer death by estimating the concordance index (C-index) and the observed versus predicted cumulative incidences at different follow-up times. A total of 139 515 men were included in the main analysis, of whom 15 961 died from prostate cancer during follow-up. The C-index at 10 yr of follow-up ranged from 0.73 (95% confidence interval [CI]: 0.72-0.73) to 0.81 (95% CI: 0.80-0.81) across the compared tools. The MSKCC nomogram (C-index: 0.81, 95% CI: 0.80-0.81), CAPRA score (C-index: 0.80, 95% CI: 0.79-0.81), and CPG system (C-index: 0.78, 95% CI: 0.78-0.79) performed the best. The order of performance between the tools remained in analyses stratified by primary treatment and year of diagnosis. The predicted cumulative incidences were close to the observed ones, with some underestimation at 5 yr. It is a limitation that the study was conducted solely in a Swedish setting (ie, case mix). The MSKCC nomogram, CAPRA score, and CPG risk grouping system performed better in discriminating prostate cancer death than the D'Amico and D'Amico-derived systems (NICE, GUROC, EAU, AUA, and NCCN). Use of these tools may improve clinical decision making. There are numerous pretreatment risk classification tools that can aid treatment decision for prostate cancer. We systematically compared the prognostic performance of the most commonly used tools in a large cohort of Swedish men with prostate cancer. The Memorial Sloan Kettering Cancer Center nomogram, Cancer of the Prostate Risk Assessment score, and Cambridge Prognostic Groups performed best in predicting prostate cancer death. The use of these tools may improve treatment decisions.


Chromosome aberration types in cells irradiated in G1 with nutrient depletion.
When cultured JU56 cells were blocked in G1 by nutrient depletion, irradiated and then subcultured, a subpopulation of cells at the next metaphase contained not only chromosome-type aberrations, but also triradials and chromatid exchanges. The triradials were found to be the result of chromosome-type breaks in three chromosomes, followed by exchange of chromatids. Obviously, chromatid exchanges and dicentrics could arise by the same mechanism. Triradials and chromatid exchanges were not found in cells irradiated in G1 without nutrient depletion. It appears, therefore, that nutrient depletion can affect the capacity of cells to repair X-ray induced damage. The types of aberrations suggest that the lesions which form them cause real physical discontinuities of the chromosomes, with movement of the broken ends before exchange formation.


A phase 2 trial of regorafenib as a single agent in patients with chemotherapy-refractory, advanced, and metastatic biliary tract adenocarcinoma.
Biliary tract cancers are rare, aggressive neoplasms. Most patients present with advanced/unresectable or metastatic disease at diagnosis, and no second-line regimen has demonstrated clinical benefit. This was a phase 2 study evaluating the efficacy and safety of regorafenib in patients who had advanced/unresectable or metastatic disease after receiving standard therapy. In this single arm-study, patients with advanced/unresectable or metastatic biliary tract cancer who failed at least 1 line of systemic chemotherapy received regorafenib once daily on a schedule of 21-days on/7-days off in a 28-day cycle. Patients initially received a standard 160 mg dose. After toxicity assessments in the first 3 patients, the dose was reduced to 120 mg for subsequent patients, as preplanned. The primary endpoint was progression-free survival (PFS). Secondary objectives included overall survival (OS), the objective response rate, and the disease control rate. Forty-three patients received at least 1 dose of regorafenib, and 34 patients who received at least 1 cycle of treatment were evaluable for tumor response. The median PFS was 15.6 weeks (90% confidence interval, 12.9-24.7 weeks), and the median OS was 31.8 weeks (90% confidence interval, 13.3-74.3 weeks), with survival rates 40% at 12 months and 32% at 18 months. A partial response was achieved in 5 patients (11%), and 19 had stable disease (44%), for a disease control rate of 56%. The toxicity profile was as expected, with grade 3 and 4 adverse events reported in 40% of patients. The most common toxicities were hypophosphatemia (40%), hyperbilirubinemia (26%), hypertension (23%), and hand-foot skin reaction (7%). The current results suggest promising efficacy of regorafenib in patients with chemotherapy-refractory, advanced/metastatic biliary tract cancer, warranting further studies to confirm its clinical efficacy. There is a clear unmet need for effective therapies in patients who have advanced and metastatic biliary tract cancer.


The Symptom-Checklist-K-9 (SCL-K-9) Discriminates between Overweight/Obese Patients with and without Significant Binge Eating Pathology: Psychometric Properties of an Italian Version.
A general personality and psychopathology evaluation is considered to be crucial part of the multidisciplinary assessment for weight-related problems. The Symptom Checklist-90-Revised (SCL-90-R) is commonly used to assess general psychopathology in both overweight and obese patients seeking weight-loss treatment. The main purpose of the present research was to investigate the psychometric properties of the brief form of the SCL-90-R (i.e., the SCL-K-9) in a clinical sample (N = 397) of patients seeking weight-loss treatment (i.e., bariatric surgery and a nutritional weight-loss program). The results of the confirmatory factor analysis supported a one-factor solution of the SCL-K-9, with all nine items loading significantly on the common latent factor (lambdas ≥ 0.587). The ordinal α (= 0.91), the inter-item mean indices of correlation (rii = 0.53), and the convergent validity were also satisfactory. A receiver operating characteristic curves procedure showed that both SCL-90-R and SCL-K-9 were able to classify patients with and without significant binge eating pathology according to the Binge Eating Scale (BES) total score. Overall, our results suggest that the SCL-K-9 has adequate psychometric properties and can be applied as a short screening tool to assess general psychopathology in overweight/obese individuals seeking weight-loss treatment and at follow-up interviews when time restraints preclude the use of the full-length form.


Two subsets of memory T lymphocytes with distinct homing potentials and effector functions.
Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.


Biomechanical evaluation of distal radius fracture stability.
(a) To determine the radiographic correlation between an artificially created dorsal comminution (via a wedge osteotomy) and dorsal tilt (clinical instability) and (b) to determine the efficacy of cast immobilization in maintaining reduction of the simulated fracture pattern as a predictor of successful treatment in the clinical setting. Biomechanical cadaveric study. Level I trauma center. In ten fresh cadaveric upper extremities, sequential dorsal wedge osteotomies (25, 50, and 75 percent of the distal radial diameter) were performed, each followed by measurement of tilt and radial inclination on posteroanterior and lateral radiographs before and after applying a load simulating the physiologic static forces of the forearm. In the last five specimens, the osteotomies were reduced and casted after the load application for each osteotomy, and radiographic measurements were again taken under loaded and unloaded conditions. In the uncasted loaded group (n = 10), average tilt changed from an initial 9 degrees palmar to 3 degrees palmar after the first osteotomy and became dorsally angulated (11 and 30 degrees) after the second and third osteotomies, respectively. Casting and loading resulted in a palmar tilt of 10, 6, and 3 degrees for the 25, 50, and 75 percent osteotomies, respectively. Increasing wedge osteotomies across the midline axis of the radius resulted in dorsal tilt and radial inclination changes representative of clinically unstable fractures that require more aggressive treatment protocols. However, in our experimental setting, casting maintained reduction of stable and unstable osteotomy patterns.


Combined cardiac and abdominal aortic surgery.
Patients with associated cardiac and abdominal aortic disease can undergo one or two separate operations for correction of both problems. The results of one (group A) and two separate operations (group B) were compared in 26 consecutive patients. There were 12 patients in group A and 14 patients in group B. Each patient underwent aortocoronary and aortofemoral bypass. In addition, three patients from group A and two patients from group B underwent cardiac valve surgery; three patients from group A and two patients from group B also had aortorenal bypass. There were no operative deaths and the complications were similar in both groups. The total amount of blood transfused in hospital, the length of stay in the operating room and intensive care unit, and the length of hospital stay were significantly shorter in group A. The average cost per patient in group A was approximately one-half of the average cost in group B. This combined approach for cardiac and abdominal aortic surgery is probably safe and is certainly cost effective.


Influence of HLA-B18 on liver fibrosis progression in a cohort of HIV/HCV coinfected individuals.
Liver fibrosis is accelerated in human immunodeficiency virus/hepatitis C virus (HIV/HCV) coinfected compared with HCV monoinfected patients, due to multiple cofactors. Recently, HLA-B18 haplotype has been associated with short-term liver disease progression in this population. Our aim was to assess the influence of HLA-B18 on the fibrosis process in HIV/HCV coinfected individuals, untreated for HCV, during a long-term follow-up. All consecutive HIV/HCV co-infectedcoinfected patients followed in our center, with positive HCV-RNA and available human leukocyte antigen (HLA) haplotypes (determined by sequence-specific oligonucleotide primed polymerase chain reaction and simple sequence repeats polymerase chain reaction using Luminex Technology) were included. Liver fibrosis progression was assessed by means of fibrosis-4 index for liver fibrosis (FIB-4) and AST to platelet ratio index. The association between FIB-4 score over time and laboratory and clinical parameters, including HLA, was evaluated by univariate and multivariate multilevel generalized linear models. A total of 29 out of 148 screened patients were excluded because of spontaneous HCV clearance (27% were HLA-B18+). Among the remaining 119 individuals (82% males; median age at first visit = 30 years [interquartile range, IQR, 26-35]; median follow-up = 21.5 years [IQR, 15-25]), 26% were HLA-B18+. No baseline differences were evidenced between HLA-B18+ and B18- patients. Fibrosis progression was significantly faster in HLA-B18+ than in HLA-B18- patients ( P < 0.001) (Figure 1). At univariate analysis, age ( P < 0.001), HLA-B18 haplotype ( P = 0.02) and HIV-RNA viral load overtime ( P < 0.001) were associated with liver disease progression. At multivariate analysis, only age ( P < 0.001) remained independently associated with liver fibrosis progression. Our data suggest a possible association between HLA-B18 and an accelerated liver fibrosis in HIV/HCV coinfected with a long-term follow-up.


A trinuclear metallasilsesquioxane of uranium(III).
The silsesquioxane ligand (iBu)7Si7O9(OH)3 (iBuPOSSH3) is revealed as an attractive system for the assembly of robust polynuclear complexes of uranium(III) and allowed the isolation of the first example of a trinuclear U(III) complex ([U3(iBuPOSS)3]) that exhibits magnetic communication and promotes dinitrogen reduction in the presence of reducing agent.


Contribution of Human Pluripotent Stem Cell-Based Models to Drug Discovery for Neurological Disorders.
One of the major obstacles to the identification of therapeutic interventions for central nervous system disorders has been the difficulty in studying the step-by-step progression of diseases in neuronal networks that are amenable to drug screening. Recent advances in the field of human pluripotent stem cell (PSC) biology offers the capability to create patient-specific human neurons with defined clinical profiles using reprogramming technology, which provides unprecedented opportunities for both the investigation of pathogenic mechanisms of brain disorders and the discovery of novel therapeutic strategies via drug screening. Many examples not only of the creation of human pluripotent stem cells as models of monogenic neurological disorders, but also of more challenging cases of complex multifactorial disorders now exist. Here, we review the state-of-the art brain cell types obtainable from PSCs and amenable to compound-screening formats. We then provide examples illustrating how these models contribute to the definition of new molecular or functional targets for drug discovery and to the design of novel pharmacological approaches for rare genetic disorders, as well as frequent neurodegenerative diseases and psychiatric disorders.


A deformation mechanism of hard metal surrounded by soft metal during roll forming.
It is interesting to imagine what would happen when a mixture of soft-boiled eggs and stones is deformed together. A foil made of pure Ti is stronger than that made of Cu. When a composite Cu/Ti foil deforms, the harder Ti will penetrate into the softer Cu in the convex shapes according to previously reported results. In this paper, we describe the fabrication of multilayer Cu/Ti foils by the roll bonding technique and report our observations. The experimental results lead us to propose a new deformation mechanism for a hard metal surrounded by a soft metal during rolling of a laminated foil, particularly when the thickness of hard metal foil (Ti, 25 μm) is much less than that of the soft metal foil (Cu, 300 μm). Transmission Electron Microscope (TEM) imaging results show that the hard metal penetrates into the soft metal in the form of concave protrusions. Finite element simulations of the rolling process of a Cu/Ti/Cu composite foil are described. Finally, we focus on an analysis of the deformation mechanism of Ti foils and its effects on grain refinement, and propose a grain refinement mechanism from the inside to the outside of the laminates during rolling.


Familial hypercholesterolaemia: new treatment options.
Familial hypercholesterolaemia is a relatively frequently occurring disease that is strongly associated with vascular disease. Current treatment with cholesterol-lowering agents is partly effective but shows variable responses between patients with familial hypercholesterolaemia. Recently, new cholesterol-lowering drugs have been developed. Here we describe the most promising of these new agents for which results from phase 2 or phase 3 trials are available. We will discuss the data regarding lipid-lowering potential and safety issues and speculate about the potential reductions of the residual risk of statin-treated FH patients.


The combination of gas-phase fluorophore technology and automation to enable high-throughput analysis of plant respiration.
Mitochondrial respiration in the dark (Rdark) is a critical plant physiological process, and hence a reliable, efficient and high-throughput method of measuring variation in rates of Rdark is essential for agronomic and ecological studies. However, currently methods used to measure Rdark in plant tissues are typically low throughput. We assessed a high-throughput automated fluorophore system of detecting multiple O2 consumption rates. The fluorophore technique was compared with O2-electrodes, infrared gas analysers (IRGA), and membrane inlet mass spectrometry, to determine accuracy and speed of detecting respiratory fluxes. The high-throughput fluorophore system provided stable measurements of Rdark in detached leaf and root tissues over many hours. High-throughput potential was evident in that the fluorophore system was 10 to 26-fold faster per sample measurement than other conventional methods. The versatility of the technique was evident in its enabling: (1) rapid screening of Rdark in 138 genotypes of wheat; and, (2) quantification of rarely-assessed whole-plant Rdark through dissection and simultaneous measurements of above- and below-ground organs. Variation in absolute Rdark was observed between techniques, likely due to variation in sample conditions (i.e. liquid vs. gas-phase, open vs. closed systems), indicating that comparisons between studies using different measuring apparatus may not be feasible. However, the high-throughput protocol we present provided similar values of Rdark to the most commonly used IRGA instrument currently employed by plant scientists. Together with the greater than tenfold increase in sample processing speed, we conclude that the high-throughput protocol enables reliable, stable and reproducible measurements of Rdark on multiple samples simultaneously, irrespective of plant or tissue type.


Rosuvastatin induces apoptosis in cultured human papillary thyroid cancer cells.
Statins show antiproliferative activity in various cancer cells. The aim of this study was to evaluate the effects of rosuvastatin treatment on papillary thyroid carcinoma. The papillary thyroid carcinoma (B-CPAP) and normal (Nthy-ori 3-1) thyroid cell lines were treated with rosuvastatin at 12.5, 18.5, 25, 50, 100, and 200 μM concentrations. After 48 and 72 h of rosuvastatin treatment, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, Ki-67 immunolabeling, FACS analysis, electron microscopy, caspase-3, and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) analysis were performed. Decreased cell viability and G1 phase arrest were detected in papillary thyroid cell line treated with rosuvastatin. Positive immunoreactivity of Ki-67 and dose-dependent increase in S phase on Nthy-ori 3-1 cells were also detected. B-CPAP cells showed intense vacuolisation and autophagosomes with low concentrations and 48 h incubations, while Nthy-ori 3-1 cells showed these changes at higher concentrations. A decrease in the percentage of cells showing autophagy was determined with increasing concentrations of rosuvastatin in B-CPAP cells. Rosuvastatin treatment also caused a dose- and time-dependent increase in caspase-3 activity and apoptotic index by TUNEL assay in B-CPAP cells compared with the Nthy-ori 3-1 cells. Apoptotic cells with nuclear condensation and fragmentation were observed in B-CPAP cell line. Rosuvastatin induced autophagic changes in B-CPAP papillary thyroid cancer cells in lower doses and caused a shift from autophagy to apoptosis. Rosuvastatin may be an alternative treatment for refractory papillary thyroid cancer. Further in vivo studies are necessary to clarify the effects of rosuvastatin in papillary thyroid carcinoma and the clinical implications of rosuvastatin treatment.


Alpelisib for treatment of patients with PIK3CA-related overgrowth spectrum (PROS).
PIK3CA-related overgrowth spectrum (PROS) encompasses several rare conditions resulting from activating variants in PIK3CA. Alpelisib, a PI3Kα-selective inhibitor, targets the underlying etiology of PROS, offering a novel therapeutic approach to current management strategies. This study evaluated the safety and efficacy of alpelisib in pediatric and adult patients with PROS. EPIK-P1 (NCT04285723) was a non-interventional, retrospective chart review of 57 patients with PROS (≥2 years) treated with alpelisib through compassionate use. Patients had severe/life-threatening PROS-related conditions and confirmed PIK3CA pathogenic variant. The primary end point assessed patient response to treatment at Week 24 (6 months). Twenty-four weeks (6 months) after treatment initiation, 12 of 32 (37.5%) patients with complete case records included in the analysis of the primary end point experienced a ≥20% reduction in target lesion(s) volume. Additional clinical benefit independent from lesion volume reduction was observed across the full study population. Adverse events (AEs) and treatment-related AEs were experienced by 82.5% (47/57) and 38.6% (22/57) of patients, respectively; the most common treatment-related AEs were hyperglycemia (12.3%) and aphthous ulcer (10.5%). No deaths occurred. EPIK-P1 provides real-world evidence of alpelisib effectiveness and safety in patients with PROS and confirms PI3Kα as a valid therapeutic target for PROS symptom management.


Classification of dermal patterns on the proximal sole.
A classification formula which includes all true patterns on the proximal sole and is based on topological principles is presented. The frequencies of all respective pattern elements were obtained from a sample of 219 healthy individuals of Croatian origin (116 males and 103 females) and all the formulae (total patterns) encountered in this sample are listed in a dictionary form. Examples of the whole configurations are also given and the applications of the topological formula, combining all patterns on the plantar surface, in studies of normal or abnormal variation of a system of parallel ridges, are indicated.


Influenza vaccination and decisional conflict among regulated and unregulated direct nursing care providers in long-term-care homes.
The purpose of this study was to determine whether direct nursing care providers have decisional conflict about receiving influenza vaccinations and characteristics associated with decisional conflict. The researchers used a self-administered questionnaire mailed to direct nursing care providers in two long-term-care organizations. Most direct nursing care providers in both organizations (80% and 93%, respectively) intended to get the influenza vaccine. Unregulated direct nursing care providers had more decisional conflict than regulated providers, especially related to feeling uninformed about the pros and cons of influenza vaccination. Unclear valuing of the pros and cons of influenza vaccination was related to the age of the direct care providers in both organizations. Decisional conflict and influenza vaccination practices may be determined, in part, by age and by the culture of a health care organization. A decision aid to improve knowledge and clarify values may improve decision quality and increase influenza vaccination rates.


Client and program characteristics associated with wait time to substance abuse treatment entry.
Wait time is among the most commonly cited barriers to access among individuals seeking entry to substance abuse treatment, yet relatively little is known about what contributes to it. To address this gap, this study draws from a national sample of substance abuse treatment clients and programs to estimate the proportion of clients entering treatment who waited more than 1 month to receive it (outpatient, residential, or methadone) and to identify client and program characteristics associated with wait time. This study used data from the National Treatment Improvement Evaluation Study (1992-1997). The data include 2920 clients from 57 substance abuse treatment programs. Generalized linear modeling was used to identify client and program characteristics associated with wait time to treatment entry. Results of modeling indicate that being African-American (OR: 1.40; CI: 1.04, 1.88), being referred by criminal justice (OR: 1.70; CI: 1.18, 2.43), and receiving methadone (OR: 3.90; CI: 1.00, 15.16) were associated with increased odds of waiting more than 1 month. Conversely, having a diagnosis of HIV/AIDS (OR: 0.38; CI: 0.19, 0.77) was associated with decreased odds of waiting for more than 1 month. A significant proportion of clients waited more than 1 month on enter treatment. Greater odds of such wait times were associated with being African-American, criminal justice-referred, and receiving methadone. This study is the first to use a national sample to examine the prevalence of wait time to substance abuse treatment entry and to identify client and program characteristics associated with it.


A Microfluidics-based Pulpal Arteriole Blood Flow Phantom for Validation of Doppler Ultrasound Devices in Pulpal Blood Flow Velocity Measurement.
Recently, Doppler ultrasound has been used for the measurement of pulpal blood flow in human teeth. However, the reliability of this method has not been verified. In this study, we developed a model to simulate arteriole blood flow within the dental pulp by using microfluidics. This arteriole simulator, or flow phantom, was used to determine the reliability of measurements obtained by using a Doppler ultrasound device. A microfluidic chip was fabricated by using the soft lithography technique, and blood-mimicking fluid was pumped through the channel by a microfluidic system. A Doppler ultrasound device was used for the measurement of flow velocity. The peak, mean, and minimal flow velocities obtained from the phantom and the Doppler ultrasound device were compared by using linear regression analysis and Pearson correlation coefficient. Bland-Altman analyses were performed to evaluate the velocity differences between the flow generated by the phantom and the flow measurements made with the Doppler ultrasound device. The microfluidic system was able to generate the flow profiles as intended, and the fluid flow could be monitored and controlled by the software program. There were excellent linear correlations between the peak, mean, and minimal flow velocities of the phantom and those of the Doppler ultrasound device (r = 0.94-0.996, P < .001). However, the velocities were overestimated by the Doppler ultrasound device. This phantom provides opportunities for research and education involving the Doppler ultrasound technique in dentistry. Although Doppler ultrasound can be an effective tool for the measurement of pulpal blood flow velocity, it is essential to validate and calibrate the device before clinical use.


Laboratory investigations in sheep with a new anthelmintic.
The efficacy of fenbendazole against the following gastrointestinal nematodes was tested in experimentally infected lambs: O circumcincta, H contortus, T colubriformis and N filicollis. As low a dose as 0.5 mg per kg reduced the egg output of a patent infection with H contortus and T colubriformis by 85 per cent to 100 per cent. A dose of 3.5 mg per kg has a 100 per cent effect on three or 10-day-old stages of H contortus and one of more than 99 per cent or 100 per cent T colubriformis. The same dose reduces seven-day-old stages of O circumcincta and N filicollis by more than 94 per cent or 100 per cent, while 10 mg per kg produces a 100 per cent elimination of seven-day-old stages of O circumcincta. In field trials and efficacy of more than 99 per cent was determined after oral dosage with 5.0 mg per kg against Ostertagia, Haemonchus, Trichostrongylus, Cooperia, Nematodirus and Chabertia. Fenbendazole has a wide therapeutic-toxic dose ratio. Discoloration of the wool does not occur. Fenbendazole can be administered as a drench or with the feed.


Myocardial infarction and thrombolysis. Electrocardiographic short term and long term results using precordial mapping.
In a consecutive series of 56 patients with acute myocardial infarction, ST segment depression and elevation in the electrocardiographic limb leads I, II, and III were summated for each patient before and immediately after intracoronary streptokinase infusion and the results compared with the angiographic findings. Forty three patients had angiographically confirmed reperfusion of an initially occluded vessel and showed a significant decrease in summated ST shift. The ST segment changes in the limb leads virtually returned to normal in all 43 patients, and in most, inverted T waves developed. Thrombolysis was unsuccessful in 10 patients, and the infarct related coronary artery was already patent in three. When these two groups are combined, all 13 patients without reperfusion showed no significant change in summated ST segment shift. During percutaneous transluminal angioplasty inflation of the balloon in the vessel that was previously occluded simulated reocclusion and was followed by new ST elevation if the artery supplied viable myocardium. In a further consecutive study of 54 patients with anterior myocardial infarction, the precordial R waves and Q waves were studied over the four to six months following infarction using a standardised 48 electrode mapping system. All patients underwent a repeat angiogram after four to six months. In 36 patients the infarct related vessel was patent. They showed a significant mean increase in summated precordial R wave amplitude and a reduction in the mean number of precordial leads without R waves. In 18 patients with unsuccessful thrombolysis or reocclusion there was a further reduction in mean summated R wave amplitude and an increased number of precordial leads not showing R waves. Precordial R wave mapping seems to be a valuable non-invasive method of assessing the salvage of myocardium after reperfusion and the damage caused by reocclusion. Loss of R waves in the acute phase of myocardial infarction does not necessarily mean an irreversibly damaged myocardium.


The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription.
Calcium/calmodulin-dependent kinase IV (CaMKIV) is a multifunctional serine/threonine kinase that is positively regulated by two main events. The first is the binding of calcium/calmodulin (Ca(2+)/CaM), which relieves intramolecular autoinhibition of the enzyme and leads to basal kinase activity. The second is activation by the upstream kinase, Ca(2+)/calmodulin-dependent kinase kinase. Phosphorylation of Ca(2+)/CaM-bound CaMKIV on its activation loop threonine (residue Thr(200) in human CaMKIV) by Ca(2+)/calmodulin-dependent kinase kinase leads to increased CaMKIV kinase activity. It has also been repeatedly noted that activation of CaMKIV is accompanied by the generation of Ca(2+)/CaM-independent or autonomous activity, although the significance of this event has been unclear. Here we demonstrate the importance of autonomous activity to CaMKIV biological function. We show that phosphorylation of CaMKIV on Thr(200) leads to the generation of a fully Ca(2+)/CaM-independent enzyme. By analyzing the behavior of wild-type and mutant CaMKIV proteins in biochemical experiments and cellular transcriptional assays, we demonstrate that CaMKIV autonomous activity is necessary and sufficient for CaMKIV-mediated transcription. The ability of wild-type CaMKIV to drive cAMP response element-binding protein-mediated transcription is strictly dependent upon an initiating Ca(2+) stimulus, which leads to kinase activation and development of autonomous activity in cells. Mutant CaMKIV proteins that are incapable of developing autonomous activity within a cellular context fail to drive transcription, whereas certain CaMKIV mutants that possess constitutive autonomous activity drive transcription in the absence of a Ca(2+) stimulus and independent of Ca(2+)/CaM binding or Thr(200) phosphorylation.


Directional sound source modeling using the adjoint Euler equations in a finite-difference time-domain approach.
An adjoint-based approach for synthesizing complex sound sources by discrete, grid-based monopoles in finite-difference time-domain simulations is presented. Previously, Stein, Straube, Sesterhenn, Weinzierl, and Lemke [(2019). J. Acoust. Soc. Am. 146(3), 1774-1785] demonstrated that the approach allows one to consider unsteady and non-uniform ambient conditions such as wind flow and thermal gradient in contrast to standard methods of numerical sound field simulation. In this work, it is proven that not only ideal monopoles but also realistic sound sources with complex directivity characteristics can be synthesized. In detail, an oscillating circular piston and a real two-way near-field monitor are modeled. The required number of monopoles in terms of the sound pressure level deviation between the directivity of the original and the synthesized source is analyzed. Since the computational effort is independent of the number of monopoles used for the synthesis, also more complex sources can be reproduced by increasing the number of monopoles utilized. In contrast to classical least-square problem solvers, this does not increase the computational effort, which makes the method attractive for predicting the effect of sound reinforcement systems with highly directional sources under difficult acoustic boundary conditions.


Optimal bearing surfaces for total hip replacement in the young patient: a meta-analysis.
Although there is general consensus about the efficacy of total hip replacement (THR) in young patients, the most appropriate bearings in young patients remain highly debated. The three most popular bearings in use include metal-on-polyethylene (MOP), metal-on-metal (MOM) and ceramic-on-ceramic (COC). We conducted a systematic review and meta-analysis of literature to summarise the best available evidence on relative success of the three most popular bearings used in THR in young active patients. Our findings support the use of MOM bearings in the management of the young arthritic hip. These findings, largely based upon observational studies, should be taken in the context of the limitations of such non-randomised study designs.


Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Plasmodium falciparum Esterase.
Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P. falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50 = 1.6 nM, n = 34) against fresh Ugandan P. falciparum isolates. The analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.


Djulis (Chenopodium Formosanum) Prevents Colon Carcinogenesis via Regulating Antioxidative and Apoptotic Pathways in Rats.
Djulis is a cereal crop rich in polyphenols and dietary fiber that may have nutraceutical activity to prevent colon cancer. This study was designed to examine the preventive effect of djulis on colon carcinogenesis in rats treated with 1,2-dimethylhydrazine (DMH). Rats were fed different AIN-93G-based diets: groups N and DMH were fed AIN-93G diet and groups LD, MD, and HD were fed AIN-93G diet containing 5, 10, and 20% djulis, respectively. All rats except for group N were injected with DMH to induce colon carcinogenesis. After 10 weeks, rats were sacrificed and colon and liver tissues were collected for analysis. The results showed that djulis-treated rats had significantly lower numbers of colonic preneoplastic lesions, aberrant crypt foci (ACF), sialomucin-producing (SIM)-ACF, and mucin-depleted foci. Djulis treatment increased superoxide dismutase and catalase activities in colon and liver. Djulis also reduced p53, Bcl-2, and proliferating cell nuclear antigen expressions and increased Bax and caspase-9 expressions. Besides, phenolic compounds and flavonoids were found rich in djulis. These results demonstrate the chemopreventive effect of djulis on carcinogen-induced colon carcinogenesis via regulating antioxidative and apoptotic pathways in rats. Djulis may have the potential to be developed as a valuable cereal product for chemoprevention of colon cancer.


The role of physical activity in rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease, causing progressive damage to the musculoskeletal system. Many patients with RA also suffer from accelerated muscle loss or cachexia, which contributes to the loss of physical function and quality of life. Physical activity plays a central role in the management of the disease as it is essential to maintain muscle strength and endurance, range of motion and the ability to perform activities of daily life. On the other hand, given the nature of the disease, there is always an increased risk for injury. There is a large amount of literature investigating the effect of exercise interventions on muscle function and disease activity. These studies show that exercise clearly improves muscle function without affecting disease activity. Studies including radiographic evaluation of joint damage as an endpoint also show that there is no evidence that exercise, even high-intensity exercise, increases inflammation or joint damage, although care should be taken with patients with severe baseline damage. Regarding daily physical activity (exercise is only one component of physical activity) there is hardly any research done showing either that physical activity is indeed decreased in patients or whether or not there is a relation between daily physical activity and disease activity. The results from studies looking at the effect of exercise on muscle mass or the ability to prevent or reverse cachexia are somewhat contradictory, but it seems that when the training dose is sufficiently large, gains in muscle mass can be achieved.


Interventions to promote cost-effectiveness in adult intensive care units: consensus statement and considerations for best practice from a multidisciplinary and multinational eDelphi study.
There is limited evidence to guide interventions that promote cost-effectiveness in adult intensive care units (ICU). The aim of this consensus statement is to identify globally applicable interventions for best ICU practice and provide guidance for judicious use of resources. A three-round modified online Delphi process, using a web-based platform, sought consensus from 61 multidisciplinary ICU experts (physicians, nurses, allied health, administrators) from 21 countries. Round 1 was qualitative to ascertain opinions on cost-effectiveness criteria based on four key domains of high-value healthcare (foundational elements; infrastructure fundamentals; care delivery priorities; reliability and feedback). Round 2 was qualitative and quantitative, while round 3 was quantitative to reiterate and establish criteria. Both rounds 2 and 3 utilized a five-point Likert scale for voting. Consensus was considered when > 70% of the experts voted for a proposed intervention. Thereafter, the steering committee endorsed interventions that were identified as 'critical' by more than 50% of steering committee members. These interventions and experts' comments were summarized as final considerations for best practice. At the conclusion of round 3, consensus was obtained on 50 best practice considerations for cost-effectiveness in adult ICU. Finally, the steering committee endorsed 9 'critical' best practice considerations. This included adoption of a multidisciplinary ICU model of care, focus on staff training and competency assessment, ongoing quality audits, thus ensuring high quality of critical care services whether within or outside the four walls of ICUs, implementation of a dynamic staff roster, multidisciplinary approach to implementing end-of-life care, early mobilization and promoting international consensus efforts on the Green ICU concept. This Delphi study with international experts resulted in 9 consensus statements and best practice considerations promoting cost-effectiveness in adult ICUs. Stakeholders (government bodies, professional societies) must lead the efforts to identify locally applicable specifics while working within these best practice considerations with the available resources.


Variance components analysis of forced expiration in families.
Familial aggregation of forced expiration (as measured by forced expiratory volume in 1 sec (FEV1) and the ratio of this to total forced vital capacity (FEV1/FVC) was analyzed in 439 adult members of 108 families ascertained through control patients who had participated in a genetic and epidemiologic study of chronic obstructive pulmonary disease. Residual values for both FEV1 and FEV1/FVC obtained from regression on age, sex, race, and cigarette smoking (and height for FEV1) were used in a variance components analysis to assess the relative importance of genetic and nongenetic factors influencing familial aggregation of pulmonary function among adults. For both residual FEV1 and residual FEV1/FVC, the "best" model among a series of genetic and nongenetic models was a simple additive genetic model. A modified score test, which is robust to the assumption of multivariate normality, was used to test the significance of these estimated components. Under the most parsimonious model, additive genetic variation accounted for 28% of the variation in residual FEV1 in 108 families and 24% of the variation in residual FEV1/FVC. After outlying individuals were identified by examining goodness-of-fit statistics, the simple genetic model still gave the best fit to these data. There was little indication of non-normality in FEV1 in these families; however, FEV1/FVC did show evidence of non-normality when examining goodness-of-fit statistics. This genetic component contributing to the distribution of forced expiration may be a factor in the familial aggregation of certain respiratory diseases.


Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP).
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder characterised by muscle weakness and impaired sensory function. The present study provides a comprehensive literature review of the burden of illness of CIDP. Systematic literature search of PubMed, Embase, and key conferences in May 2019. Search terms identified studies on the epidemiology, humanistic burden, current treatment, and economic burden of CIDP published since 2009 in English. Forty-five full texts and nineteen conference proceedings were identified on the epidemiology (n = 9), humanistic burden (n = 7), current treatment (n = 40), and economic burden (n = 8) of CIDP. Epidemiological studies showed incidence and prevalence of 0.2-1.6 and 0.8-8.9 per 100,000, respectively, depending on geography and diagnostic criteria. Humanistic burden studies revealed that patients experienced physical and psychosocial burden, including impaired physical function, pain and depression. Publications on current treatments reported on six main types of therapy: intravenous immunoglobulins, subcutaneous immunoglobulins, corticosteroids, plasma exchange, immunosuppressants, and immunomodulators. Treatments may be burdensome, due to adverse events and reduced independence caused by treatment administration setting. In Germany, UK, France, and the US, CIDP economic burden was driven by direct costs of treatment and hospitalisation. CIDP was associated with indirect costs driven by impaired productivity. This first systematic review of CIDP burden of illness demonstrates the high physical and psychosocial burden of this rare disease. Future research is required to fully characterise the burden of CIDP, and to understand how appropriate treatment can mitigate burden for patients and healthcare systems.


Managing antipsychotic-related sexual dysfunction in patients with schizophrenia.
Schizophrenia is a psychotic disorder and one of the most severe and impactful mental illnesses. Sexual dysfunction is highly prevalent in patients with schizophrenia but remains underdiagnosed and undertreated. Sexual dysfunction is frequently attributed to antipsychotics which may reduce medication adherence, but negative symptoms can also reduce sexual drive. This review provides an overview of the current knowledge about sexual dysfunction in patients with schizophrenia. The authors first review the literature concerning the mechanisms of sexual dysfunction and explore the impact of antipsychotics on sexual function. Finally, they present the available non-pharmacological and pharmacological treatment strategies for sexual dysfunction in patients with schizophrenia. Sexual dysfunction in patients with schizophrenia is still underrated by clinicians despite having a negative impact on the quality of life and therapeutic adherence. Antipsychotic treatment is still perceived as a major cause of sexual impairment. Psychiatrists must be aware of this condition and actively question the patients. A comprehensive approach, addressing pharmacological and non-pharmacological aspects, is fundamental for managing sexual dysfunction in schizophrenia. Pharmacological strategies include (1) Serum-level adjustment of the antipsychotic dose, if possible (2) switching to a well-tolerable antipsychotic (aripiprazole, brexpiprazole) and (3) adding a coadjuvant drug (phosphodiesterase-5 inhibitors).


The burden of urological disease in Zomba, Malawi: A needs assessment in a sub-Saharan tertiary care center.
A large part of the developing world continues to lack access to surgical care. Urology remains one of the least represented surgical subspecialties in global health. To begin understanding the burden of urological illness in sub-Saharan Africa, we sought to characterize all patients presenting to a tertiary care hospital in Malawi with a urological diagnosis or related complaint in the past year. Retrospective review of the surgical clinic and surgical theater record books at Zomba Central Hospital (ZCH) was performed over a one-year time span. Patients presenting with urological diagnoses or undergoing a urological procedure under local or general anesthetic in the operating theater were identified and entered into a database. We reviewed 440 clinical patients. The most common clinical presentations were for urinary retention (34.7%) and lower urinary tract symptoms (15.5%). A total of 182 surgical cases were reviewed. The most common diagnoses for surgical patients were urethral stricture disease (22%), bladder masses (17%), and benign prostatic hyperplasia (BPH) symptoms (14.8%). Urethral stricture-related procedures, including direct visual internal urethrotomy and urethral dilatation, were the most common (14.2% and 7.7%, respectively). BPH-related procedures, including simple prostatectomy and transurethral resection of the prostate were the second most common (6.7% and 8.2%, respectively). Urethral stricture disease, BPH, and urinary retention represent the clinical diagnoses with the highest burden of visits. Despite these numbers, few definitive procedures are performed annually. Further focus on urological training in sub-Saharan Africa should focus on these conditions and their surgical management.


[O2-* burst of tobacco leaves triggered by Erwinia carotovora subsp. carotovora inoculation].
O(-.)(2) production based on chemical method by Ecc-treated intact tobacco leaves was observed. It showed a long-lasting one-phase course beginning 1 h and ending 14 h after Erwinia carotovora subsp. carotovora (Ecc) was inoculated. In Ecc-treated leaves, O(-.)(2) production rate of 3 h is 2 times of 1 h, and of 10 h it remains 1.7 times. It decreases rapidly between 10 h and 14 h, at 14 h it falls to the level before inoculation. This is a completely different course from the widely accepted two-phase course obtained from suspension-cultured cells. Electron spin resonance (ESR) spectrum of O(-.)(2) produced by intact tobacco leaves after Ecc inoculation 2 h and 6 h was also observed, the amplitude of 6 h is larger than of 2 h in Ecc-treated group. In the control group, there is no difference between the amplitude of 2 h and 6 h. This indicated that O(-.)(2) amount of Ecc-treated group is higher than of the control group, which is the same result as obtained through chemical method. The ESR spectrum of O(-.)(2) produced by chloroplasts and mitochondria from tobacco leaves after 2 h and 6 h after Ecc inoculation were observed. In chloroplast experiment, the amplitude of 6 h was larger than of 2 h in Ecc-treated group while it was the same in the control group. ESR spectrum of O(-.)(2) produced by mitochondria was proved to be a same result after a careful comparison, in spite of a greater difference between 2 h and 6 h in control group than chloroplast experiment. The fact that spectra of these two organelles were both synchronous with that of intact leaves implied that these two organelles possibly participated in cellular O(-.)(2) burst. Chloroplasts in the dark showed no ESR spectrum 2 h and 6 h after Ecc inoculation in Ecc-treated group as well as in the control group, indicating that O(-.)(2) in the chloroplast probably originated from the photosynthetic electron transport process.


Readmission After Craniotomy for Tumor: A National Surgical Quality Improvement Program Analysis.
Although readmission has become a common quality indicator, few national studies have examined this metric in patients undergoing cranial surgery. To utilize the prospective National Surgical Quality Improvement Program 2011-2013 registry to evaluate the predictors of unplanned 30-d readmission and postdischarge mortality after cranial tumor resection. Multivariable logistic regression was applied to screen predictors, which included patient age, sex, tumor location and histology, American Society of Anesthesiologists class, functional status, comorbidities, and complications from the index hospitalization. Of the 9565 patients included, 10.7% (n = 1026) had an unplanned readmission. Independent predictors of unplanned readmission were male sex, infratentorial location, American Society of Anesthesiologists class 3 designation, dependent functional status, a bleeding disorder, and morbid obesity (all P ≤ .03). Readmission was not associated with operative time, length of hospitalization, discharge disposition, or complications from the index admission. The most common reasons for readmission were surgical site infections (17.0%), infectious complications (11.0%), venous thromboembolism (10.0%), and seizures (9.4%). The 30-d mortality rate was 3.2% (n = 367), of which the majority (69.7%, n = 223) occurred postdischarge. Independent predictors of postdischarge mortality were greater age, metastatic histology, dependent functional status, hypertension, discharge to institutional care, and postdischarge neurological or cardiopulmonary complications (all P < .05). Readmissions were common after cranial tumor resection and often attributable to new postdischarge complications rather than exacerbations of complications from the initial hospitalization. Moreover, the majority of 30-d deaths occurred after discharge from the index hospitalization. The preponderance of postdischarge mortality and complications requiring readmission highlights the importance of posthospitalization management.


MORBIDITY AND MORTALITY PATTERNS OF INDIAN RIVER LAGOON COMMON BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS TRUNCATUS) 2002-2020.
Mortality patterns in cetaceans are critical to understanding population health. Common bottlenose dolphins (Tursiops truncatus truncatus) inhabiting the Indian River Lagoon (IRL), Florida have been subjected to four unusual mortality events (UMEs), highlighting the need to evaluate morbidity and mortality patterns. Complete gross examinations were conducted on 392 stranded dolphins and histopathological analyses were conducted for 178 animals (2002-2020). The probable causes of mortality were grouped by etiologic category: degenerative, metabolic, nutritional, inflammatory (infectious and noninfectious disease), and trauma. Probable cause of mortality was determined in 57% (223/392) of cases. Inflammatory disease (infectious/noninfectious) and trauma were the most common. Inflammatory disease accounted for 41% of cases (91/223), with the lungs (pneumonia) most commonly affected. Trauma accounted for 36% of strandings (80/223). The majority of trauma cases were due to anthropogenic activities (entanglement, fishing gear or other debris ingestion, and propeller strikes), accounting for 58% of trauma cases (46/80). Natural trauma (prey-associated esophageal obstruction or asphyxiation, shark bites, and stingray interactions) accounted for 12% of all cases (26/223), and trauma of undetermined origin was identified in 4% of cases (8/223). Starvation or inanition (nutritional) were the probable cause of mortality in 17% of cases and peaked during the 2013 UME (61% of cases). Degenerative and metabolic etiologies accounted for 5% of cases. This study represents the most comprehensive evaluation of morbidity and mortality patterns in IRL dolphins. Because IRL dolphins are routinely exposed to anthropogenic threats and have endured multiple UMEs, these baseline data are critical to the conservation and management of this population.


Isolation of intact vacuoles and proteomic analysis of tonoplast from suspension-cultured cells of Arabidopsis thaliana.
A large number of proteins in the tonoplast, including pumps, carriers, ion channels and receptors support the various functions of the plant vacuole. To date, few proteins involved in these activities have been identified at the molecular level. In this study, proteomic analysis was used to identify new tonoplast proteins. A primary requirement of any organelle analysis by proteomics is that the purity of the isolated organelle needs to be high. Using suspension-cultured Arabidopsis cells (Arabidopsis Col-0 cell suspension), a method was developed for the isolation of intact highly purified vacuoles. No plasma membrane proteins were detected in Western blots of the isolated vacuole fraction, and only a few proteins from the Golgi and endoplasmic reticulum. The proteomic analysis of the purified tonoplast involved fractionation of the proteins by SDS-PAGE and analysis by LC-MS/MS. Using this approach, it was possible to identify 163 proteins. These included well-characterized tonoplast proteins such as V-type H+ -ATPases and V-type H+ -PPases, and others with functions reasonably expected to be related to the tonoplast. There were also a number of proteins for which a function has not yet been deduced.


Is the psychological impact of genetic testing moderated by support and sharing of test results to family and friends?
Receiving the results of genetic tests for a breast and ovarian cancer susceptibility can be a stressful experience. Here we studied the effects of social support (SS) and the sharing of test results on the psychological impact of BRCA1/2 test result disclosure. We also compared carriers and non-carriers on sharing, SS and psychological impact. Five-hundred and twenty-two unaffected women were followed prospectively for 2 years after receiving their test results. Psychological impact was measured on the impact of event scale. Multivariate multi-level models were used, and all the analyses were stratified depending on mutation status (carriers vs non-carriers). Two weeks after receiving their BRCA1/2 results, carriers had shared their test results less frequently than non-carriers (p < 0.01). Sharing test results was not significantly associated with psychological impact. Availability of SS was significantly associated with better psychological adjustment across time among carriers (p < 0.01), but not among non-carriers. For female BRCA1/2 mutation carriers, the importance of SS should be stressed, and possible ways of enlisting people in their entourage for this purpose should be discussed in the context of clinical encounters.


Genotype by sex and genotype by age interactions with sedentary behavior: the Portuguese Healthy Family Study.
Sedentary behavior (SB) expression and its underlying causal factors have been progressively studied, as it is a major determinant of decreased health quality. In the present study we applied Genotype x Age (GxAge) and Genotype x Sex (GxSex) interaction methods to determine if the phenotypic expression of different SB traits is influenced by an interaction between genetic architecture and both age and sex. A total of 1345 subjects, comprising 249 fathers, 327 mothers, 334 sons and 325 daughters, from 339 families of The Portuguese Healthy Family Study were included in the analysis. SB traits were assessed by means of a 3-d physical activity recall, the Baecke and IPAQ questionnaires. GxAge and GxSex interactions were analyzed using SOLAR 4.0 software. Sedentary behaviour heritability estimates were not always statistically significant (p>0.05) and ranged from 3% to 27%. The GxSex and GxAge interaction models were significantly better than the single polygenic models for TV (min/day), EEsed (kcal/day), personal computer (PC) usage and physical activty (PA) tertiles. The GxAge model is also significantly better than the polygenic model for Sed (min/day). For EEsed, PA tertiles, PC and Sed, the GxAge interaction was significant because the genetic correlation between SB environments was significantly different from 1. Further, PC and Sed variance heterogeneity among distinct ages were observed. The GxSex interaction was significant for EEsed due to genetic variance heterogeneity between genders and for PC due to a genetic correlation less than 1 across both sexes. Our results suggest that SB expression may be influenced by the interactions between genotype with both sex and age. Further, different sedentary behaviors seem to have distinct genetic architectures and are differentially affected by age and sex.


Physostigmine in mania.
Seven men and one woman with primary affective disorder, mania, were given a slow intravenous infusion of physostigmine salicylate. In six patients, mood and thought content changed from mania toward depression as evaluated by either a visual analog mood scale or the Pettersen scale. Two other patients, who were the only predominantly irritable manics in the study, demonstrated little change in their hostility, although one became somewhat depressed. These findings are consistent with earlier reports of suppression of manic symptoms after physostigmine infusion in some but not all patients with mania. The pharmacologic mechanism of physostigmine reversal of manic symptoms may be the direct result of increased cholinergic activity or a result of the effect of increased cholinergic activity on other brain neurotransmitters.


Haplotype Analysis of GmSGF14 Gene Family Reveals Its Roles in Photoperiodic Flowering and Regional Adaptation of Soybean.
Flowering time and photoperiod sensitivity are fundamental traits that determine soybean adaptation to a given region or a wide range of geographic environments. The General Regulatory Factors (GRFs), also known as 14-3-3 family, are involved in protein-protein interactions in a phosphorylation-dependent manner, thus regulating ubiquitous biological processes, such as photoperiodic flowering, plant immunity and stress response. In this study, 20 soybean GmSGF14 genes were identified and divided into two categories according to phylogenetic relationships and structural characteristics. Real-time quantitative PCR analysis revealed that GmSGF14g, GmSGF14i, GmSGF14j, GmSGF14k, GmSGF14m and GmSGF14s were highly expressed in all tissues compared to other GmSGF14 genes. In addition, we found that the transcript levels of GmSGF14 family genes in leaves varied significantly under different photoperiodic conditions, indicating that their expression responds to photoperiod. To explore the role of GmSGF14 in the regulation of soybean flowering, the geographical distribution of major haplotypes and their association with flowering time in six environments among 207 soybean germplasms were studied. Haplotype analysis confirmed that the GmSGF14mH4 harboring a frameshift mutation in the 14-3-3 domain was associated with later flowering. Geographical distribution analysis demonstrated that the haplotypes related to early flowering were frequently found in high-latitude regions, while the haplotypes associated with late flowering were mostly distributed in low-latitude regions of China. Taken together, our results reveal that the GmSGF14 family genes play essential roles in photoperiodic flowering and geographical adaptation of soybean, providing theoretical support for further exploring the function of specific genes in this family and varietal improvement for wide adaptability.


Decoding Analysis of Alpha Oscillation Networks on Maintaining Driver Alertness.
The countermeasure of driver fatigue is valuable for reducing the risk of accidents caused by vigilance failure during prolonged driving. Listening to the radio (RADIO) has been proven to be a relatively effective "in-car" countermeasure. However, the connectivity analysis, which can be used to investigate its alerting effect, is subject to the issue of signal mixing. In this study, we propose a novel framework based on clustering and entropy to improve the performance of the connectivity analysis to reveal the effect of RADIO to maintain driver alertness. Regardless of reducing signal mixing, we introduce clustering algorithm to classify the functional connections with their nodes into different categories to mine the effective information of the alerting effect. Differential entropy (DE) is employed to measure the information content in different brain regions after clustering. Compared with the Louvain-based community detection method, the proposed method shows more superior ability to present RADIO effectin confused functional connection matrices. Our experimental results reveal that the active connection clusters distinguished by the proposed method gradually move from frontal region to parieto-occipital regionwith the progress of fatigue, consistent with the alpha energy changes in these two brain areas. The active class of the clusters in parieto-occipital region significantly decreases and the most active clusters remain in the frontal region when RADIO is taken. The estimation results of DE confirm the significant change (p < 0.05) of information content due to the cluster movements. Hence, preventing the movement of the active clusters from frontal region to parieto-occipital region may correlate with maintaining driver alertness. The revelation of alerting effect is helpful for the targeted upgrade of fatigue countermeasures.


Role of thiols in degradation of proteins by cathepsins.
The effects of thiols on the breakdown of 125I-labelled insulin, albumin and formaldehyde-treated albumin by highly purified rat liver cathepsins B, D, H and L at pH 4.0 and 5.5 were studied. At both pH values degradation was strongly activated by the thiols cysteamine, cysteine, dithiothreitol, glutathione and 2-mercaptoethanol, and its rate increased with increasing thiol concentration. Preincubation of the protein substrates with 5 mM-glutathione did not affect concentration. Preincubation of the protein substrates with 5 mM-glutathione did not affect the rate of degradation by cathepsin D or L, and determination of free thiol groups after incubation of the proteins in the presence of glutathione but without cathepsin showed that their disulphide bonds were stable under the incubation conditions. Sephadex G-75 chromatography of the acid-soluble products of insulin digestion by cathepsin D or L suggested that thiols can reduce disulphide bonds in proteins after limited proteolysis. The resultant opening-up of the protein structure would lead to further proteolysis, so that the two processes (proteolysis and reduction) may act synergistically. By using the osmotic protection method it was shown that, at a physiological pH, cysteamine, and its oxidized form cystamine, can cross the lysosome membrane and thus may well be the physiological hydrogen donor for the reduction of disulphides in lysosomes. The results are discussed in relation to the lysosomal storage disease cystinosis.


A case of lithium poisoning? A cautionary tale.
The case of a 58 year old woman on maintenance lithium therapy who developed an acute organic brain syndrome is reported. The patient subsequently showed evidence of persistent brain damage. It is suggested that lithium toxicity was precipitated by electrolyte disturbances possibly caused by self medication with a diuretic, where serum levels of lithium were an unreliable measure of impending toxicity.


The oldest patient to undergo aortic valve replacement.
As the American population ages, more elderly patients will present with significant heart disease. This group has an increase in morbidity and mortality with heart surgery as compared to a younger population. Severe aortic stenosis has a grave prognosis, and therefore surgical options should be considered even in the most elderly patient with this condition. We present the oldest reported patient to undergo aortic valve replacement for severe aortic stenosis.


Prevalence of undiagnosed eye/vision disorders in a VA hospital.
A study population of one hundred and one subjects, chosen according to recommended epidemiologic procedures to assure an accurate representation of the total Birmingham veteran population, were given complete optometric examinations. The primary criterion for inclusion in the study was a need for coming to the hospital on the interview day for any health problem other than visual or ocular. The results of the statistical analysis showed agreement between the Birmingham veteran population and the general population with regard to vision and ocular disorders. Presbyopia was found to be the most prevalent vision disorder, and fifty-four per cent of the study population needed either prescription lenses for the first time or a significant change in their present spectacles for maximum visual acuity. When this figure is projected nationally, fifty-four percent of the fourteen million outpatients treated last year in VA medical care facilities would represent 7,616,000 veterans in need of vision care services annually. In fact, since the sample average age was 46, and the average age for veterans nationally is 55, the figure for those with uncorrected vision defects may be even higher.


Monoclonal antibody-based time-resolved fluorescence immunoassays for daidzein, genistein, and equol in blood and urine: application to the Isoheart intervention study.
Time-resolved fluorescence immunoassays (TR-FIAs) for phytoestrogens in biological samples are an alternative to mass spectrometric methods. These immunoassays were used to test urine and plasma samples from individuals in a dietary intervention trial aimed at determining the efficacy of dietary isoflavones in reducing the risk of coronary heart disease in postmenopausal women. We established murine monoclonal TR-FIA methods for daidzein, genistein, and equol. These assays could be performed manually or adapted to an automated analyzer for high throughput and increased accuracy. Analysis of urine was conducted on nonextracted samples. Blood analysis was performed on nonextracted samples for daidzein, whereas genistein and equol required diethyl-ether extraction. Comparison of monoclonal TR-FIA, commercial polyclonal antibody-based TR-FIA, and gas chromatography-mass spectrometry showed correlations (r, 0.911-0.994) across the concentration range observed in the Isoheart study (50 mg/day isoflavones). The concentrations of urinary daidzein and genistein observed during intervention demonstrated good compliance, and a corresponding increase in serum daidzein and genistein confirmed bioavailability of the isoflavone-rich foods; 33 of the 117 volunteers (28.2%) were classified as equol producers on the basis of their urinary equol concentration (>936 nmol/L), and significant differences in the numbers of equol producers were observed between Berlin and the 3 other European cohorts studied. The validated monoclonal TR-FIA methods are applicable for use in large-scale human phytoestrogen intervention studies and can be used to monitor compliance, demonstrate bioavailability, and assess equol producer status.


Dose adjustment of anaesthetics in the morbidly obese.
Anaesthesiologists must be prepared to deal with pharmacokinetic and pharmacodynamic (PD) differences in morbidly obese individuals. As drug administration based on total body weight can result in overdose, weight-based dosing scalars must be considered. Conversely, administration of drugs based on ideal body weight can result in a sub-therapeutic dose. Changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetic drugs. With the exception of neuromuscular antagonists, lean body weight is the optimal dosing scalar for most drugs used in anaesthesia including opioids and anaesthetic induction agents. The increased incidence of obstructive sleep apnoea and fat deposition in the pharynx and chest wall places the morbidly obese at increased risk for adverse respiratory events secondary to anaesthetic agents, thus altering the PD properties of these drugs. Awareness of the pharmacology of the commonly used anaesthetic agents including induction agents, opioids, inhalation agents and neuromuscular blockers is necessary for safe and effective care of morbidly obese patients.