Frailty: Identifying elderly patients at high risk of poor outcomes.
To help family physicians better recognize frailty and its implications for managing elderly patients. PubMed-MEDLINE was searched from 1990 to 2013. The search was restricted to English-language articles using the following groups of MeSH headings and key words: frail elderly, frail, frailty; aged, geriatrics, geriatric assessment, health services for the aged; and primary health care, community health services, and family practice. Frailty is common, particularly in elderly persons with complex chronic conditions such as heart failure and chronic obstructive pulmonary disease. Emerging evidence demonstrates the value of frailty as a predictor of adverse outcomes in older persons. While there is currently a lack of consensus as to how best to assess and diagnose frailty in primary care practice, individual markers of frailty such as low gait speed offer a promising feasible means of screening for frailty. Identification of frailty in primary care might provide an opportunity to delay the progression of frailty through proactive interventions such as exercise, and awareness of frailty can guide appropriate counseling and anticipatory preventive measures for patients when considering medical interventions. Recognition of frailty might also help identify and optimize the management of coexisting conditions that might contribute to or be affected by frailty. Further research should be directed at identifying feasible and effective ways to appropriately assess and manage these vulnerable patients at the primary care level. Despite its importance, little attention has been given to the concept of frailty in family medicine. Frailty is easily overlooked because its manifestations can be subtle, slowly progressive, and thus dismissed as normal aging; and physician training has been focused on specific medical diseases rather than overall vulnerability. For primary care physicians, recognition of frailty might help them provide appropriate counseling to patients and family members about the risks of medical interventions.


Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: an example from a vertigo phase III study with longitudinal count data as primary endpoint.
A statistical analysis plan (SAP) is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. We focus on generalized linear mixed models (GLMMs) for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs). The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC) or probability integral transform (PIT), and by using proper scoring rules (e.g. the logarithmic score). The instruments under study provide excellent tools for preparing decisions within the SAP in a transparent way when structuring the primary analysis, sensitivity or ancillary analyses, and specific analyses for secondary endpoints. The mean logarithmic score and DIC discriminate well between different model scenarios. It becomes obvious that the naive choice of a conventional random effects Poisson model is often inappropriate for real-life count data. The findings are used to specify an appropriate mixed model employed in the sensitivity analyses of an ongoing phase III trial. The proposed Bayesian methods are not only appealing for inference but notably provide a sophisticated insight into different aspects of model performance, such as forecast verification or calibration checks, and can be applied within the model selection process. The mean of the logarithmic score is a robust tool for model ranking and is not sensitive to sample size. Therefore, these Bayesian model selection techniques offer helpful decision support for shaping sensitivity and ancillary analyses in a statistical analysis plan of a clinical trial with longitudinal count data as the primary endpoint.


Schema Modes and Personality Disorder Symptoms in Alcohol-Dependent and Cocaine-Dependent Patients.
Substance use disorders (SUD) and personality disorders co-occur frequently. This relationship might be understood by studying schema modes (a key concept in Schema therapy), which explain the dysfunctions characterizing personality disorder patients. In the present study, we compared the schema modes and personality disorder symptoms between alcohol-dependent patients, cocaine-dependent patients and healthy controls. We found indications that specific schema modes are specific for SUD patients. However, no differences between specific subtypes of SUD patients (alcohol- vs. cocaine-dependent patients) could be found regarding schema modes. Further, it is suggested that borderline personality disorder symptoms are highly relevant for SUD patients. A first step is made in understanding the relationship between schema modes and SUD, which may contribute to the understanding of the problematic behaviour seen in patients with personality disorders and SUD (and may possibly contribute to the improvement of the treatment of this group of patients).


Telepsychiatry in India - Where Do We Stand? A Comparative Review between Global and Indian Telepsychiatry Programs.
A wide discrepancy exists in India between the existing mental healthcare repertoire and the alarmingly high burden of individuals requiring immediate attention from requisite mental healthcare services. Providing equitable mental healthcare across a vast country characterized by profound cultural variations and territorial caveats has remained a major public health concern. Against this gloomy backdrop, the emergence of distant communications technology offers solace and optimism as an ingenious approach to bridge the existing gap between clients and mental health professionals. Using inexpensive equipment and basic technical knowhow, telepsychiatry expands the scope of the discipline to distant and hazy suburbs and villages from its urban centers of excellence. The current academic endeavor intends to perform a systematic review of relevant literature from India as well as from other countries. The various models of telepsychiatry-both asynchronous and synchronous models-in practice have been elaborated on with a focus on effectiveness, feasibility and acceptability of this latest modality. A sincere attempt to chronicle the remarkable journey of telepsychiatry in India, beginning in the dawn of the 21st century to the current Indian scenario, has been made. The legal and ethical issues, along with a few words of caution and contemplation, have been briefly touched on. A set of recommendations has been provided with the hope that policy makers and administrators in the domain of mental health may benefit from them. It is anticipated that telepsychiatry will be adequately utilized in India to tackle the raging menace of inadequate mental healthcare services.


Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation.
In patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), treatment-induced changes to the gastrointestinal tract (GIT) microbiome have been linked to adverse outcomes, most notably graft-versus-host disease (GvHD). However, it is presently unknown whether this relationship is causal or consequential. Here, we performed an integrated meta-omic analysis to probe deeper into the GIT microbiome changes during allo-HSCT and its accompanying treatments. We used 16S and 18S rRNA gene amplicon sequencing to resolve archaea, bacteria, and eukaryotes within the GIT microbiomes of 16 patients undergoing allo-HSCT for the treatment of hematologic malignancies. These results revealed a major shift in the GIT microbiome after allo-HSCT including a marked reduction in bacterial diversity, accompanied by only limited changes in eukaryotes and archaea. An integrated analysis of metagenomic and metatranscriptomic data was performed on samples collected from a patient before and after allo-HSCT for acute myeloid leukemia. This patient developed severe GvHD, leading to death 9 months after allo-HSCT. In addition to drastically decreased bacterial diversity, the post-treatment microbiome showed a higher overall number and higher expression levels of antibiotic resistance genes (ARGs). One specific Escherichia coli strain causing a paravertebral abscess was linked to GIT dysbiosis, suggesting loss of intestinal barrier integrity. The apparent selection for bacteria expressing ARGs suggests that prophylactic antibiotic administration may adversely affect the overall treatment outcome. We therefore assert that such analyses including information about the selection of pathogenic bacteria expressing ARGs may assist clinicians in "personalizing" regimens for individual patients to improve overall outcomes.


Self-collimating photonic crystal antireflection structure for both TE and TM polarizations.
We present a high-efficiency antireflection structure for both TE and TM polarizations in two-dimensional self-collimating square lattice photonic crystal consisting of air holes in silicon. The design parameters of the optimal antireflection structure can be obtained by using the concept of Fresnel coefficients and the finite-difference time-domain simulations. The photonic crystal operating in almost identical self-collimation frequencies for two polarizations exhibits a large reflection coefficient for TE and a very small one for TM polarization. In this case, the antireflection structure for TE can also improve the transmission for TM polarization. To confirm a highly efficient antireflection structure designed, we investigate the transmission data of three finite photonic crystal samples consisting of 36, 38 and 40 unit cells for the cases without and with the antireflection structures through finite-difference time-domain simulations.


Fracture resistance of three-unit zirconia fixed partial denture with modified framework.
Obtaining ideal prosthetic framework design is at times hindered by anatomical limitations in the posterior region that might increase the risk for zirconia restoration fracture. Modification such as increasing the bulk thickness especially in the connector region could result in strengthening the zirconia framework. Three-unit zirconia fixed partial dentures replacing mandibular molars were fabricated using the following two techniques: CAD/CAM technology and manual copy milling. Modified framework with unveneered full thickness connectors were designed and fabricated with the aforementioned methods. Conventional frameworks (0.5 mm thick with rounded 3 mm connectors) served as control (N = 20). After cementation on epoxy dies, the frameworks were loaded to fracture in a universal testing machine. Fractured surfaces were prepared for examination using scanning electron microscopy. Statistical analysis revealed significant differences in fracture resistance between conventional and modified framework design for both fabrication techniques tested. SEM examination indicated that critical crack originated at the tensile surface of the connectors for conventional frameworks. The critical crack for modified frameworks occurred on the axial wall of the abutments. The modification of the zirconia framework design presented significant improvement of the fracture resistance compared to the conventional design.


Characteristics of chest pain and its acute management in a low-middle income country: analysis of emergency department surveillance data from Pakistan.
Chest pain is one of the most frequent causes of emergency department (ED) visits in high-income countries. Little is known about chest pain patients presenting to EDs of low- and middle-income countries (LMICs). The objective of this study was to describe the characteristics of chest pain patients presenting to emergency departments (EDs) of Pakistan and to determine the utilization of ED resources in the management of chest pain patients and their outcomes. This study used pilot active surveillance data from seven major EDs in Pakistan. Data were collected on all patients presenting to the EDs of the participating sites to seek emergency care for chest pain. A total of 20,435 patients were admitted to the EDs with chest pain. The majority were males (M 60%, F 40%) and the mean age was 42 years (SD+/- 14). The great majority (97%, n = 19,164) of patients were admitted to the EDs of public hospitals compared to private hospitals and only 3% arrived by ambulance. Electrocardiograms (ECGs) were used in more than half of all chest pain patients (55%, n = 10,890) while cardiac enzymes were performed in less than 5% of cases. Chest X-rays were the most frequently performed radiological procedure (21%, n = 4,135); more than half of the admitted chest pain patients were discharged from the EDs and less than 1% died in the ED. Chest pain is a common presenting complaint in EDs in Pakistan. The majority received an ECG and the use of diagnostic testing, such as cardiac enzymes, is quite uncommon.


Whole-body MRI and PET-CT in the management of cancer patients.
Mortality rate, prognosis, and treatment outcome of cancer patients depend strongly on the detection of malignancy at an early stage and efficient monitoring of the disease. Multimodality diagnostic approaches are now widely applied for tumor detection, staging, and follow-up. However, the introduction of whole-body imaging modalities into clinical practice has substantially expanded diagnostic options. PET-CT has increased diagnostic accuracy by providing "anatometabolic" information by fusing tumor glucose-uptake measures from the PET examination and accurate delineation of anatomical structures given by spiral CT. Since PET-CT is associated with high doses of ionizing radiation, it is used in mainly tumor staging and screening within the scope of tertiary prevention. Here promising results have been reported for various tumor entities. MRI provides excellent tissue contrast, detailed morphological information and lack of ionizing radiation. MRI has been employed for the assessment of focal pathologies in specific anatomical regions. Whole-body MRI scanners using multiple receiver channels with parallel acquisition techniques now allow tumor screening from head to toe within substantially shorter examination times and without compromises in image resolution. We report our experience with these two novel techniques and discuss their benefits and drawbacks in terms of systemic tumor screening.


Enhanced cognitive behavior therapy for severe and extreme anorexia nervosa: An outpatient case series.
The study aimed to assess outcomes in patients with severe and extreme anorexia nervosa managed with enhanced cognitive behavior therapy (CBT-E) in a real-world outpatient setting. Thirty patients with anorexia nervosa and body mass index (BMI) <16 aged ≥17 years were recruited from consecutive referrals to an eating disorder service clinic offering outpatient CBT-E. BMI and Eating Disorder Examination Questionnaire (EDE-Q), Brief Symptom Inventory (BSI), and Clinical Impairment Assessment (CIA) scores were recorded at admission, end of treatment, and 20- and 60-week follow-ups for treatment completers. Twenty patients (66.7%) completed the treatment and showed both considerable weight gain (Cohen's f = 1.43), and significantly reduced scores for clinical impairment (f = 1.26) and eating-disorder (f = 1.03) and general psychopathology (f = 0.99). Changes remained stable at both follow-ups. About half of the patients who completed treatment had a BMI ≥18.5 at the end of treatment and follow-ups. CBT-E seems suitable and promising for patients with severe and extreme anorexia nervosa seeking treatment in a real-world clinical setting, provided that their medical conditions are stable, and they have no current major depressive episodes or substance abuse; it may represent a valid alternative to inpatient treatment for those who are able to sustain engagement in a full course of outpatient treatment.


Emergence of spike correlations in periodically forced excitable systems.
In sensory neurons the presence of noise can facilitate the detection of weak information-carrying signals, which are encoded and transmitted via correlated sequences of spikes. Here we investigate the relative temporal order in spike sequences induced by a subthreshold periodic input in the presence of white Gaussian noise. To simulate the spikes, we use the FitzHugh-Nagumo model and to investigate the output sequence of interspike intervals (ISIs), we use the symbolic method of ordinal analysis. We find different types of relative temporal order in the form of preferred ordinal patterns that depend on both the strength of the noise and the period of the input signal. We also demonstrate a resonancelike behavior, as certain periods and noise levels enhance temporal ordering in the ISI sequence, maximizing the probability of the preferred patterns. Our findings could be relevant for understanding the mechanisms underlying temporal coding, by which single sensory neurons represent in spike sequences the information about weak periodic stimuli.


Bottle-weaning intervention tools: the "how" and "why" of a WIC-based educational flipchart, parent brochure, and website.
This article describes the development of educational materials for a Women, Infants, and Children (WIC)-based randomized controlled trial of an intervention encouraging timely bottle weaning. Following a systematic process to develop of patient education materials, messages were first tested in 4 focus groups with 26 caregivers of WIC toddlers aged 7 to 36 months of age at the 2 study sites. Following review and revision, the materials were retested in one-on-one nutritional counseling sessions with 10 clients at the WIC sites who met the study's eligibility criteria. Materials development was an iterative process requiring several levels of input, review, and revision. Use of a systematic process guided by steps adapted from the health education literature was crucial in ensuring continuous feedback from stakeholders, experts, and priority populations and to develop an intervention instrument that met the needs and expectations of all groups. The content, theoretical orientation, and format of the materials were influenced at every turn by feedback from frontline WIC nutritionists, WIC policy staff at the state level, and WIC clients. Development of effective, easy to use materials requires constant input from key stakeholders.


Acupuncture Treatment of Diabetic Peripheral Neuropathy in an American Indian Community.
Diabetic peripheral neuropathy (DPN) develops in 30% of type 2 diabetes patients, increases the risk for foot ulcers and amputation, and is a significant source of disability and medical costs. Treatment remains challenging, propelling research to focus on therapeutic methods that aim to improve blood circulation or ameliorate oxidative stress that drives development of DPN. The aim of this study was to assess the effectiveness of acupuncture treatment for DPN symptoms and lower extremity arterial circulation in people with type 2 diabetes. Twenty-five patients seen at a Southern California Tribal Health Center who reported a threshold level of diabetic neuropathy symptoms in the lower extremities during the previous 4 weeks received acupuncture treatment once per week over a 10-week period between 2011 and 2013. The Neuropathy Total Symptom Scale (NTSS-6), Neuropathy Disability Score (NDS), and laser Doppler fluxmetry (LDF) were used for assessment at baseline and 10 weeks. A total of 19 of 25 study participants completed the study and reported a significant reduction in the NTSS symptoms of aching pain, burning pain, prickling sensation, numbness, and allodynia. Lancinating pain did not decrease significantly. LDF measures improved but not significantly. Acupuncture may effectively ameliorate selected DPN symptoms in these American Indian patients.


Pattern segmentation with activity dependent natural frequency shift and sub-threshold resonance.
Understanding the mechanisms underlying distributed pattern formation in brain networks and its content driven dynamical segmentation is an area of intense study. We investigate a theoretical mechanism for selective activation of diverse neural populations that is based on dynamically shifting cellular resonances in functionally or structurally coupled networks. We specifically show that sub-threshold neuronal depolarization from synaptic coupling or external input can shift neurons into and out of resonance with specific bands of existing extracellular oscillations, and this can act as a dynamic readout mechanism during information storage and retrieval. We find that this mechanism is robust and suggest it as a general coding strategy that can be applied to any network with oscillatory nodes.


Coordinated action of NSF and PKC regulates GABAB receptor signaling efficacy.
The obligatory heterodimerization of the GABAB receptor (GBR) raises fundamental questions about molecular mechanisms controlling its signaling efficacy. Here, we show that NEM sensitive fusion (NSF) protein interacts directly with the GBR heterodimer both in rat brain synaptosomes and in CHO cells, forming a ternary complex that can be regulated by agonist stimulation. Inhibition of NSF binding with a peptide derived from GBR2 (TAT-Pep-27) did not affect basal signaling activity but almost completely abolished agonist-promoted GBR desensitization in both CHO cells and hippocampal slices. Taken with the role of PKC in the desensitization process, our observation that TAT-Pep-27 prevented both agonist-promoted recruitment of PKC and receptor phosphorylation suggests that NSF is a priming factor required for GBR desensitization. Given that GBR desensitization does not involve receptor internalization, the NSF/PKC coordinated action revealed herein suggests that NSF can regulate GPCR signalling efficacy independently of its role in membrane trafficking. The functional interaction between three bona fide regulators of neurotransmitter release, such as GBR, NSF and PKC, could shed new light on the modulation of presynaptic GBR action.


CD4 monoclonal antibody pairs for immunosuppression and tolerance induction.
A pair of rat anti-mouse CD4 monoclonal antibodies (mAb) have been selected which bind to different epitopes of the molecule. Both the mAb are rat IgG2b and show clear synergistic activity in complement lysis in vitro. When injected together in vivo, they exhibit an improved immunosuppressive effect, compared to each antibody alone, on allogeneic graft rejection, humoral responses and on tolerance induction. Limiting dilution analysis indicates that the in vivo depletion of interleukin 2-producing cells is improved using both mAb by 2-3-fold over that obtained with the individual antibodies. As little as 60 ng per mouse of the CD4 antibody pair was sufficient to allow the induction of tolerance to human gamma-globulin, even without elimination of the CD4+ cells. The results suggest that appropriate antibody pairs may be good candidates for effective immunosuppressive serotherapy in man.


Structural plasticity of histones H3-H4 facilitates their allosteric exchange between RbAp48 and ASF1.
The mechanisms by which histones are disassembled and reassembled into nucleosomes and chromatin structure during DNA replication, repair and transcription are poorly understood. A better understanding of the processes involved is, however, crucial if we are to understand whether and how histone variants and post-translationally modified histones are inherited in an epigenetic manner. To this end we have studied the interaction of the histone H3-H4 complex with the human retinoblastoma-associated protein RbAp48 and their exchange with a second histone chaperone, anti-silencing function protein 1 (ASF1). Exchange of histones H3-H4 between these two histone chaperones has a central role in the assembly of new nucleosomes, and we show here that the H3-H4 complex has an unexpected structural plasticity, which is important for this exchange.


Relationship between polymerase gamma (POLG) polymorphisms and antiretroviral therapy-induced lipodystrophy in HIV-1 infected patients: a case-control study.
Nucleoside Reverse Transcriptase Inhibitors (NRTIs) used for the treatment of HIV-1 inhibit the replication of mitochondrial DNA (mtDNA), which may contribute to severe mitochondrial toxicity including lipodystrophy, through the inhibition of polymerase gamma (POLG). Polymorphisms of POLG could explain the variation in mitochondrial toxicity in HIV-1-infected patients. We explored the relationship between selected polymorphisms of POLG and lipodystrophy related to NRTIs. We studied single nucleotide polymorphisms (SNP) at three amino acid residues (R1142, E1143 and R1146) and the CAG repeats of POLG in a case-control study including HIV-1 treated patients with lipodystrophy (n=69) and 2 controls (without lipodystrophy) per case matched by age, race and sex (n=138). Compared with matched controls, the polymorphisms in E1143 were significantly more frequent in case patients with lipodystrophy (aOR=4.7; p=0.048), and this was associated with a significant decrease of mtDNA in PBMC. In addition, among the parameters tested, the conditional logistic regression showed that the lipodystrophy has a strong link with E1143 polymorphisms, associated with D4T treatment (aOR=9.29, p=0.002). In conclusion, patients harbouring the changes of E1143 in the catalytic site of POLG exhibit a 4-fold increased risk to develop lipodystrophy than HIV-1 treated patients who do not have changes in E1143 and this risk can increase if the patient presenting the SNP received D4T. These could be due to decreased content of mtDNA in PBMC in these patients. Therefore, the toxicity of NRTIs leading to lipodystrophy in some HIV-1 infected patients could be explained in part by the occurrence of POLG polymorphisms.


Mutational spectrum of myeloid malignancies with inv(3)/t(3;3) reveals a predominant involvement of RAS/RTK signaling pathways.
Myeloid malignancies bearing chromosomal inv(3)/t(3;3) abnormalities are among the most therapy-resistant leukemias. Deregulated expression of EVI1 is the molecular hallmark of this disease; however, the genome-wide spectrum of cooperating mutations in this disease subset has not been systematically elucidated. Here, we show that 98% of inv(3)/t(3;3) myeloid malignancies harbor mutations in genes activating RAS/receptor tyrosine kinase (RTK) signaling pathways. In addition, hemizygous mutations in GATA2, as well as heterozygous alterations in RUNX1, SF3B1, and genes encoding epigenetic modifiers, frequently co-occur with the inv(3)/t(3;3) aberration. Notably, neither mutational patterns nor gene expression profiles differ across inv(3)/t(3;3) acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome cases, suggesting recognition of inv(3)/t(3;3) myeloid malignancies as a single disease entity irrespective of blast count. The high incidence of activating RAS/RTK signaling mutations may provide a target for a rational treatment strategy in this high-risk patient group.


Proteome-wide analysis of chaperone-mediated autophagy targeting motifs.
Chaperone-mediated autophagy (CMA) contributes to the lysosomal degradation of a selective subset of proteins. Selectivity lies in the chaperone heat shock cognate 71 kDa protein (HSC70) recognizing a pentapeptide motif (KFERQ-like motif) in the protein sequence essential for subsequent targeting and degradation of CMA substrates in lysosomes. Interest in CMA is growing due to its recently identified regulatory roles in metabolism, differentiation, cell cycle, and its malfunctioning in aging and conditions such as cancer, neurodegeneration, or diabetes. Identification of the subset of the proteome amenable to CMA degradation could further expand our understanding of the pathophysiological relevance of this form of autophagy. To that effect, we have performed an in silico screen for KFERQ-like motifs across proteomes of several species. We have found that KFERQ-like motifs are more frequently located in solvent-exposed regions of proteins, and that the position of acidic and hydrophobic residues in the motif plays the most important role in motif construction. Cross-species comparison of proteomes revealed higher motif conservation in CMA-proficient species. The tools developed in this work have also allowed us to analyze the enrichment of motif-containing proteins in biological processes on an unprecedented scale and discover a previously unknown association between the type and combination of KFERQ-like motifs in proteins and their participation in specific biological processes. To facilitate further analysis by the scientific community, we have developed a free web-based resource (KFERQ finder) for direct identification of KFERQ-like motifs in any protein sequence. This resource will contribute to accelerating understanding of the physiological relevance of CMA.


Effects of caffeine on metabolism and mitochondria biogenesis in rhabdomyosarcoma cells compared with 2,4-dinitrophenol.
This work investigated if treatment with caffeine or 2,4-dinitrophenol (DNP) induce expression of peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α) and increase both mitochondrial biosynthesis and metabolism in skeletal muscle. Human rhabdomyosarcoma cells were treated with either ethanol control (0.1% final concentration) caffeine, or DNP at 250 or 500 μM for 16 or 24 hours. PGC-1α RNA levels were determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). PGC-1α protein and mitochondrial content was determined using flow cytometry and immunohistochemistry. Metabolism was determined by quantification of extracellular acidification rate and oxygen consumption rate. Treatment with either caffeine or DNP induced PGC-1α RNA and protein as well as mitochondrial content compared with control. Treatment with caffeine and DNP also significantly increased oxidative metabolism and total metabolic rate compared with control. Caffeine similarly increased metabolism and mitochondrial content compared with DNP. This work identified that both caffeine and DNP significantly induce PGC-1α, and increase both metabolism and mitochondrial content in skeletal muscle.


Insurance type and sepsis-associated hospitalizations and sepsis-associated mortality among US adults: a retrospective cohort study.
Socio-demographic and clinical factors associated with increased sepsis risk, including older age, non-white race and specific co-morbidities, are more common among patients with Medicare or Medicaid or no health insurance. We hypothesized that patients with Medicare and/or Medicaid or without health insurance have a higher risk of sepsis-associated hospitalization or sepsis-associated death than those with private health insurance. We performed a retrospective cohort study of records from the 2003 Nationwide Inpatient Sample. We stratified the study cohort by Medicare age-qualification (18 to 64 and 65+ years old). We examined the association between insurance category and sepsis diagnosis and death among admissions involving sepsis. We used validated diagnostic codes to determine the presence of sepsis, co-morbidities and organ dysfunction and to provide risk-adjustment. Among patients 18 to 64 years old, those with Medicaid (adjusted odds ratio (AOR) 1.50), Medicare (AOR 1.96), Medicaid + Medicare (AOR 2.22) and the uninsured (AOR 1.18) had significantly higher risk-adjusted odds of a sepsis-associated admission than those with private insurance (all P < 0.0001). Those with Medicaid (AOR 1.17, P < 0.001) and those without insurance (AOR 1.45, P < 0.001) also had significantly higher adjusted odds of sepsis-associated hospital mortality than those with private insurance. Among those 65+ years old, those with Medicaid (AOR 1.43), Medicare alone (AOR 1.13) or Medicaid + Medicare (AOR 1.62) had significantly higher risk-adjusted odds of sepsis-associated admission than those with private insurance and Medicare (all P < 0.0001). Among sepsis patients 65+, uninsured patients had significantly higher risk-adjusted odds (AOR 1.45, P = 0.0048) and those with Medicare alone had significantly lower risk-adjusted odds (AOR 0.92, P = 0.0072) of hospital mortality than those with private insurance and Medicare. Lack of health insurance remained associated with sepsis-associated mortality after stratification of hospitals into quartiles based on rates of sepsis-associated admissions or mortality in both age strata. Risks of sepsis-associated hospitalization and sepsis-associated death vary by insurance. These increased risks were not fully explained by the available socio-demographic factors, co-morbidities or hospital rates of sepsis-related admissions or deaths.


Versatility of the Profunda Artery Perforator Flap: Creative Uses in Breast Reconstruction.
Flaps based on the profunda artery perforators were first used for reconstruction of pressure sores, burn contractures, and extremity wounds. Recently, a revised profunda artery perforator flap was introduced for breast reconstruction. However, the flap is rarely used despite interesting reports on its use. The authors present their experience with the profunda artery perforator flap, describing its versatile applications in breast reconstruction. The authors conducted a retrospective review of all patients of the lead author who underwent breast reconstruction with profunda artery perforator flaps before January of 2015. Patient demographics, perioperative data, and postoperative complications were recorded and analyzed. Seventy-three consecutive profunda artery perforator flaps were used to reconstruct 71 breasts. In 21 breasts, a profunda artery perforator flap was used in conjunction with another flap-with a deep inferior epigastric perforator flap (n = 18), a superior gluteal artery perforator flap (n = 1), or as stacked profunda artery perforator flaps (n = 2). The flap failure rate was 2.7 percent. There was one case of clinically apparent fat necrosis. There were no other major flap complications. Donor-site complications included cellulitis in two thighs (2.7 percent) and minor wound dehiscence in six thighs (8.2 percent). All donor-site complications healed satisfactorily by secondary intention without any additional procedures. The profunda artery perforator flap is a safe and versatile option for breast reconstruction. It can be combined with other flaps when additional volume or skin requirements are present. Flap and donor-site complications are comparable to other free tissue breast reconstruction options. Therapeutic, IV.


Serial serum AFP heterogeneity changes in patients with hepatocellular carcinoma during chemotherapy.
Serum alpha fetoprotein (AFP) is heterogeneous, one form binding to the lectin concanavalin A (conA) and the other not. The relative amounts, of the two forms in the serum of patients has diagnostic applications in differentiating between primary hepato-cellular carcinoma and metastatic liver disease. In 36 patients with primary hepatocellular carcinoma, the conA-nonreactive form of AFP comprised less than 20% of the total (range 1.6%-19.2%; median 8.7%), whereas in 13 patients with metastatic liver disease the conA-nonreactive form comprised more than 20% of the total (range 26.6%-91.7%; median 57.6%). Four patients with primary hepatocellular carcinoma were treated with CB3717, and serial changes in the serum AFP characteristics were examined. In two patients in whom the total serum AFP concentration fell, the percentage of the conA-nonreactive fraction, initially less than 20% rose steadily. In two other patients the total serum AFP did not fall significantly and the proportion of the conA-nonreactive fraction remained below 20%.


Characteristics of individuals who identify a regular source of medical care.
Having a source where medical services are regularly received is an antecedent to securing high quality medical care; it facilitates access and indicates that the individual is not alienated from the health care delivery system. In this paper we develop models to characterize individuals, both children and adults, who claim a regular source of care. The models are estimated using a logit analysis (since the dependent variable is 0-1) applied to survey data on residents of East Palo Alto, California. These data indicate that in this low-income, predominately black population the most important factor influencing whether a child will have a regular source of medical care is whether the parents have a regular source. For adults, the anticipated need for care (as measured by health status), time in community, and sex were all found to be important. The type of individual least likely to have a regular source of care is a low-income, unmarried male who is in good health and is a recent arrival to the community. The individuals most likely to need easy access to medical care and continuity of care are most likely to have a regular source of care, and vice versa.


Differential Effects of Different Warm-up Protocols on Repeated Sprints-Induced Muscle Damage.
Chen, CH, Ye, X, Wang, YT, Chen, YS, and Tseng, WC. Differential effects of different warm-up protocols on repeated sprints-induced muscle damage. J Strength Cond Res 32(11): 3276-3284, 2018-The purpose of this investigation was to examine whether adding a set of hamstring resistance exercise or dynamic stretching to a regular running-based warm-up before a bout of repeated sprints provides protective effects against the sprinting-induced muscle damage. Twelve elite tennis players participated in this study. After the familiarization, subjects completed 3 separate randomly sequenced experimental visits, during which 3 different warm-up interventions were performed before the muscle-damaging protocol (12 sets of 30-m maximal repeated sprints): 5 minutes of running (control); control with single leg slide curl (SLC); and control with active hamstring stretching (AHS). Before, immediately (POST0), 1 day (POST1), and 2 days after (POST2) the sprints, hip flexion passive range of motion, hamstring muscle thickness and pennation angle, muscle stiffness, and knee flexion concentric peak torque were measured. Repeated sprints have induced muscle damage in all 3 visits. For AHS, the muscle thickness and stiffness values at POST2 were significantly lower than those of other 2 protocols. In addition, the decrements of concentric strength at POST0, POST1, and POST2 for AHS were also significantly less than those of control and SLC. Therefore, adding a set of dynamic hamstrings stretching to a regular warm-up protocol before repeated sprints has protective effect on the sprinting-induced muscle damage. Athletes whose competitions are densely scheduled (e.g., tennis player in a tournament) may take advantage of this strategy to facilitate muscle recovery from the potential muscle damage, thus, to get maximal recovery for the subsequent competitions.


Environmental influences on energy balance-related behaviors: a dual-process view.
Studies on the impact of the 'obesogenic' environment have often used non-theoretical approaches. In this journal's debate and in other papers authors have argued the necessity of formulating conceptual models for differentiating the causal role of environmental influences on behavior. The present paper aims to contribute to the debate by presenting a dual-process view on the environment--behavior relationship. This view is conceptualized in the EnRG framework (Environmental Research framework for weight Gain prevention). In the framework, behavior is postulated to be the result of a simultaneous influence of conscious and unconscious processes. Environmental influences are hypothesized to influence behavior both indirectly and directly. The indirect causal mechanism reflects the mediating role of behavior-specific cognitions in the influence of the environment on behavior. A direct influence reflects the automatic, unconscious, influence of the environment on behavior. Specific personal and behavioral factors are postulated to moderate the causal path (i.e., inducing either the automatic or the cognitively mediated environment - behavior relation). In addition, the EnRG framework applies an energy balance-approach, stimulating the integrated study of determinants of diet and physical activity. The application of a dual-process view may guide research towards causal mechanisms linking specific environmental features with energy balance-related behaviors in distinct populations. The present paper is hoped to contribute to the evolution of a paradigm that may help to disentangle the role of 'obesogenic' environmental factors.


Clinical protection from falciparum malaria correlates with neutrophil respiratory bursts induced by merozoites opsonized with human serum antibodies.
Effective vaccines to combat malaria are urgently needed, but have proved elusive in the absence of validated correlates of natural immunity. Repeated blood stage infections induce antibodies considered to be the main arbiters of protection from pathology, but their essential functions have remained speculative. This study evaluated antibody dependent respiratory burst (ADRB) activity in polymorphonuclear neutrophils (PMN) induced by Plasmodium falciparum merozoites and antibodies in the sera of two different African endemic populations, and investigated its association with naturally acquired clinical protection. Respiratory bursts by freshly isolated PMN were quantified by chemiluminescence readout in the presence of isoluminol, which preferentially detects extra-cellular reactive oxygen species (ROS). Using a standardized, high throughput protocol, 230 sera were analyzed from individuals of all age groups living in meso- (Ndiop) or holo-endemic (Dielmo) Senegalese villages, and enrolled in a cross-sectional prospective study with intensive follow-up. Statistical significance was determined using non-parametric tests and Poisson regression models. The most important finding was that PMN ADRB activity was correlated with acquired clinical protection from malaria in both high and low transmission areas (P = 0.006 and 0.036 respectively). Strikingly, individuals in Dielmo with dichotomized high ADRB indexes were seventeen fold less susceptible to malaria attacks (P = 0.006). Complementary results showed that ADRB activity was (i) dependent on intact merozoites and IgG opsonins, but not parasitized erythrocytes, or complement, (ii) correlated with merozoite specific cytophilic IgG1 and IgG3 antibody titers (P<0.001 for both), and (iii) stronger in antisera from a holo-endemic compared to a meso-endemic site (P = 0.002), and reduced in asymptomatic carriers (P<0.001). This work presents the first clearly demonstrated functional antibody immune correlate of clinical protection from Plasmodium falciparum malaria, and begs the question regarding the importance of ADRB by PMN for immune protection against malaria in vivo.


RNAi factors are present and active in human cell nuclei.
RNAi is widely appreciated as a powerful regulator of mRNA translation in the cytoplasm of mammalian cells. However, the presence and activity of RNAi factors in the mammalian nucleus has been the subject of considerable debate. Here, we show that Argonaute-2 (Ago2) and RNAi factors Dicer, TRBP, and TRNC6A/GW182 are in the human nucleus and associate together in multiprotein complexes. Small RNAs can silence nuclear RNA and guide site-specific cleavage of the targeted RNA, demonstrating that RNAi can function in the human nucleus. Nuclear Dicer is active and miRNAs are bound to nuclear Ago2, consistent with the existence of nuclear miRNA pathways. Notably, we do not detect loading of duplex small RNAs in nuclear extracts and known loading factors are absent. These results extend RNAi into the mammalian nucleus and suggest that regulation of RNAi via small RNA loading of Ago2 differs between the cytoplasm and the nucleus.


Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117.
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg(-1) infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8-2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.


Cascades in multiplex financial networks with debts of different seniority.
The seniority of debt, which determines the order in which a bankrupt institution repays its debts, is an important and sometimes contentious feature of financial crises, yet its impact on systemwide stability is not well understood. We capture seniority of debt in a multiplex network, a graph of nodes connected by multiple types of edges. Here an edge between banks denotes a debt contract of a certain level of seniority. Next we study cascading default. There exist multiple kinds of bankruptcy, indexed by the highest level of seniority at which a bank cannot repay all its debts. Self-interested banks would prefer that all their loans be made at the most senior level. However, mixing debts of different seniority levels makes the system more stable in that it shrinks the set of network densities for which bankruptcies spread widely. We compute the optimal ratio of senior to junior debts, which we call the optimal seniority ratio, for two uncorrelated Erdős-Rényi networks. If institutions erode their buffer against insolvency, then this optimal seniority ratio rises; in other words, if default thresholds fall, then more loans should be senior. We generalize the analytical results to arbitrarily many levels of seniority and to heavy-tailed degree distributions.


The effect of vitamin E and vitamin C supplementation on LDL oxidizability and neutrophil respiratory burst in young smokers.
The purpose of this study was to determine the effect of vitamin E and/or vitamin C supplementation on low-density lipoprotein (LDL) oxidizability and neutrophil (PMN) superoxide anion production in young smokers. Thirty smokers with a <5 pack-year history were randomly assigned to take placebo; vitamin C (1 g/day); vitamin E (400 IU/day), or both vitamins in a double-blind fashion. Subjects took the supplements for 8 weeks. At weeks 0 and 8, blood was collected for isolation of LDL and PMN, and for antioxidant vitamin analysis. LDL was oxidized with a copper (Cu) catalyst, and oxidation was measured by formation of conjugated dienes over a 5-hour time course. Lag times and maximum oxidation rates were calculated from the time course data. PMN superoxide anion release was assessed by respiratory burst after stimulation with phorbol ester and opsonized zymosan, and their ability to oxidize autologous LDL following treatment with the above stimuli was measured with the conjugated diene assay. Subjects who received vitamin E alone had a significant increase in the lag phase of Cu-catalyzed LDL oxidation (week 0, 118+/-31 min vs. week 8, 193+/-80 min, mean +/- SD, p < 0.05), whereas the vitamin C and placebo groups had no changes in LDL oxidation kinetics. The group receiving both vitamins E and C had a significant reduction in oxidation rate (week 0. 7.4+/-2.3 vs. week 8, 5.1+/-2.1, p < 0.05). There were no significant changes for any group in PMN superoxide anion production or PMN LDL oxidation after stimulation with either phorbol ester or opsonized zymosan. Plasma and LDL vitamin E concentrations were significantly increased in both groups that received vitamin E. The subjects who received vitamin C alone had no significant change in plasma vitamin C concentrations; however, when data were pooled from both groups who received vitamin C, the increases were significant. Vitamin E supplementation of young smokers was effective in reducing Cu-catalyzed LDL oxidizability; however, vitamin E and/or C supplementation showed few significant effects on the more physiologically relevant PMN function. This casts doubt on the ability of antioxidant supplementation to reduce oxidative stress in smokers in vivo. Therefore, smoking cessation remains the only means by which young smokers can prevent premature coronary heart disease.


The Children's Oncology Group: Organizational Structure, Membership, and Institutional Characteristics.
The Children's Oncology Group (COG) is the only organization within the National Cancer Institute's National Clinical Trials Network dedicated exclusively to pediatric cancer research. The purpose of this article is to provide an overview of COG's organizational structure, to characterize its institutional and individual membership, and to summarize enrollments onto COG clinical trials. Data from 2013 to 2015 were compiled from sources internal (Network Operations, Statistics and Data Center, Chair's Office) and external (American Hospital Association, American Nurses Credentialing Center) to COG, to present a comprehensive overview of COG's structure, individual and institutional membership, and group operations. In 2016, COG comprised 8,785 individuals from 223 member institutions, across seven countries. An average of 9,661 new patients were registered with COG per year over the most recent (2013-2015) 3-year period. Over the same 3-year time frame, there were an average of 16,836 enrollments onto therapeutic (i.e., treatment) and nontherapeutic (e.g., epidemiology, survivorship, biology) trials per year. COG institutions have diverse characteristics related to size, geographical location, and infrastructure. Individual membership also reflects diversity with representation from over 28 disciplines and groups. The diversity of COG institutions and individual members allows for unique perspectives and contributions to science unified under a common goal to enroll children/adolescents onto clinical trials. COG's collaborative, multidisciplinary approach to science functions to support the development of research that seeks to continually improve outcomes for children and adolescents with cancer.


Myocardial Fibrosis in Athletes.
Myocardial fibrosis (MF) is a common phenomenon in the late stages of diverse cardiac diseases and is a predictive factor for sudden cardiac death. Myocardial fibrosis detected by magnetic resonance imaging has also been reported in athletes. Regular exercise improves cardiovascular health, but there may be a limit of benefit in the exercise dose-response relationship. Intense exercise training could induce pathologic cardiac remodeling, ultimately leading to MF, but the clinical implications of MF in athletes are unknown. For this comprehensive review, we performed a systematic search of the PubMed and MEDLINE databases up to June 2016. Key Medical Subject Headings terms and keywords pertaining to MF and exercise (training) were included. Articles were included if they represented primary MF data in athletes. We identified 65 athletes with MF from 19 case studies/series and 14 athletic population studies. Myocardial fibrosis in athletes was predominantly identified in the intraventricular septum and where the right ventricle joins the septum. Although the underlying mechanisms are unknown, we summarize the evidence for genetic predisposition, silent myocarditis, pulmonary artery pressure overload, and prolonged exercise-induced repetitive micro-injury as contributors to the development of MF in athletes. We also discuss the clinical implications and potential treatment strategies of MF in athletes.


Locating irregularly shaped clusters of infection intensity.
Patterns of disease may take on irregular geographic shapes, especially when features of the physical environment influence risk. Identifying these patterns can be important for planning, and also identifying new environmental or social factors associated with high or low risk of illness. Until recently, cluster detection methods were limited in their ability to detect irregular spatial patterns, and limited to finding clusters that were roughly circular in shape. This approach has less power to detect irregularly-shaped, yet important spatial anomalies, particularly at high spatial resolutions. We employ a new method of finding irregularly-shaped spatial clusters at micro-geographical scales using both simulated and real data on Schistosoma mansoni and hookworm infection intensities. This method, which we refer to as the "greedy growth scan", is a modification of the spatial scan method for cluster detection. Real data are based on samples of hookworm and S. mansoni from Kitengei, Makueni district, Kenya. Our analysis of simulated data shows how methods able to find irregular shapes are more likely to identify clusters along rivers than methods constrained to fixed geometries. Our analysis of infection intensity identifies two small areas within the study region in which infection intensity is elevated, possibly due to local features of the physical or social environment. Collectively, our results show that the "greedy growth scan" is a suitable method for exploratory geographical analysis of infection intensity data when irregular shapes are suspected, especially at micro-geographical scales.


Four versus six weeks of antibiotic therapy for osteoarticular infections after implant removal: a randomized trial.
The optimal duration of antibiotic therapy for treating orthopaedic implant infections after surgical drainage and complete implant removal is unknown. This was a single-centre, unblinded, prospective trial randomizing (1:1) eligible patients to either 4 or 6 weeks of systemic, pathogen-targeted antibiotic therapy. Clinical trial registration number: ClinicalTrials.gov (NCT0362209). We analysed 123 eligible patients (62 in the 4 week antibiotic arm and 61 in the 6 week arm) in the ITT analysis. The patients' median age was 64 years, 75 (61%) were men and 38 (31%) were immunocompromised. The most common types of infection treated included: two-stage exchange procedure for prosthetic joint infection (n = 38); orthopaedic plate infection (44) and infected nail implants (11). The median duration of post-explant intravenous antibiotic therapy was 4 days. Overall, 120 episodes (98%) were cured microbiologically and 116 (94%) clinically after a median follow-up period of 2.2 years. During follow-up, four patients had a clinical recurrence with a pathogen other than the initial causative agent. We noted recurrence of clinical infection in four patients in the 4 week arm and three patients in the 6 week arm (4/62 versus 3/61; χ2 test; P = 0.74); in all cases, this occurred at around 2 months following the end of antibiotic treatment. We found no statistically significant difference in the rates of clinical or microbiological remission between patients randomized to only 4 compared with 6 weeks of systemic antibiotic therapy after removal of an infected osteoarticular implant.


Repair of the oxidative DNA damage 8-oxoguanine as a biomarker for lung cancer risk.
DNA repair has a major role in suppressing the rate of accumulation of mutations. Therefore, variations in DNA repair are likely to play an important role in determining cancer risk. While there is compelling evidence that defects in DNA repair cause high predisposition to several hereditary cancers, there is a paucity of data on the role of DNA repair in sporadic cancers. We present our approach of using functional DNA repair tests, rather than gene polymorphism, to study the potential of DNA repair enzymes to serve as biomarkers for lung cancer risk. We have previously developed a functional DNA repair blood test for the enzymatic repair of the oxidative DNA lesion 8-oxoguanine, and found that reduced OGG activity is a risk factor in non-small cell lung cancer. Moreover the combination of smoking and low OGG activity was associated with a greatly increased lung cancer risk (Paz-Elizur et al, JNCI 95 (2003) 1312-1319). The use of OGG activity as a potential biomarker for lung cancer risk is validated in collaboration with the M. D. Anderson Cancer Center, under the sponsorship of the Associate Members Program of the Early Detection Research Network (EDRN, NCI, NIH).


Exploring the impact of foreign direct investment on tobacco consumption in the former Soviet Union.
Tobacco is the single largest cause of morbidity and mortality in the developed world; in the former socialist bloc tobacco kills twice as many men as in the west. Although evidence shows that liberalisation of the cigarette trade through the elimination of import barriers leads to significant increases in consumption, far less is known about the impact of foreign direct investment on cigarette consumption. This paper seeks to explore the impact that the substantial transnational tobacco company investments have had on patterns of tobacco trade and consumption in the former Soviet Union. Routine data were used to explore trends in cigarette trade and consumption in the 15 countries of the former Soviet Union from the 1960s to the present day. Comparisons were made between trends in countries that have received substantial investment from the tobacco transnationals and countries that have not. Between 1991 and 2000 cigarette production increased by 96% in countries receiving industry investment and by 11% in countries that did not. Over the same period cigarette consumption increased by 40%; the increase was concentrated in countries receiving investments. Despite these investments, cigarette imports still outweigh exports and no trade surplus has yet to result. The findings suggest that liberalisation of inward investment has a significant and positive impact on cigarette consumption and that without appropriate safeguards, market liberalisation may have long term negative impacts on health. Specific trade rules are needed to govern trade and investment in this uniquely harmful product. Implementation of effective tobacco control policies should precede tobacco industry privatisation. International financial organisations pressing for privatisation should ensure this occurs.


Acute total hip arthroplasty for selected displaced acetabular fractures: two to twelve-year results.
We assessed the role of acute total hip arthroplasty in a selected group of patients with a displaced acetabular fracture and complicating features that greatly diminished the likelihood of a favorable outcome after open reduction and internal fixation. Between 1985 and 1997, fifty-seven patients underwent an acute total hip arthroplasty for a displaced acetabular fracture. Patients were followed for a mean of 8.1 years (range, two to twelve years). The mean time from the injury to the arthroplasty was six days (range, one to twenty days). The mean age of the patients at the time of the arthroplasty was sixty-nine years (range, twenty-six to eighty-nine years). Indications for the acute arthroplasty included intra-articular comminution as well as full-thickness abrasive loss of the articular cartilage, impaction of the femoral head, and impaction of the acetabulum that involved >40% of the joint surface and included the weight-bearing region. At the time of the latest follow-up, the mean Harris hip score was 89 points (range, 69 to 100 points); forty-five patients (79%) had an excellent or good outcome. There were six cases of heterotopic bone formation, including one of symptomatic grade-IV ossification. During the initial six postoperative weeks, the acetabular cups subsided an average of 3 mm medially and 2 mm vertically. All of the cups then stabilized, and none were loose at the latest follow-up evaluation. Six patients had excessive medialization of the cup, but none had late loosening or osteolysis. Nine cups (16%) had notable polyethylene wear, but none were revised. No cup or stem had late clinical or radiographic evidence of loosening. There were three late procedures: one for revision of a malaligned cup because of recurrent dislocations, one for removal of hardware from the greater trochanter, and one for excision of heterotopic bone. In selected patients with a displaced acetabular fracture that has a low likelihood of a favorable outcome after fracture treatment, an acute total hip arthroplasty may provide an alternative means with which to achieve a painless, mobile hip. These complex procedures are best undertaken by a surgical team with substantial experience with both acetabular trauma and hip arthroplasty.


Effects of spinach powder fat-soluble extract on proliferation of human gastric adenocarcinoma cells.
Four kinds of assays were used to study the effect of a fat-soluble extract of spinach powder (SPFE) on the proliferation of human gastric adenocarcinoma cell line (SGC-7901) in vitro. These studies included: (i) cell growth assay, (ii) colony forming assay, (iii) MTT colorimetric assay, and (iv) 3H-TdR incorporation assay. The concentrations of SPFE expressed as the level of beta-carotene in the medium were 2 x 10(-8), 2 x 10(-7) and 2 x 10(-6) mol/L beta-carotene in assay (i)-(iii), but 4 x 10(-8), 4 x 10(-7) and 4 x 10(-6) mol/L beta-carotene in assay (iv) respectively. The results indicated that SPFE inhibited the proliferation and colony forming ability of SGC-7901 cells. And in MTT assay, SPFE inhibited the viability of SGC-7901 cells, but no inhibitory effect of SPFE was observed on the viability of lymphocytes in peripheral blood of healthy people. Finally, in the 3H-TdR incorporation test, both SPFE and beta-carotene showed significant inhibitory effects on DNA synthesis in SGC-7901 cells, but SPFE was more effective than beta-carotene.


Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: evidence for circadian rhythm dysfunction in severe autism.
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.


Controlled synthesis of monodisperse α-calcium sulfate hemihydrate nanoellipsoids with a porous structure.
We report a facile and green chemical solution approach to synthesize monodisperse α-calcium sulfate hemihydrate (α-HH) nanoellipsoids with a length of 600 nm and a width of 300 nm by simply mixing Ca(2+) and SO4(2-) glycerol-water precursor solutions in the presence of Na2EDTA. The α-HH nanoellipsoid is formed through a Na2EDTA-mediated self-assembly of small primary building blocks (α-HH domains: ∼14 nm). The study on the morphological evolution of α-HH reveals that the controlled synergy of supersaturation (precursor concentration) and Na2EDTA is crucial for the development of α-HH into nanoellipsoids. Further thermal annealing of the nanoellipsoid could make the α-HH domains transit into calcium sulfate anhydrites and grow up, generating the gaps between them and resulting in a porous structure. This work paves a new way for preparing high-quality α-HH nanoellipsoids with a monodisperse nanosize and a porous structure, promising their future application in many fields such as biomedicine.


Vertebral bone loss: an unheeded side effect of therapeutic bed rest.
1. The skeletal effects of simple bed rest and re-ambulation were studied in a consecutive series of 34 patients (aged 18-60 years) hospitalized with low backache due to protrusion of a lumbar intervertebral disc. The bone mineral content of the second, third and fourth lumbar vertebrae was determined by dual-photon (153Gd) absorptiometry immediately after admission to the hospital, at the end of the bed-rest period (mean 27 days, range 11-61 days) and approximately 15 weeks later (range 11-24 weeks). 2. During recumbency a mean decrease in lumbar spine bone mineral content of 0.9% per week was observed. 3. Re-ambulation resulted in bone mineral gain, and restoration of lumbar spine bone mineral content was nearly complete after 4 months. 4. The findings suggest that the simple therapeutic bed-rest regimen leads to excessive vertebral bone loss. Recurrent bed-rest periods may predispose to spinal osteoporosis.


Colliding and merging galaxies.
Aided by advances in computer technology and observations from space, astronomers have begun to unravel the mysteries of galaxy formation and evolution. Galaxies evolve by interacting with their environment and especially with each other. During brief but often fierce galactic encounters, gravitational forces generate strong tides that survive as telltale signatures for billions of years. Because these so-called collisions dissipate orbital energy, galaxies on bound orbits may eventually merge. Collisions and mergers are responsible for a great variety of phenomena, including the triggering of widespread star formation in galaxies and the fueling of nuclear activity in quasars. Evidence is accumulating that not all galaxies formed shortly after the Big Bang. A sizable fraction of them may have formed later, and many are still experiencing significant dynamical evolution.


Use of prophylactic Saccharomyces boulardii to prevent Clostridium difficile infection in hospitalized patients: a controlled prospective intervention study.
Clostridium difficile infection (CDI) is a common complication to antibiotic use. Saccharomyces boulardii has shown effect as a prophylactic agent. We aimed to evaluate the efficacy of S. boulardii in preventing CDI in unselected hospitalized patients treated with antibiotics. We conducted a 1 year controlled prospective intervention study aiming to prescribe Sacchaflor (S. boulardii 5 × 109, Pharmaforce ApS) twice daily to hospitalized patients treated with antibiotics. Comparable departments from three other hospitals in our region were included as controls. All occurrences of CDI in patients receiving antibiotics were reported and compared to a baseline period defined as 2 years prior to intervention. Results were analyzed using run chart tests for non-random variation in CDI rates. In addition, odds ratios for CDI were calculated. S. boulardii compliance reached 44% at the intervention hospital, and 1389 patients were treated with Sacchaflor. Monthly CDI rates dropped from a median of 3.6% in the baseline period to 1.5% in the intervention period. S. boulardii treatment was associated with a reduced risk of CDI at the intervention hospital: OR = 0.06 (95% CI 0.02-0.16). At two control hospitals, CDI rates did not change. At one control hospital, the median CDI rate dropped from 3.5 to 2.4%, possibly reflecting the effects of simultaneous multifaceted intervention against CDI at that hospital. The results from this controlled prospective interventional study indicate that S. boulardii is effective for the prevention of CDI in an unselected cohort of mainly elderly patients from departments of internal medicine.


Screening and eradication of Helicobacter pylori for gastric cancer prevention: the Taipei global consensus.
A global consensus meeting was held to review current evidence and knowledge gaps and propose collaborative studies on population-wide screening and eradication of Helicobacter pylori for prevention of gastric cancer (GC). 28 experts from 11 countries reviewed the evidence and modified the statements using the Delphi method, with consensus level predefined as ≥80% of agreement on each statement. The Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach was followed. Consensus was reached in 26 statements. At an individual level, eradication of H. pylori reduces the risk of GC in asymptomatic subjects and is recommended unless there are competing considerations. In cohorts of vulnerable subjects (eg, first-degree relatives of patients with GC), a screen-and-treat strategy is also beneficial. H. pylori eradication in patients with early GC after curative endoscopic resection reduces the risk of metachronous cancer and calls for a re-examination on the hypothesis of 'the point of no return'. At the general population level, the strategy of screen-and-treat for H. pylori infection is most cost-effective in young adults in regions with a high incidence of GC and is recommended preferably before the development of atrophic gastritis and intestinal metaplasia. However, such a strategy may still be effective in people aged over 50, and may be integrated or included into national healthcare priorities, such as colorectal cancer screening programmes, to optimise the resources. Reliable locally effective regimens based on the principles of antibiotic stewardship are recommended. Subjects at higher risk of GC, such as those with advanced gastric atrophy or intestinal metaplasia, should receive surveillance endoscopy after eradication of H. pylori. Evidence supports the proposal that eradication therapy should be offered to all individuals infected with H. pylori. Vulnerable subjects should be tested, and treated if the test is positive. Mass screening and eradication of H. pylori should be considered in populations at higher risk of GC.


Deregulated MITF sumoylation: A route to melanoma.
Metastatic melanoma is a deadly form of skin cancer. Extraordinary breakthroughs have been recently achieved in the treatment of the disease,1 leading to objective increase in patient survival. However, early detection of potential dangerous melanocytic lesions remains the best strategy to avoid metastatic dissemination, which is still the main cause of death in melanoma patients. In 2011, our team identified a germline mutation in microphthalmia-associated transcription factor (MITFE318K ) that predisposes carriers to melanoma. Recently, we demonstrated that this mutation interfered with oncogene-induced senescence, one of the first events that should be overcome to allow melanoma development. Therefore, our works provide important clues on the early steps of melanomagenesis and as such might be useful for prevention or early therapeutic interventions in at risk-patients.


The effect of equipment scaling on the skill acquisition of beginning tennis players.
In this study, we examined the effectiveness of equipment scaling (tennis ball modification and court size) on beginner tennis player skill acquisition and associated psychological responses within a structured competitive development/participation programme. The participants' ability to rally and their stroke proficiency were recorded before and after a 5-week acquisition phase. Coupled to these dependent measures were within-practice session recording of hitting opportunities, resultant success, and the affective measure of session happiness. The participants who practised using a standard ball and standard court (adult constraints) were afforded a significantly poorer learning experience relative to the other ball/court scaling combinations. In particular, the adult standardized intervention group recorded significantly less hitting opportunities on the forehand and backhand side than the scaled-court intervention conditions. The decreased hitting opportunities experienced within the standardized adult condition then flowed into significantly poorer hitting success relative to the scaled court groups. The modified ball/scaled court intervention group rated their experience significantly happier than the standardized adult group. Discussion centres on the stronger learning effect generated by court scaling relative to the influence of ball type and the broader application of these findings to skill acquisition theory and practice.


Should biomedical research be like Airbnb?
The thesis presented here is that biomedical research is based on the trusted exchange of services. That exchange would be conducted more efficiently if the trusted software platforms to exchange those services, if they exist, were more integrated. While simpler and narrower in scope than the services governing biomedical research, comparison to existing internet-based platforms, like Airbnb, can be informative. We illustrate how the analogy to internet-based platforms works and does not work and introduce The Commons, under active development at the National Institutes of Health (NIH) and elsewhere, as an example of the move towards platforms for research.


A co-design process developing heuristics for practitioners providing end of life care for people with dementia.
The end of life for someone with dementia can present many challenges for practitioners; such as, providing care if there are swallowing difficulties. This study aimed to develop a toolkit of heuristics (rules-of-thumb) to aid practitioners making end-of-life care decisions for people with dementia. An iterative co-design approach was adopted using a literature review and qualitative methods, including; 1) qualitative interviews and focus groups with family carers and 2) focus groups with health and care professionals. Family carers were recruited from a national charity, purposively sampling those with experience of end-of-life care for a person with dementia. Health and care professionals were purposively sampled to include a broad range of expertise including; general practitioners, palliative care specialists, and geriatricians. A co-design group was established consisting of health and social care experts and family carers, to synthesise the findings from the qualitative work and produce a toolkit of heuristics to be tested in practice. Four broad areas were identified as requiring complex decisions at the end of life; 1) eating/swallowing difficulties, 2) agitation/restlessness, 3) ending life-sustaining treatment, and 4) providing "routine care" at the end of life. Each topic became a heuristic consisting of rules arranged into flowcharts. Eating/swallowing difficulties have three rules; ensuring eating/swallowing difficulties do not come as a surprise, considering if the situation is an emergency, and considering 'comfort feeding' only versus time-trialled artificial feeding. Agitation/restlessness encourages a holistic approach, considering the environment, physical causes, and the carer's wellbeing. Ending life-sustaining treatment supports practitioners through a process of considering the benefits of treatment versus quality-of-life and comfort. Finally, a heuristic on providing routine care such as bathing, prompts practitioners to consider adapting the delivery of care, in order to promote comfort and dignity at the end of life. The heuristics are easy to use and remember, offering a novel approach to decision making for dementia end-of-life care. They have the potential to be used alongside existing end-of-life care recommendations, adding more readily available practical assistance. This is the first study to synthesise experience and existing evidence into easy-to-use heuristics for dementia end-of-life care.


Activity of fluconazole (UK 49,858) and ketoconazole against Candida albicans in vitro and in vivo.
Fluconazole (UK 49,858), a new orally administered bis-triazole, was compared with ketoconazole for activity in synthetic broth dilution susceptibility tests against Candida albicans and also in treatment of experimental systemic candidal infections in rats. In vitro studies indicated that fluconazole activity is less sensitive to acidic medium than is that of ketoconazole. At physiologic pH, fluconazole was approximately 16-fold less active than ketoconazole against 35 representative isolates of C. albicans. Two additional isolates (K-1 and K-3) recovered from patients who had failed ketoconazole therapy were 32- to 64-fold more resistant than the median of each drug for other isolates. In animal studies, fluconazole was very effective in prolonging survival of rats infected with a representative candidal strain. With an inoculum sufficient to kill 29 of 38 sham-treated animals, only 1 of 18 animals treated with 0.5 mg of fluconazole per kg per day died compared with 13 of 20 animals treated with 10.0 mg of ketoconazole per kg per day. However, when similar fluconazole treatment was administered to rats infected with the more resistant strain, K-1, no prolongation of survival was found. Thus, in vivo and in vitro results between strains correlated well for fluconazole. However, in comparing results between drugs, ketoconazole was 16-fold more active in vitro and fluconazole was 20-fold more active in vivo. This discrepancy may be due to drug distribution, modes of drug metabolism, or other pharmacologic differences between the two agents.


Extramasticatory dental wear reflecting habitual behavior and health in past populations.
In skeletal remains, teeth are valuable sources of information regarding age, diet, and health. Dental wear is especially helpful in reconstructions of dietary patterns in populations of varying subsistence. In past societies, teeth have also been used as "a third hand" or as a "tool." The present article examines this type of dental wear and traits attributed to habitual behavior during prehistoric and historic times. Terminology and classification of habitual dental wear are described mainly by appearance, for instance, notching, grooving, cuts, scrapes, and polished surfaces, and their characteristics are illuminated by different case studies. Secondary health effects caused by the extramasticatory use of teeth, such as periapical lesions, tilting, skeletal changes at the temporomandibular joint, chipping, and antemortem tooth loss are also examined. During the examination of extramasticatory dental wear, information should be recorded on morphology, size, frequency, intensity, and location within the dental arch, as well as descriptions and detailed photographic documentation. The advantage of using a low- to medium-resolution microscope in all dental examination is emphasized. By categorizing the wear marks, characteristics are emphasized rather than an exact causing agent. In this way, tentative analogies for the origin of different extramasticatory wear, and consequently for human behavior in the past, can be avoided.


Induction, Propagation, and Activity of Host Nitric Oxide: Lessons from Leishmania Infection.
The production of nitric oxide (NO) by the inducible NO synthase (iNOS) is a key defense mechanism against intracellular pathogens such as Leishmania. Numerous studies have investigated the antimicrobial properties of this small molecule in vitro but its precise mode of action during Leishmania infection in vivo is still unclear. In this review, we discuss how iNOS is induced in infected tissues and how NO acts to control the expansion of Leishmania parasites and limit tissue damage resulting from the infection. We highlight recently described mechanisms that result in widespread iNOS expression in infected tissues. We also discuss how the collective production and subsequent diffusion of NO generates an antimicrobial milieu that promotes parasite control at the tissue level.


Cost-effectiveness of artemisinin combination therapy for uncomplicated malaria in children: data from Papua New Guinea.
To compare the cost-effectiveness of conventional antimalarial therapy with that of three artemisinin combination treatment regimens in children from Papua New Guinea aged 6 to 60 months. An incremental cost-effectiveness analysis was performed using data from 656 children with Plasmodium falciparum and/or P. vivax malaria who participated in a large intervention trial in two clinics in northern Papua New Guinea. The children were randomized to one of the following groups: (i) conventional treatment with chloroquine plus sulfadoxine plus pyrimethamine (CQ+S+P); (ii) artesunate plus S plus P; (iii) dihydroartemisinin plus piperaquine (DHA+PQ); and (iv) artemether plus lumefantrine (A+L). For treatment outcomes, World Health Organization definitions were used. The cost of transport between home and the clinic plus direct health-care costs served as a basis for determining each regimen's incremental cost per incremental treatment success relative to CQ+S+P by day 42 and its cost per life year saved. A+L proved to be the most effective regimen against P. falciparum malaria and was highly cost-effective at 6.97 United States dollars (US$) per treatment success (about US$ 58 per life year saved). DHA+PQ was the most effective regimen against P. vivax malaria and was more cost-effective than CQ+S+P. A+L and DHA+PQ are highly cost-effective regimens for the treatment of paediatric P. falciparum and P. vivax malaria, respectively, in parts of Papua New Guinea. Future research will be required to determine if these findings hold true for other territories in Asia and Oceania with similar malaria epidemiology.


Conditionally immortalized syncytiotrophoblast cell lines as new tools for study of the blood-placenta barrier.
Syncytiotrophoblasts play an essential role in restriction of drug delivery through the blood-placenta barrier (BPB). Conditionally immortalized syncytiotrophoblast cell lines, TR-TBTs, were established at gestational day 18 from pregnant transgenic rats (Tg-rats) harboring the temperature-sensitive SV 40 (ts SV40) large T-antigen. TR-TBTs exhibit temperature-sensitive cell growth due to the expression of SV 40 large T-antigen, and thus the cell growth can be regulated by changing the culture temperature. TR-TBTs exhibit typical properties of syncytiotrophoblast cells, such as syncytium-like morphology, the expression of cytokeratins and hormones, and polarized expression of glucose transporter 1 (GLUT1) and GLUT3. TR-TBTs express in vivo influx and efflux transporters, such as taurine transporter (TauT), betaine/GABA transporter (BGT-1), amino acid transporter 2 (ATA2), organic anion transporting polypeptide 2 (oatp2), organic cation/carnitine transporter (OCTN2), P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP/ABCG2). Moreover, TR-TBTs exhibit taurine, GABA, and DHEA-S uptake activity via TauT, BGT-1, and oatp2, respectively. Therefore, TR-TBTs can be used for the analysis of these functions and would be a good in vitro models for investigating carrier-mediated transport functions at the BPB.


Assessing FDG-PET diagnostic accuracy studies to develop recommendations for clinical use in dementia.
FDG-PET is frequently used as a marker of synaptic damage to diagnose dementing neurodegenerative disorders. We aimed to adapt the items of evidence quality to FDG-PET diagnostic studies, and assess the evidence available in current literature to assist Delphi decisions for European recommendations for clinical use. Based on acknowledged methodological guidance, we defined the domains, specific to FDG-PET, required to assess the quality of evidence in 21 literature searches addressing as many Population Intervention Comparison Outcome (PICO) questions. We ranked findings for each PICO and fed experts making Delphi decisions for recommending clinical use. Among the 1435 retrieved studies, most lacked validated measures of test performance, an adequate gold standard, and head-to-head comparison of FDG-PET and clinical diagnosis, and only 58 entered detailed assessment. Only two studies assessed the accuracy of the comparator (clinical diagnosis) versus any kind of gold-/reference-standard. As to the index-test (FDG-PET-based diagnosis), an independent gold-standard was available in 24% of the examined papers; 38% used an acceptable reference-standard (clinical follow-up); and 38% compared FDG-PET-based diagnosis only to baseline clinical diagnosis. These methodological limitations did not allow for deriving recommendations from evidence. An incremental diagnostic value of FDG-PET versus clinical diagnosis or lack thereof cannot be derived from the current literature. Many of the observed limitations may easily be overcome, and we outlined them as research priorities to improve the quality of current evidence. Such improvement is necessary to outline evidence-based guidelines. The available data were anyway provided to expert clinicians who defined interim recommendations.


Neuroprotective Effect of Hydrogen-Rich Saline in Global Cerebral Ischemia/Reperfusion Rats: Up-Regulated Tregs and Down-Regulated miR-21, miR-210 and NF-κB Expression.
Recently, it has been suggested that molecular hydrogen (H2) can selectively reduce the levels of hydroxyl radicals (.OH), and ameliorate oxidative and inflammatory injuries to organs in global cerebral ischemia reperfusion models. Global cerebral ischemia/reperfusion (I/R) can induce a sudden activation of inflammatory cytokines and later influence the systemic immunoreactivity which may contribute to a worse outcome. Regulatory T cells (Tregs) are involved in several pathological aspects of cerebral I/R. In addition, miRNA took part in the processes of cellular response to hypoxia. Since the expression of a specific set of miRNA called "hypoxamirs" is upregulated by hypoxia. Therefore, the aim of this study was to analyze the effect of HRS on I/R inducing cerebral damage, Tregs, and specific miRNA. Our results showed that rats undergone global cerebral I/R and treated with HRS have milder injury than I/R animals without HRS treatment. miR-210 expression in the hippocampus of the I/R group at 6, 24 and 96 h after reperfusion was significantly increased at each time point, while its expression in the group treated with HRS was significantly decreased. In addition, Tregs number in group I/R was decreased at each time points, while its number in the group treated with HRS was increased at 24 and 96 h after reperfusion. We focus on the relationship among Tregs, TGF-β1, TNF-α and NF-κB at 24 h, and we found that there is a high correlation among them. Therefore, our results indicated that the brain resuscitation mechanism in the HRS-treated rats may be related with the effect of upregulating the number of Treg cells.


Aspergillus hancockii sp. nov., a biosynthetically talented fungus endemic to southeastern Australian soils.
Aspergillus hancockii sp. nov., classified in Aspergillus subgenus Circumdati section Flavi, was originally isolated from soil in peanut fields near Kumbia, in the South Burnett region of southeast Queensland, Australia, and has since been found occasionally from other substrates and locations in southeast Australia. It is phylogenetically and phenotypically related most closely to A. leporis States and M. Chr., but differs in conidial colour, other minor features and particularly in metabolite profile. When cultivated on rice as an optimal substrate, A. hancockii produced an extensive array of 69 secondary metabolites. Eleven of the 15 most abundant secondary metabolites, constituting 90% of the total area under the curve of the HPLC trace of the crude extract, were novel. The genome of A. hancockii, approximately 40 Mbp, was sequenced and mined for genes encoding carbohydrate degrading enzymes identified the presence of more than 370 genes in 114 gene clusters, demonstrating that A. hancockii has the capacity to degrade cellulose, hemicellulose, lignin, pectin, starch, chitin, cutin and fructan as nutrient sources. Like most Aspergillus species, A. hancockii exhibited a diverse secondary metabolite gene profile, encoding 26 polyketide synthase, 16 nonribosomal peptide synthase and 15 nonribosomal peptide synthase-like enzymes.


24-Hour Alberta Stroke Program Early CT Score Assessment in Post-Stroke Spasticity Development in Patients with a First Documented Anterior Circulation Ischemic Stroke.
Neuroanatomic substrates responsible for development of post-stroke spasticity are still poorly understood. The study is focused on identification of brain regions within the territory of the middle cerebral artery associated with spasticity development. This is a single-center prospective cohort study of first documented anterior circulation ischemic strokes with a neurologic deficit lasting >7 days (from March 2014 to September 2016, all patients are involved in a registry). Ischemic cerebral lesions within the territory of middle cerebral artery were evaluated using the Alberta Stroke Program Early CT Score (ASPECTS) on control 24-hour computed tomography or magnetic resonance imaging. Spasticity was assessed with modified Ashworth scale. Seventy-six patients (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen activator, 6.5% mechanical thrombectomy) fulfilled the study inclusion criteria. Forty-nine (64%) developed early elbow or wrist flexor spasticity defined as modified Ashworth scale >1 (at day 7-10), in 44 (58%) the spasticity remained present at 6 months. There were no differences between the patients who developed spasticity and those who did not when comparing admission stroke severity (National Institutes of Health Stroke Scale 5 [interquartile range {IQR} 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease). Nor was there a difference in 24-hour ASPECTS score (9 [IQR 8-10] versus 9 [IQR 7-10]). No differences were found between the groups with and without the early upper limb flexor spasticity of particular regions (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentral-postcentral gyrus, premotor cortex, supplementary motor area, posterior limb of internal capsule, and thalamus were compared. We did not find any middle cerebral artery territory associated with post-stroke spasticity development by detailed evaluation of ASPECTS.


Genotyping for Blast (Pyricularia oryzae) Resistance Genes in F2 Population of Supa Aromatic Rice (Oryza sativa L.).
The ascomycete fungus, Pyricularia oryzae or Magnaporthe oryzae, is known to cause blast disease in more than 80 host plants of the Gramineae family-cereals including rice and grasses. The improvement of the Supa234 rice line (IR97012-27-3-1-1-B, containing badh2 gene for aroma) developed at IRRI-ESA Burundi consisted of introgression of R genes (Pita and Pi9) for blast resistance. The F2 population obtained via the cross had been screened for blast resistance using inoculation with Pyricularia oryzae spore's suspension. The objectives of this study were to assess the presence of Pita and Pi9 genes for blast resistance and to assess the presence of the badh2 gene for aroma in the screened F2 plants using molecular markers. Genotyping was carried out in 103 F2 plants which grew to maturity using the KASP genotyping method with SNP markers (snpOS0007, snpOS0006, and snpOS0022) targeting the Pita and Pi9 genes for blast resistance and the badh2 gene for aromatic fragrance. The genotyping results showed that 38 F2 plants had the Pita gene present in both alleles, 31 F2 plants with the Pita gene in one allele, and only one plant (3B1) was found with the Pi9 gene in one allele. The badh2 gene for aroma was detected in 27 F2 plants on both alleles and in 57 F2 plants on one allele. There were thirteen plants which had both the Pita gene and the badh2 gene for aroma, and only one plant (3B1) had a combination of the three genes (Pita, Pi9, and badh2). Seven plants resistant to blast disease (2H2, 2H4, 1G2, 1C12, 1E13, 1B12, and 1C5) with the Pita and badh2 genes were found, and only one resistant plant (3B1) had a combination of the three genes Pi9, Pita, and badh2 which is recommended to be bulked for the development of the Supa aromatic rice variety resistant to blast disease. The plants generated by the best line 3B1 should further be evaluated for grain quality (Supa type) after F5 generation in the field.


Estimation of the repeatability and reproducibility of three diagnostic tests for infectious salmon anaemia virus.
Reverse transcriptase polymerase chain reaction (RT-PCR), virus isolation (VI) and indirect fluorescent antibody tests (IFAT) are three assays currently used by the salmon industry to identify fish infected with infectious salmon anaemia virus (ISAV). However, no data are available on the repeatability (within-laboratory consistency) and reproducibility (between-laboratory consistency) of these assays and very limited information is available on the effect of freezing samples on test results. In order to evaluate these assays, five laboratories participated in a blinded study of 400 kidney samples representing four populations of farmed Atlantic salmon with different prevalence of ISAV. Each laboratory used its own testing protocols. Repeatability and reproducibility were evaluated using kappa as the measure of agreement. The effect of freezing was evaluated using the McNemar test. Freezing did not affect VI but improved the sensitivity of RT-PCR. The repeatability and reproducibility of VI was almost perfect. There was a substantial difference in repeatability of RT-PCR among the three laboratories with kappa ranging from 0.5 to 0.96. The repeatability for RT-PCR was generally low. The repeatability of IFAT was moderate when the results were analysed using 1+ and above as a positive result. The results of the study show the need to standardize the protocol and interpretation of RT-PCR.


Development of autoantibody signatures as novel diagnostic biomarkers of non-small cell lung cancer.
To select autoantibody signatures as noninvasive biomarkers of non-small cell lung cancer (NSCLC). A phage cDNA expression library was constructed with fresh samples from 30 lung cancer patients and biopanned using serum pools of 10 NSCLC patients and 10 healthy controls. A six-phage peptide detector was discovered by two-step immunoscreenings and was validated in an independent set of 90 NSCLC patients and 90 matched healthy controls, 30 NSCLC patients with chemotherapy, and 12 chronic obstructive pulmonary disease (COPD) patients. The expression of a peptide target was validated by using immunohistochemistry. Factors affecting NSCLC-related death were evaluated by Cox regression analysis. Six phage peptide clones showing higher seroreactivity than others in 30 NSCLC patients were selected for diagnostic validation. The six-phage peptide detector was able to discriminate between NSCLC patients and healthy controls with a sensitivity and specificity of >92%, and had similar validity for indicating NSCLC at early stage. The seroreactivity of the six phage peptides was significantly higher in the NSCLC patients than in those with chemotherapy and the COPD patients, respectively. Of the six phage peptides, one encoded a peptide showing 100% homology to olfactomedin 1. Expression of olfactomedin 1 protein was significantly higher in lung adenocarcinoma than in lung cancer of other histologic types and normal lung tissues. The autoantibody signature was not associated with the prognosis of the NSCLC patients. The six-phage peptide detector stands out as promising diagnostic biomarkers for NSCLC, unlikely for NSCLC relapse after chemotherapy. Olfactomedin 1 may be a novel target of lung adenocarcinoma.