Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody-Drug Conjugate for Treatment of CLDN18.2-Positive Cancers.
Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody-drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2-307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.


ESMira: A decentralized open-source application for collecting experience sampling data.
This paper introduces ESMira, a server and mobile app (Android, iOS) developed for research projects using experience sampling method (ESM) designs. ESMira offers a very simple setup process and ease of use, while being free, decentralized, and open-source (source code is available on GitHub). The ongoing development of ESMira started in early 2019, with a focus on scientific requirements (e.g., informed consent, ethical considerations), data security (e.g., encryption), and data anonymity (e.g., completely anonymous data workflow). ESMira sets itself apart from other platforms by both being free of charge and providing study administrators with full control over study data without the need for specific technological skills (e.g., programming). This means that study administrators can have ESMira running on their own webspace without needing much technical knowledge, allowing them to remain independent from any third-party service. Furthermore, ESMira offers an extensive list of features (e.g., an anonymous built-in chat to contact participants; a reward system that allows participant incentivization without breaching anonymity; live graphical feedback for participants) and can deal with complex study designs (e.g., nested time-based sampling). In this paper, we illustrate the basic structure of ESMira, explain how to set up a new server and create studies, and introduce the platform's basic functionalities.


LAEO-Net++: Revisiting People Looking at Each Other in Videos.
Capturing the 'mutual gaze' of people is essential for understanding and interpreting the social interactions between them. To this end, this paper addresses the problem of detecting people Looking At Each Other (LAEO) in video sequences. For this purpose, we propose LAEO-Net++, a new deep CNN for determining LAEO in videos. In contrast to previous works, LAEO-Net++ takes spatio-temporal tracks as input and reasons about the whole track. It consists of three branches, one for each character's tracked head and one for their relative position. Moreover, we introduce two new LAEO datasets: UCO-LAEO and AVA-LAEO. A thorough experimental evaluation demonstrates the ability of LAEO-Net++ to successfully determine if two people are LAEO and the temporal window where it happens. Our model achieves state-of-the-art results on the existing TVHID-LAEO video dataset, significantly outperforming previous approaches. Finally, we apply LAEO-Net++ to a social network, where we automatically infer the social relationship between pairs of people based on the frequency and duration that they LAEO, and show that LAEO can be a useful tool for guided search of human interactions in videos.


[Role of determination of creatine kinase isoenzyme MB in the diagnosis of myocardial lesions after surgery of the major vessels].
A considerable increase in CPK activity is usually noted after reconstructive surgery on thoracic and abdominal aorta and its branches (75 patients), MB-CPK activity being increased in 48.0% of the cases. Increased cumulative MB-CPK activity, pointing to the isoenzyme's withdrawal from the myocardium (3.2 to 5.6 Eq), was established in 8 patients. It was only in one case (1.3%) that a typical curve and a high cumulative activity of the isoenzyme (29.14 Eq) suggested the diagnosis of acute myocardial infarction. Therefore, increased MB-CPK activity alone cannot signal focal myocardial necrosis. Although the increase in cumulative MB-CPK activity correlates, to some degree, with negative ECG developments in the patients with basic coronary disease, it is only the typical curve and high MB-CPK activity that can be used as specific criteria in the enzymatic diagnosis of myocardial infarction after reconstructive surgery on main vessels.


Systemic Colonization by Metarhizium robertsii Enhances Cover Crop Growth.
Fungi in the genus Metarhizium (Hypocreales: Clavicipitaceae) are insect pathogens that can establish as endophytes and can benefit their host plant. In field experiments, we observed a positive correlation between the prevalence of M. robertsii and legume cover crops, and a negative relationship with brassicaceous cover crops and with increasing proportion of cereal rye in mixtures. Here, we report the effects of endophytic M. robertsii on three cover crop species under greenhouse conditions. We inoculated seeds of Austrian winter pea (Pisum sativum L., AWP), cereal rye (Secale cereale L.), and winter canola (Brassica napus L.) with conidia of M. robertsii to assess the effects of endophytic colonization on cover crop growth. We recovered M. robertsii from 59%, 46%, and 39% of seed-inoculated AWP, cereal rye, and canola plants, respectively. Endophytic M. robertsii significantly increased height and above-ground biomass of AWP and cereal rye but did not affect chlorophyll content of any of the cover crop species. Among inoculated plants from which we recovered M. robertsii, above-ground biomass of AWP was positively correlated with the proportion of colonized root but not leaf tissue sections. Our results suggest that winter cover crops may help to conserve Metarhizium spp. in annual cropping systems.


Low tobacco-related cancer incidence in offspring of long-lived siblings: a comparison with Danish national cancer registry data.
Familial clustering of longevity is well documented and includes both genetic and other familial factors, but the specific underlying mechanisms are largely unknown. We examined whether low incidence of specific cancers is a mechanism for familial clustering of longevity. The study population of individuals from longevity-enriched families consisted of 3267 offspring from 610 Danish long-lived families defined by two siblings attaining an age of 90 years or more. The offspring of the long-lived siblings were followed from 1968 to 2009. Using high-quality registry data, observed numbers of cancers were compared with expected numbers based on gender-, calendar period-, and age-specific incidence rates in the general population. During the 41-year-follow-up period, a total of 423 cancers occurred in 397 individuals. The standardized incidence ratios (95% confidence interval) for offspring of long-lived individuals were 0.78 (0.70-0.86) for overall cancer; 0.66 (0.56-0.77) for tobacco-related cancer; 0.34 (0.22-0.51) for lung cancer; 0.88 (0.71-1.10) for breast cancer; 0.91 (0.62-1.34) for colon cancer. The low incidence of tobacco-related cancers in long-lived families compared with non-tobacco-related cancers suggests that health behavior plays a central role in lower early cancer incidence in offspring of long-lived siblings in Denmark.


The atrial FibriLlatiOn real World management registry in the Middle East and Africa: design and rationale.
Atrial fibrillation is the most common cardiac arrhythmia, affecting 33.5 million patients globally. It is associated with increased morbidity, leading to significant clinical and economic burden. There exist only limited data in the Middle Eastern region from the existing registries. The goal of the FLOW-AF (atrial FibriLlatiOn real World management registry in the Middle East and Africa) registry is to evaluate the characteristics, treatment patterns, and clinical and economic outcomes associated with anticoagulation among patients newly diagnosed with nonvalvular atrial fibrillation in Egypt, Lebanon, the Kingdom of Saudi Arabia, and the United Arab Emirates. This study will be a multicountry, multicenter, prospective observational registry aiming to enroll 1446 newly diagnosed nonvalvular atrial fibrillation patients at more than 20 sites across the four countries. During the recruitment period, patients will be included if they were newly diagnosed with nonvalvular atrial fibrillation and had initiated treatment for the prevention of stroke/systemic embolism. Patient data will be assessed prospectively at 6 and 12 months from their enrollment date. Demographics, clinical characteristics, antithrombotic treatments received, clinical outcomes, adverse events, healthcare resource utilization, and direct costs associated with management of nonvalvular atrial fibrillation will be collected and analyzed overall, by country, and by groups created based on treatment, demographics, and clinical characteristics, medical history and risk factors. The FLOW-AF registry will provide information on the uptake of oral anticoagulants, treatment patterns, clinical outcomes, and healthcare utilization and costs among newly diagnosed nonvalvular atrial fibrillation patients in the Middle Eastern region.


Selective expansion of CD16highCCR2- subpopulation of circulating monocytes with preferential production of haem oxygenase (HO)-1 in response to acute inflammation.
Monocytes are composed of two distinct subpopulations in the peripheral blood as determined by their surface antigen expressions, profiles of cytokine production and functional roles played in vivo. We attempted to delineate the unique functional roles played by a minor CD16(high)CCR2(-) subpopulation of circulating monocytes. They produced significant levels of interleukin (IL)-6 and tumour necrosis factor (TNF)-alpha, but very low levels of IL-10 upon in vitro stimulation. Characteristic profiles of cytokine production were confirmed by stimulating purified subpopulations of monocytes after cell sorting. It was noteworthy that freshly isolated CD16(high)CCR2(-) monocyte subpopulations produced significant levels of haem oxygenase (HO)-1, whereas the major CD16(low)CCR2(+) subpopulation produced little. These results were contrary to the generally accepted notion that the CD16(high)CCR2(-) monocyte subpopulation plays a predominantly proinflammatory role in vivo. The CD16(high)CCR2(-) subpopulation increased in Kawasaki disease and influenza virus infection. In accord with this, HO-1 mRNA expression by mononuclear cells was significantly increased in these illnesses. These results indicate that CD16(high)CCR2(-) subpopulations are of a distinct lineage from CD16(low)CCR2(+) monocytes. More importantly, they may represent a monocyte subpopulation with a unique functional role to regulate inflammation by producing HO-1 in steady state in vivo.


Non-adiabatic quantum interference in the ultracold Li + LiNa → Li2 + Na reaction.
Electronically non-adiabatic effects play an important role in many chemical reactions. However, how these effects manifest in cold and ultracold chemistry remains largely unexplored. Here for the first time we present from first principles the non-adiabatic quantum dynamics of the reactive scattering between ultracold alkali-metal LiNa molecules and Li atoms. We show that non-adiabatic dynamics induces quantum interference effects that dramatically alter the ultracold rotationally resolved reaction rate coefficients. The interference effect arises from the conical intersection between the ground and an excited electronic state that is energetically accessible even for ultracold collisions. These unique interference effects might be exploited for quantum control applications such as a quantum molecular switch. The non-adiabatic dynamics are based on full-dimensional ab initio potential energy surfaces for the two electronic states that includes the non-adiabatic couplings and an accurate treatment of the long-range interactions. A statistical analysis of rotational populations of the Li2 product reveals a Poisson distribution implying the underlying classical dynamics are chaotic. The Poisson distribution is robust and amenable to experimental verification and appears to be a universal property of ultracold reactions involving alkali metal dimers.


Talar compression syndrome.
Ballet dancers frequently stand on the tips of their toes in the en pointe and demi pointe positions, resulting in compression of the posterior structures of the ankle during repeated plantar flexion of the foot, producing the talar compression syndrome. This mechanism may result in posterior block or impingement of an os trigonum or Stieda's process. When the dancer attempts to force the foot into plantar flexion, the os trigonum or the Stieda's process may be impinged between the calcaneus and the posterior edge of the tibia. Pain and tenderness are localized at the posterolateral aspect of the ankle behind the peroneal tendons. In nondancing members of the population, these conditions are usually asymptomatic. It is the requirement of the classical dance for a well-pointed foot that produces symptoms. We are reporting up to 7 years' followup of six professional ballet dancers in whom we removed the os trigonum for symptomatic talar compression syndrome, caused by the trauma of the en pointe position of toe dancing. Two patients had bilateral operations. All six patients returned to professional dancing within a few months and remained asymptomatic. The anatomy of this condition is reviewed, as well as the diagnosis and treatment.


Bacterial intermediate filaments: in vivo assembly, organization, and dynamics of crescentin.
Crescentin, which is the founding member of a rapidly growing family of bacterial cytoskeletal proteins, was previously proposed to resemble eukaryotic intermediate filament (IF) proteins based on structural prediction and in vitro polymerization properties. Here, we demonstrate that crescentin also shares in vivo properties of assembly and dynamics with IF proteins by forming stable filamentous structures that continuously incorporate subunits along their length and that grow in a nonpolar fashion. De novo assembly of crescentin is biphasic and involves a cell size-dependent mechanism that controls the length of the structure by favoring lateral insertion of crescentin subunits over bipolar longitudinal extension when the structure ends reach the cell poles. The crescentin structure is stably anchored to the cell envelope, and this cellular organization requires MreB function, identifying a new function for MreB and providing a parallel to the role of actin in IF assembly and organization in metazoan cells. Additionally, analysis of an MreB localization mutant suggests that cell wall insertion during cell elongation normally occurs along two helices of opposite handedness, each counterbalancing the other's torque.


Polysomnography for Obstructive Sleep Apnea Should Include Arousal-Based Scoring: An American Academy of Sleep Medicine Position Statement.
The diagnostic criteria for obstructive sleep apnea (OSA) in adults, as defined in the International Classification of Sleep Disorders, Third Edition, requires an increased frequency of obstructive respiratory events demonstrated by in-laboratory, attended polysomnography (PSG) or a home sleep apnea test (HSAT). However, there are currently two hypopnea scoring criteria in The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and Technical Specifications (AASM Scoring Manual). This dichotomy results in differences among laboratory reports, patient treatments and payer policies. Confusion occurs regarding recognizing and scoring "arousal-based respiratory events" during OSA testing. "Arousal-based scoring" recognizes hypopneas associated with electroencephalography-based arousals, with or without significant oxygen desaturation, when calculating an apnea-hypopnea index (AHI), or it includes respiratory effort-related arousals (RERAs), in addition to hypopneas and apneas, when calculating a respiratory disturbance index (RDI). Respiratory events associated with arousals, even without oxygen desaturation, cause significant, and potentially dangerous, sleep apnea symptoms. During PSG, arousal-based respiratory scoring should be performed in the clinical evaluation of patients with suspected OSA, especially in those patients with symptoms of excessive daytime sleepiness, fatigue, insomnia, or other neurocognitive symptoms. Therefore, it is the position of the AASM that the RECOMMENDED AASM Scoring Manual scoring criteria for hypopneas, which includes diminished airflow accompanied by either an arousal or ≥ 3% oxygen desaturation, should be used to calculate the AHI. If the ACCEPTABLE AASM Scoring Manual criteria for scoring hypopneas, which includes only diminished airflow plus ≥ 4% oxygen desaturation (and does not allow for arousal-based scoring alone), must be utilized due to payer policy requirements, then hypopneas as defined by the RECOMMENDED AASM Scoring Manual criteria should also be scored. Alternatively, the AASM Scoring Manual includes an option to report an RDI which also provides an assessment of the sleep-disordered breathing that results in arousal from sleep. Furthermore, given the inability of most HSAT devices to capture arousals, a PSG should be performed in any patient with an increased risk for OSA whose HSAT is negative. If the PSG yields an AHI of 5 or more events/h, or if the RDI is greater than or equal to 5 events/h, then treatment of symptomatic patients is recommended to improve quality of life, limit neurocognitive symptoms, and reduce accident risk.


Impact and process evaluation of integrated community and clinic-based HIV-1 control: a cluster-randomised trial in eastern Zimbabwe.
HIV-1 control in sub-Saharan Africa requires cost-effective and sustainable programmes that promote behaviour change and reduce cofactor sexually transmitted infections (STIs) at the population and individual levels. We measured the feasibility of community-based peer education, free condom distribution, income-generating projects, and clinic-based STI treatment and counselling services and evaluated their impact on the incidence of HIV-1 measured over a 3-y period in a cluster-randomised controlled trial in eastern Zimbabwe. Analysis of primary outcomes was on an intention-to-treat basis. The income-generating projects proved impossible to implement in the prevailing economic climate. Despite greater programme activity and knowledge in the intervention communities, the incidence rate ratio of HIV-1 was 1.27 (95% confidence interval [CI] 0.92-1.75) compared to the control communities. No evidence was found for reduced incidence of self-reported STI symptoms or high-risk sexual behaviour in the intervention communities. Males who attended programme meetings had lower HIV-1 incidence (incidence rate ratio 0.48, 95% CI 0.24-0.98), and fewer men who attended programme meetings reported unprotected sex with casual partners (odds ratio 0.45, 95% CI 0.28-0.75). More male STI patients in the intervention communities reported cessation of symptoms (odds ratio 2.49, 95% CI 1.21-5.12). Integrated peer education, condom distribution, and syndromic STI management did not reduce population-level HIV-1 incidence in a declining epidemic, despite reducing HIV-1 incidence in the immediate male target group. Our results highlight the need to assess the community-level impact of interventions that are effective amongst targeted population sub-groups.


Soft-bottom fishes and spatial protection: findings from a temperate marine protected area.
Numerous studies over the last decades have focused on marine protected areas (MPAs) and their effects on fish communities. However, there is a knowledge gap regarding how species that live associated with soft-substrates (e.g., sand, mud) respond to spatial protection. We analyzed abundance, biomass and total lengths of the soft-bottom fishes in a multiple-use MPA in the north-eastern Atlantic, the Luiz Saldanha Marine Park (Portugal), during and after the implementation of its management plan. Data were collected by experimental fishing in areas with three different levels of protection, during the implementation period and for three years after full implementation of the MPA. Univariate analysis detected significant biomass increases between the two periods. Fish assemblages were mainly structured by depth and substrate, followed by protection level. Community composition analyses revealed significant differences between protection levels and between the two periods. Species exhibited a broad variation in their response to protection, and we hypothesize that factors such as species habitat preferences, body size and late maturity might be underlying determinants. Overall, this study provides some evidence of protection effectiveness in soft-bottom fish communities, supported by the significant increase in biomass in the protected areas and the positive trends of some species.


Performance of Chimeric Trypanosoma cruzi Antigens in Serological Screening for Chagas Disease in Blood Banks.
Chagas disease (CD) is among the top 10 causes of inability to blood donation. Blood donation centers screen for anti-Trypanosoma cruzi antibodies using highly sensitive immunoenzymatic (ELISA) or chemiluminescent methods, which can lead to false positive results. Since positive samples cannot be used, to avoid the loss of valuable blood donations, it is necessary to improve specificity without reducing the sensitivity of the tests used for blood screening. For this purpose, our group has developed four chimeric proteins (IBMP-8.1, IBMP-8.2, IBMP-8.3, and IBMP-8.4) that have been evaluated in phase I and II studies with high performance and low cross-reactivity rates. The study included a panel of 5,014 serum samples collected from volunteer blood donors at the Hematology and Hemotherapy Foundation of the State of Bahia (Brazil). They were subjected to the detection of anti-T. cruzi antibodies, using all four IBMP antigens individually and latent class analysis (LCA) as a reference test, since there is no gold standard test for this purpose. Considering the sample size analyzed, LCA classified 4,993 (99.6%) samples as T. cruzi-negative and 21 (0.42%) as T. cruzi-positive. Sensitivity values ranged from 85.71% for IBMP-8.1 and 90.48% for IBMP-8.2-95.24% for IBMP-8.3 and 100% for IBMP-8.4, while specificity ranged from 99.98% for IBMP-8.3 and IBMP-8.4-100% for IBMP-8.1 and IBMP-8.2. Accuracy values ranged from 99.4 to 99.98%. The pretest probability for the molecules was 0.42, whereas the positive posttest probability ranged from 95.24 to 99.95% and the negative posttest probability ranged from 0.00001 to 0.0006% for all antigens. The higher odds ratio diagnosis was found for IBMP-8.4, which has been shown to be a safe single antigen for serological screening of CD in blood samples. The use of chimeric IBMP antigens is an alternative to reduce the number of bags discarded due to false-positive results. These molecules have high diagnostic performance and were shown to be suitable for use in screening CD in blood banks, isolated (IBMP-8.4) or in combination; and their use in blood banks could significantly reduce unnecessary disposal of blood bags or the risk of T. cruzi transmission.


Salivary Cortisol Dynamics After Mild Traumatic Brain Injury.
To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery. Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community. Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed). A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]). Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample. Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT. Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent mTBI.


Role of plasmid-encoded adherence factors in adhesion of enteropathogenic Escherichia coli to HEp-2 cells.
Plasmid-encoded adherence factors have been shown to be important for the full expression of enteropathogenic Escherichia coli (EPEC) pathogenicity and for EPEC adhesion to cultured HEp-2 cells. EPEC strain E2348 (O127) shows localized HEp-2 cell adhesion and possesses a 60-megadalton plasmid, pMAR2. When E2348 is cured of pMAR2 it loses the ability to adhere to HEp-2 cells, while nonadherent E. coli K-12 strains P678-54 and HB101 acquire HEp-2 adhesiveness after they gain the plasmid. By electron microscopy, E2348 was seen to adhere to HEp-2 cells in a manner that closely resembled EPEC adhesion to intestinal mucosa; bacteria were intimately attached to projections of the apical HEp-2 cell membrane and caused localized destruction of microvilli. The plasmid-containing K-12 strains, on the other hand, did not show intimate attachment and there was no modification of cell surface architecture. It is concluded that plasmid pMAR2 codes for an adhesin, possibly fimbrial in nature, that promotes HEp-2 adhesion but that other chromosomally encoded factors are required for EPEC to achieve the characteristic mode of intimate cell attachment.


[Infections in the surgical management of pelvic ring fractures].
Infections that occur after the surgical management of pelvic fractures may involve potentially devastating complications. The broader approaches involving soft tissue dissection and a long operative time may increase the infection rate when compared with more conservative approaches. This incidence may be reduced with a better understanding of the approaches, lymph node sparing and antibiotic use. The purpose of this study is to assess the incidence and severity of local infections in a series of adult patients with pelvic ring lesions treated surgically. This is a prospective observational descriptive study. A total of 49 patients operated on by a single surgeon from 2004 to 2008 were included. Forty-four patients (90%) had no signs of infection during the treatment period. In the remaining 5 cases (10%), 5 episodes of infection were documented. The identification of a local postoperative infection warrants an aggressive and urgent assessment of the patient. The devitalized tissue should be removed and empiric antibiotic therapy should be instituted after taking culture samples. A deep infection rate after pelvic fixation ranging from 0 to 10% has been published. The prevalence is higher among the surgical teams with less expertise. The incidence rate in our review was similar to the one reported in the literature.


Effectiveness of meningococcal C conjugate vaccine in Salvador, Brazil: a case-control study.
During a citywide epidemic of serogroup C meningococcal disease in Salvador in 2010, Brazil, the state government initiated mass vaccination targeting two age groups with high attack rates: individuals aged <5 years and 10-24 years. More than 600,000 doses of meningococcal serogroup C conjugate vaccines were administered. We performed a case-control study to evaluate vaccine uptake, document vaccine effectiveness and identify reasons for non-vaccination. Population-based surveillance identified patients with laboratory-confirmed invasive meningococcal C (MenC) disease during 2010. Information on MenC vaccination was obtained from case patients and age-matched individuals from the same neighborhoods. MenC vaccine effectiveness was estimated based on the exact odds ratios obtained by conditional logistic regression analysis. Of 51 laboratory-confirmed cases of serogroup C meningococcal disease among patients <5 and 10-24 years of age 50 were included in the study and matched with 240 controls. Overall case-fatality was 25%. MenC vaccine coverage among controls increased from 7.1% to 70.2% after initiation of the vaccination campaign. None of the 50 case patients but 70 (29.2%) of the 240 control individuals, including 59 (70.2%) of 84 matched with cases from the period after MenC vaccination, had received at least one MenC vaccine dose. Overall effectiveness of MenC was 98% with a lower 95% exact confidence limit of 89%. MenC vaccines administered during the meningococcal epidemic were highly effective, suggesting that rapid vaccine uptake through campaigns contributed to control of meningococcal disease.


The Association Between Frailty and Visual Field Loss in US Adults.
To describe the association between visual field loss and frailty in a nationally representative cohort of US adults. Retrospective cross-sectional study. The cohort included adults 40 years or older with complete eye examination data from the 2005-2006 and 2007-2008 National Health and Nutrition Examination Surveys (NHANES). Visual field loss (VFL) was determined by frequency doubling technology and a 2-2-1 algorithm. A 36-item deficit accumulation-based frailty index was used to divide subjects into 4 categories of increasing frailty severity. Of the 4897 participants, 4402 (93.2%) had no VFL, 301 (4.1%) had unilateral VFL, and 194 (2.73%) had bilateral VFL. Within the sample, 2 subjects197 (53.1%) were categorized as non-frail, 1659 (31.3%) as vulnerable, 732 (11.3%) as mildly frail, and 312 (4.3%) as most frail. In multivariable models adjusted for demographics, visual acuity, and history of cataract surgery, subjects with unilateral VFL had higher adjusted odds of being in a more frail category (adjusted odds ratio [aOR], 2.07; 95% CI, 1.42-3.02) than subjects without VFL. Subjects with bilateral VFL also had higher odds of a more frail category compared to subjects without VFL (aOR, 1.74; 95% CI, 1.20-2.52). In the 2005-2008 NHANES adult population, VFL is associated with higher odds of frailty, independent of central visual acuity loss. Frail individuals may be more susceptible to diseases that can cause VFL, and/or VFL may predispose to frailty. Additional studies are needed to determine the directionality of this relationship and to assess potential interventions.


Open Science in Education Sciences.
The Open Science movement has gained considerable traction in the last decade. The Open Science movement tries to increase trust in research results and open the access to all elements of a research project to the public. Central to these goals, Open Science has promoted five critical tenets: Open Data, Open Analysis, Open Materials, Preregistration, and Open Access. All Open Science elements can be thought of as extensions to the traditional way of achieving openness in science, which has been scientific publication of research outcomes in journals or books. Open Science in education sciences, however, has the potential to be much more than a safeguard against questionable research. Open Science in education science provides opportunities to (a) increase the transparency and therefore replicability of research and (b) develop and answer research questions about individuals with learning disabilities and learning difficulties that were previously impossible to answer due to complexities in data analysis methods. We will provide overviews of the main tenets of Open Science (i.e., Open Data, Open Analysis, Open Materials, Preregistration, and Open Access), show how they are in line with grant funding agencies' expectations for rigorous research processes, and present resources on best practices for each of the tenets.


Evaluation of the role of genital human papillomavirus in the pathogenesis of ungual squamous cell carcinoma.
Human papillomaviruses (HPV), and particularly HPV 16, have been associated with ungual squamous cell carcinoma (USCC). But their role in tumor development remains unclear. In genital carcinoma, where the oncogenic role of HPV is well established, integration of HPV DNA into the host cell genome seems to be important for malignant transformation. To clarify the issue, we have studied the physical state of HPV 16 in 3 cases of in situ USCC by the polymerase chain reaction and by in situ hybridization. HPV DNA was integrated into the human genome in 2 cases and episomal in 1 case. This particular physical state of HPV 16 in USCC, similar to those encountered in anogenital SCC, confirms the probable role of this kind of virus in the pathogenesis of USCC.


Protein Family Content Uncovers Lineage Relationships and Bacterial Pathway Maintenance Mechanisms in DPANN Archaea.
DPANN are small-celled archaea that are generally predicted to be symbionts, and in some cases are known episymbionts of other archaea. As the monophyly of the DPANN remains uncertain, we hypothesized that proteome content could reveal relationships among DPANN lineages, constrain genetic overlap with bacteria, and illustrate how organisms with hybrid bacterial and archaeal protein sets might function. We tested this hypothesis using protein family content that was defined in part using 3,197 genomes including 569 newly reconstructed genomes. Protein family content clearly separates the final set of 390 DPANN genomes from other archaea, paralleling the separation of Candidate Phyla Radiation (CPR) bacteria from all other bacteria. This separation is partly driven by hypothetical proteins, some of which may be symbiosis-related. Pacearchaeota with the most limited predicted metabolic capacities have Form II/III and III-like Rubisco, suggesting metabolisms based on scavenged nucleotides. Intriguingly, the Pacearchaeota and Woesearchaeota with the smallest genomes also tend to encode large extracellular murein-like lytic transglycosylase domain proteins that may bind and degrade components of bacterial cell walls, indicating that some might be episymbionts of bacteria. The pathway for biosynthesis of bacterial isoprenoids is widespread in Woesearchaeota genomes and is encoded in proximity to genes involved in bacterial fatty acids synthesis. Surprisingly, in some DPANN genomes we identified a pathway for synthesis of queuosine, an unusual nucleotide in tRNAs of bacteria. Other bacterial systems are predicted to be involved in protein refolding. For example, many DPANN have the complete bacterial DnaK-DnaJ-GrpE system and many Woesearchaeota and Pacearchaeota possess bacterial group I chaperones. Thus, many DPANN appear to have mechanisms to ensure efficient protein folding of both archaeal and laterally acquired bacterial proteins.


Assessing Upper Limb Function in Breast Cancer Survivors Using Wearable Sensors and Machine Learning in a Free-Living Environment.
(1) Background: Being able to objectively assess upper limb (UL) dysfunction in breast cancer survivors (BCS) is an emerging issue. This study aims to determine the accuracy of a pre-trained lab-based machine learning model (MLM) to distinguish functional from non-functional arm movements in a home situation in BCS. (2) Methods: Participants performed four daily life activities while wearing two wrist accelerometers and being video recorded. To define UL functioning, video data were annotated and accelerometer data were analyzed using a counts threshold method and an MLM. Prediction accuracy, recall, sensitivity, f1-score, 'total minutes functional activity' and 'percentage functionally active' were considered. (3) Results: Despite a good MLM accuracy (0.77-0.90), recall, and specificity, the f1-score was poor. An overestimation of the 'total minutes functional activity' and 'percentage functionally active' was found by the MLM. Between the video-annotated data and the functional activity determined by the MLM, the mean differences were 0.14% and 0.10% for the left and right side, respectively. For the video-annotated data versus the counts threshold method, the mean differences were 0.27% and 0.24%, respectively. (4) Conclusions: An MLM is a better alternative than the counts threshold method for distinguishing functional from non-functional arm movements. However, the abovementioned wrist accelerometer-based assessment methods overestimate UL functional activity.


A Dynamic-Shape-Prior Guided Snake Model with Application in Visually Tracking Dense Cell Populations.
This work proposes a dynamic-shape-prior guided snake model (DSP G-snake) that is designed to improve the overall stability of the point-based snake model. The dynamic shape prior is first proposed for snakes, that efficiently unifies different types of high-level priors into a new force term. To be specific, a global-topology regularity is first introduced that settles the inherent self-intersection problem with snakes. The problem that a snake's snaxels tend to unevenly distribute along the contour is also handled, leading to good parameterization. Unlike existing methods that employ learning templates or commonly enforce hard priors, the dynamic-template scheme strongly respects the deformation flexibility of the model, while retaining a decent global topology for the snake. It is verified by experiments that the proposed algorithm can effectively prevent snakes from self-crossing, or automatically untie an already selfintersected contour. In addition, the proposed model is combined with existing forces and applied to the very challenging task of tracking dense biological cell populations. The DSP G-snake model has enabled an improvement of up to 30% in tracking accuracy with respect to regular model-based approaches. Through experiments on real cellular datasets, with highly dense populations and relatively large displacements, it is confirmed that the proposed approach has enabled superior performance, in comparison to modern active-contour competitors as well as state-of-the-art cell tracking frameworks.


Bcl-2-mediated alterations in endoplasmic reticulum Ca2+ analyzed with an improved genetically encoded fluorescent sensor.
The endoplasmic reticulum (ER) serves as a cellular storehouse for Ca(2+), and Ca(2+) released from the ER plays a role in a host of critical signaling reactions, including exocytosis, contraction, metabolism, regulation of transcription, fertilization, and apoptosis. Given the central role played by the ER, our understanding of these signaling processes could be greatly enhanced by the ability to image [Ca(2+)](ER) directly in individual cells. We created a genetically encoded Ca(2+) indicator by redesigning the binding interface of calmodulin and a calmodulin-binding peptide. The sensor has improved reaction kinetics and a K(d) ideal for imaging Ca(2+) in the ER and is no longer perturbed by large excesses of native calmodulin. Importantly, it provides a significant improvement over all previous methods for monitoring [Ca(2+)](ER) and has been used to directly show that, in MCF-7 breast cancer cells, the antiapoptotic protein B cell lymphoma 2 (Bcl-2) (i) lowers [Ca(2+)](ER) by increasing Ca(2+) leakage under resting conditions and (ii) alters Ca(2+) oscillations induced by ATP, and that acute inhibition of Bcl-2 by the green tea compound epigallocatechin gallate results in an increase in [Ca(2+)](ER) due to inhibition of Bcl-2-mediated Ca(2+) leakage.


Response functions of Fuji imaging plates to monoenergetic protons in the energy range 0.6-3.2 MeV.
We have measured the responses of Fuji MS, SR, and TR imaging plates (IPs) to protons with energies ranging from 0.6 to 3.2 MeV. Monoenergetic protons were produced with the 3.5 MV AIFIRA (Applications Interdisciplinaires de Faisceaux d'Ions en Région Aquitaine) accelerator at the Centre d'Etudes Nucléaires de Bordeaux Gradignan (CENBG). The IPs were irradiated with protons backscattered off a tantalum target. We present the photo-stimulated luminescence response of the IPs together with the fading measurements for these IPs. A method is applied to allow correction of fading effects for variable proton irradiation duration. Using the IP fading corrections, a model of the IP response function to protons was developed. The model enables extrapolation of the IP response to protons up to proton energies of 10 MeV. Our work is finally compared to previous works conducted on Fuji TR IP response to protons.


An evolutionary genomics view on neuropeptide genes in Hydrozoa and Endocnidozoa (Myxozoa).
The animal phylum Cnidaria consists of six classes or subphyla: Hydrozoa, Scyphozoa, Cubozoa, Staurozoa, Anthozoa, and Endocnidozoa. Cnidarians have an early evolutionary origin, diverging before the emergence of the Bilateria. Extant members from this phylum, therefore, are important resources for understanding the evolution of the nervous system. Cnidarian nervous systems are strongly peptidergic. Using genomics, we have recently shown that three neuropeptide families (the X1PRX2amides, GRFamides, and GLWamides) are wide-spread in four (Scyphozoa, Cubozoa, Staurozoa, Anthozoa) out of six cnidarian classes or subphyla, suggesting that these three neuropeptide families emerged in the common cnidarian ancestor. In the current paper, we analyze the remaining cnidarian class, Hydrozoa, and the subphylum Endocnidozoa, to make firm conclusions about the evolution of neuropeptide genes in Cnidaria. We analyzed sixteen hydrozoan species with a sequenced genome or transcriptome, using a recently developed software program for discovering neuropeptide genes. These species belonged to various hydrozoan subclasses and orders, among them the laboratory models Hydra, Hydractinia, and Clytia. We found that each species contained three to five neuropeptide families. A common feature for all hydrozoans was that they contained genes coding for (i) X1PRX2amide peptides, (ii) GRFamide peptides, and (iii) GLWamide peptides. These results support our previous conclusions that these three neuropeptide families evolved early in evolution. In addition to these three neuropeptide families, hydrozoans expressed up to two other neuropeptide gene families, which, however, were only occurring in certain animal groups. Endocnidozoa (Myxozoa) are microscopically small endoparasites, which are strongly reduced. For long, it was unknown to which phylum these parasites belonged, but recently they have been associated with cnidarians. We analyzed nine endocnidozoan species and found that two of them (Polypodium hydriforme and Buddenbrockia plumatellae) expressed neuropeptide genes. These genes coded for neuropeptides belonging to the GRFamide and GLWamide families with structures closely resembling them from hydrozoans. We found X1PRX2amide, GRFamide, and GLWamide peptides in all species belonging to the Hydrozoa, confirming that these peptides originated in the common cnidarian ancestor. In addition, we discovered GRFamide and GLWamide peptide genes in some members of the Endocnidozoa, thereby linking these parasites to Hydrozoa.


Differential effects of dietary linoleic and alpha-linolenic acid on lipid metabolism in rat tissues.
Comparative effects of feeding dietary linoleic (safflower oil) and alpha-linolenic (linseed oil) acids on the cholesterol content and fatty acid composition of plasma, liver, heart and epididymal fat pads of rats were examined. Animals fed hydrogenated beef tallow were used as isocaloric controls. Plasma cholesterol concentration was lower and the cholesterol level in liver increased in animals fed the safflower oil diet. Feeding the linseed oil diet was more effective in lowering plasma cholesterol content and did not result in cholesterol accumulation in the liver. The cholesterol concentration in heart and the epididymal fat pad was not affected by the type of dietary fatty acid fed. Arachidonic acid content of plasma lipids was significantly elevated in animals fed the safflower oil diet and remained unchanged by feeding the linseed oil diet, when compared with the isocaloric control animals fed hydrogenated beef tallow. Arachidonic acid content of liver and heart lipids was lower in animals fed diets containing safflower oil or linseed oil. Replacement of 50% of the safflower oil in the diet with linseed oil increased alpha-linolenic, docosapentaenoic and docosahexaenoic acids in plasma, liver, heart and epididymal fat pad lipids. These results suggest that dietary 18:2 omega 6 shifts cholesterol from plasma to liver pools followed by redistribution of 20:4 omega 6 from tissue to plasma pools. This redistribution pattern was not apparent when 18:3 omega 3 was included in the diet.


Current methods to analyze lysosome morphology, positioning, motility and function.
Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent research has shown that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyze lysosome morphology, positioning, motility and function. We highlight the principles behind these methods, the methodological strategies and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground-breaking discoveries on an organelle that continues to surprise and excite cell biologists.


[Characteristics of surgical treatment of pathologic conditions of the cervical stump].
The paper gives the results of surgical management in 65 patients with cervical stump diseases. According to the pattern of the disease, 4 groups of patients were identified: 1) those with inflammatory diseases, 2) those with endometriosis, 3) those with myoma, and 4) those with prolapse of the cervical stump. Low-quality and inadequate suture material was found to be a cause of inflammatory diseases of the cervical stump. It is concluded that it is not expedient to use capron, lavsan, and silk to suture the cervical stump during supravaginal amputation of the uterus. Catgut, vicryl, debone were shown to be an optimal suture material. The practice of surgical management of patients with inflammatory diseases, endometriosis, cervical stump myoma and prolapse indicates that it is advisable to extend indications for uterine extirpation.


Evidence-Based Performance Measures: Quality Metrics for the Care of Patients Undergoing Breast Reconstruction.
The American Society of Plastic Surgeons commissioned the Breast Reconstruction Performance Measure Development Work Group to identify and draft quality measures for the care of patients undergoing breast reconstruction surgery. Two outcome measures were identified. The first desired outcome was to reduce the number of returns to the operating room following reconstruction within 60 days of the initial reconstructive procedure. The second desired outcome was to reduce flap loss within 30 days of the initial reconstructive procedure. All measures in this report were approved by the American Society of Plastic Surgeons Breast Reconstruction Performance Measures Work Group and the American Society of Plastic Surgeons Executive Committee. The Work Group recommends the use of these measures for quality initiatives, Continuing Medical Education, Maintenance of Certification, American Society of Plastic Surgeons' Qualified Clinical Data Registry reporting, and national quality reporting programs.


PEPSI: Polarity measurements from spatial proteomics imaging suggest immune cell engagement.
Subcellular protein localization is important for understanding functional states of cells, but measuring and quantifying this information can be difficult and typically requires high-resolution microscopy. In this work, we develop a metric to define surface protein polarity from immunofluorescence (IF) imaging data and use it to identify distinct immune cell states within tumor microenvironments. We apply this metric to characterize over two million cells across 600 patient samples and find that cells identified as having polar expression exhibit characteristics relating to tumor-immune cell engagement. Additionally, we show that incorporating these polarity-defined cell subtypes improves the performance of deep learning models trained to predict patient survival outcomes. This method provides a first look at using subcellular protein expression patterns to phenotype immune cell functional states with applications to precision medicine.


Neoplastic disease and deletion 22q11.2: a multicentric study and report of two cases.
Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.


A large invasive consumer reduces coastal ecosystem resilience by disabling positive species interactions.
Invasive consumers can cause extensive ecological damage to native communities but effects on ecosystem resilience are less understood. Here, we use drone surveys, manipulative experiments, and mathematical models to show how feral hogs reduce resilience in southeastern US salt marshes by dismantling an essential marsh cordgrass-ribbed mussel mutualism. Mussels usually double plant growth and enhance marsh resilience to extreme drought but, when hogs invade, switch from being essential for plant survival to a liability; hogs selectively forage in mussel-rich areas leading to a 50% reduction in plant biomass and slower post-drought recovery rate. Hogs increase habitat fragmentation across landscapes by maintaining large, disturbed areas through trampling of cordgrass during targeted mussel consumption. Experiments and climate-disturbance recovery models show trampling alone slows marsh recovery by 3x while focused mussel predation creates marshes that may never recover from large-scale disturbances without hog eradication. Our work highlights that an invasive consumer can reshape ecosystems not just via competition and predation, but by disrupting key, positive species interactions that underlie resilience to climatic disturbances.


Multi potent aromatic nano colloid: synthesis, characterization and applications.
In this study the aromatic nanocolloids (CANCs) are synthesized using the noble metal silver by using Citronella extract and confirmed through physio chemical analysis. The synthesised CANCs were evaluated for its antimicrobial activity and antibiofilm activity against pathogenic biofilm forming E. coli. In addition, synthesized CANCs were evaluated for the expression of virulent genes encoding AmpC and CTX-M-15. The results confirmed that CANCs showed effective antimicrobial activity through its bacteriostatic, bactericidal and quorum quencher activity and downregulated CTX-M-15 gene. CANCs were validated as alternate to the commercial fungicides to control plant pathogenic fungi such as A. niger MTCC (281), Fusarium graminearum MTCC (2089) and F. udum MTCC (2204). Furthermore, analysis of CANCs on breast cancer (MCF-7) cells under in vitro condition showed that the cytotoxicity of CANCs is dose dependent. Thus, the multifunctional CANCs can be utilized as potential antimicrobial, antifungal and anticancer agent.


Canine submandibular-gland hyaluronidase. Identification and subcellular distribution.
1. Submandibular glands from four species of mammal have been shown to contain a hyaluronidase active at acid pH; glands from dog and cat had a much higher content of this enzyme than has been found in other sources. 2. Product formation from hyaluronate after 24hr. incubation was almost the same as with testicular hyaluronidase, indicating that the enzyme is an endo-poly-beta-hexosaminidase. 3. When submandibular-gland homogenates were fractionated by the scheme developed for liver by de Duve, Pressman, Gianetto, Wattiaux & Appelmans (1955), all the enzymes assayed, except cytochrome c oxidase, were found to occur partly in the soluble fraction and partly in the particulate fractions. Among the particular fractions, the highest specific activity was found in the heavy-mitochondrial fraction for cytochrome c oxidase, in the microsomal fraction for alkaline phosphatase and in the light-mitochondrial fraction for acid phosphatase, beta-N-acetylhexosaminidase and acid-active hyaluronidase. 4. Release of the enzyme activity from the sedimentable fractions occurred in 0.1% Triton X-100 or after high-speed homogenization. 5. Stimulation of dogs by pilocarpine was found to decrease the hyaluronidase content of the submandibular gland by 5% and to cause the occurrence of a corresponding amount of acid-active hyaluronidase in the submandibular saliva. 6. The results are discussed in relation to the subcellular localization of hyaluronidase.


Transmyocardial laser revascularization: results of a multicenter trial with transmyocardial laser revascularization used as sole therapy for end-stage coronary artery disease.
Transmyocardial laser revascularization was used as the sole therapy for patients with ischemic heart disease not amenable to percutaneous transluminal coronary angioplasty or coronary artery bypass grafting. This technique uses a carbon dioxide laser to create transmyocardial channels for direct perfusion of the ischemic heart. Since 1992, 200 patients, at eight hospitals in the United States, have undergone transmyocardial laser revascularization. The patients have a combined 1560 months of follow-up for an average of 10 +/- 3 months per patient. Their age was 63 +/- 10 years and their ejection fraction was 47% +/- 12%. Eighty-two percent had at least one previous bypass graft operation and 38% had a prior angioplasty. Preoperatively, the patients underwent nuclear single photon emission computed tomography perfusion scans to identify the extent and severity of their ischemia. These scans were repeated at 3, 6, and 12 months. Angina class, admissions for angina, and medications were recorded. The perioperative mortality was 9%. Angina class decreased significantly from before treatment to 3, 6, and 12 months (p < 0.001). Likewise, there was a significant decrease in the number of perfusion defects in the treated left ventricular free wall. Concomitantly, there was a significant decrease in the number of admissions for angina in the year after the procedure when compared with the year before treatment (2.5 vs 0.5 admissions per patient-year). These combined results indicate that transmyocardial laser revascularization provides angina relief, decreases hospital admissions, and improves perfusion in patients with severe coronary artery disease.


Prevalence and risk factors of dry eye disease among a hospital-based population in southeast China.
To investigate the prevalence of dry eye disease (DED) and distribution of associated risk factors among a hospital-based population. In this cross-sectional study, we collected detailed information of clinically defined moderate-to-severe patients with dry eye among a consecutive hospital-based population, including age trend, gender structure, frequency of symptoms, and distribution of associated environmental/occupational risk factors. Of 6,657 consecutive outpatients aged older than 20 years, symptomatic dry eye presented in 635 subjects (9.54%). Five hundred thirty-two of these 635 subjects (7.99%) were clinically diagnosed as defined DED that combined with positive signs. Women (10.41%) were significantly higher than men (5.21%) (P<0.001). Overexposure to visual display terminal was a major risk factor for DED among young men and women (56.2%). Our study also found occupational conditions with the risk of exposure to adverse environment made up over half of all 532 patients with dry eye. The use of contact lenses was closely associated with DED in young women, and history of ocular surgeries might be another factor associated with DED in old people. One hundred sixty-three of 371 female patients with dry eye (43.9%) were associated with hormonal changes. The incidence of meibomian gland dysfunction-related DED increased gradually with age. There were only 10 patients with dry eye (1.9%) associated with Sjögren syndrome, and all of them were women. Environmental and occupational factors were strongly associated with DED and constituted the major proportion in a hospital-based population. A classification of DED based on the distribution of risk factors was recommended for clinical use.


Is it possible to accurately predict outcome of a drop-foot in patients admitted to a hospital stroke unit?
The aim of this study was to determine whether recovery from a drop-foot at 6 months can be predicted within 72 h after stroke and to investigate the effect of timing on the accuracy of prediction. One hundred and five patients with a first-ever anterior circulation stroke without full voluntary ankle dorsiflexion in standing position following the Fugl-Meyer motor score at 72 h were included for further analysis. Determinants were measured within 72 h, and at days 5 and 9 after stroke onset. Multivariable logistic regression analysis was used to predict the recovery of full ankle dorsiflexion while standing at 6 months. Having the item 'Motricity Index ankle dorsiflexion 19 or more (full range of motion ankle dorsiflexion againsts gravity)' was the best predictive variable. The sensitivity was 0.74 [95% confidence interval (CI) 0.62-0.80], specificity was 0.72 (95% CI 0.62-0.81), positive predictive value was 0.74 (95% CI 0.63-0.82), and negative predictive value was 0.71 (95% CI 0.60-0.80). No significant changes at day 5 and 9 after stroke were found. In stroke patients, the presence of full ankle dorsiflexion against gravity within 72 h is an accurate predictor for the absence of a drop-foot at 6 months. The accuracy of prediction of true positives and negatives is irrespective of the time of assessment in a stroke unit.


Calibrating a high-resolution wavefront corrector with a static focal-plane camera.
We present a method to calibrate a high-resolution wavefront (WF)-correcting device with a single, static camera, located in the focal-plane; no moving of any component is needed. The method is based on a localized diversity and differential optical transfer functions to compute both the phase and amplitude in the pupil plane located upstream of the last imaging optics. An experiment with a spatial light modulator shows that the calibration is sufficient to robustly operate a focal-plane WF sensing algorithm controlling a WF corrector with 40,000 degrees of freedom. We estimate that the locations of identical WF corrector elements are determined with a spatial resolution of 0.3% compared to the pupil diameter.


Dizziness is a predictor factor for the risk of falls in institutionalised older adults in Brazil.
Considering the small number of studies aimed at evaluating outcomes related to dizziness and falls in the older adults who live in long-term care facilities, especially in north-eastern Brazil, and considering the negative impact of these events on the quality of life of these individuals, this study purpose was to evaluate dizziness as a predictor of risk of falls in institutionalised older adults. This cross-sectional analysis of data on falls and dizziness of 187 institutionalised older adults carried out between the years 2014 and 2016. The data collection instruments used were a socioeconomic and demographic questionnaire and questionnaires for assessing variables related to falls. The different diagnostic methods were compared using the Spearman correlation, and the Dizziness variable was evaluated by means of logistic regression. Inferential statistical analysis showed a significant association between dizziness and number of morbidities (p = .03) and dizziness and a history of falls (p = .04). Spearman's correlation analysis revealed statistically significant results only for FES-I (Falls Efficacy Scale-International) (p < .01). Dizziness was a predictor of risk of falls and that it was associated with a greater number of morbidities and previous history of falls. Implementing rehabilitation practices to reduce dizziness symptoms can significantly reduce the risk of falls for institutionalised older adults.


Efficacy and pregnancy outcomes of focused ultrasound for cervical high-grade squamous intraepithelial lesions.
To investigate the efficacy and adverse effects of focused ultrasound (FU) in the treatment of high-grade squamous intraepithelial lesions (HSIL) and follow up on pregnancy outcomes in patients. This retrospective study recruited 57 patients aged 20-40 years with cervical HSIL combined with HR-HPV infection who received FU treatment between September 2019 and April 2022. Clinical data of the patients were obtained from hospital records. HSIL cure rate and cumulative HR-HPV clearance rate were assessed after treatment. Patients were followed up on fertility and pregnancy outcomes after treatment by telephone interviews until April 1, 2023. During a 6-month follow-up, the HSIL cure rate was 73.7%, and a statistical difference between CIN2 and CIN3 (75.6% vs. 66.7%, p = 0.713) was not present. HSIL -recurrence was not observed during the follow-up period, and the median follow-up duration was 12 months. The cumulative HR-HPV clearance rates at the 6- and 12-month follow-ups were 56.1% and 75.4%, respectively. The median clearance time of HR-HPV was 6 (95% confidence interval, 5.46-6.54) months. The clearance rate was higher in HPV16/18 than in non-HPV16/18 (86.7% vs. 62.9%, p = 0.038). After treatment, the successful pregnancy rate in patients with fertility intentions and spontaneous abortion rate were 73.9% and 5.9%, respectively. Preterm birth, preterm premature rupture of membranes, or low-birth-weight infants were not observed. FU treatment can regress HSIL and accelerate HR-HPV clearance in young women of childbearing age with cervical HSIL associated with HR-HPV infection, and has no significant adverse effects on pregnancy outcomes.


Probing thermal interactions of ionic liquids with dimethyl sulfoxide.
Interactions between ionic liquids and dimethyl sulfoxide (DMSO) are probed by isothermal titration calorimetry. The excess partial molar enthalpies of ionic liquids H(IL)(E) in DMSO are discussed in terms of solute-solvent interactions. The specific interaction theory originally developed by Pitzer is used to analyze the apparent molar enthalpy φ(L) of ionic liquids in DMSO with the help of ion-interaction parameters. Furthermore, quantitative information on solvent reorganization and clathrate formation is obtained and interpreted.


Coffee consumption may influence hippocampal volume in young women.
Caffeine is the most often used psychoactive substance. Caffeine may influence neuroplasticity in animals. We investigated the relationship between caffeine intake (coffee consumption) and brain morphology. Forty-five healthy, non-smoking women aged 19-30 were included in the present study. We used semi-automatic user-independent MR volumetry and voxel-based morphometry. We investigated the relationship between caffeine intake (coffee consumption) and the volumes of the cortical brain structures where caffeine is supposed to act. We found that high-level and low-level caffeine intake was associated with a larger hippocampus compared to moderate-level caffeine intake. The other brain structures showed no association with coffee consumption or caffeine intake. The U-shape association between caffeine concentration and its effect has already been described in some experimental studies. To our knowledge this is one of the very first studies, which tries to find an association between brain morphology and coffee consumption or caffeine intake in humans using MR imaging.


Enhanced survival of lethally irradiated adenosine A3 receptor knockout mice. A role for hematopoietic growth factors?
Adenosine A3 receptor knockout (A3AR KO) mice and their wild-type (WT) counterparts were compared from the point of view of their abilities to survive exposures to lethal doses of γ-radiation belonging to the range of radiation doses inducing the bone marrow acute radiation syndrome. Parameters of cumulative 30-day survival (experiment using a midlethal radiation dose) or cumulative 11-day survival (experiment using an absolutely lethal radiation dose), and of mean survival time were evaluated. The values of A3AR KO mice always reflected their higher survival in comparison with WT ones, the P values being above the limit for statistical significance after the midlethal radiation dose and standing for statistical significance after the absolutely lethal radiation dose. This finding was considered surprising, taking into account the previously obtained findings on defects in numbers and functional properties of peripheral blood cells in A3AR KO mice. Therefore, previous hematological analyses of A3AR KO mice were supplemented in the present studies with determination of serum levels of the granulocyte colony-stimulating factor, erythropoietin, and thrombopoietin. Though distinct differences in these parameters were observed between A3AR KO and WT mice, none of them could explain the relatively high postirradiation survival of A3AR KO mice. Further studies on these mice comprising also those on other than hemopoietic tissues and organs can help to clarify their relative radioresistance.


Specificity in formation of type II F' plasmids.
Eight new F' plasmids derived from Hfr strains in which F is integrated at the chromosomal element alpha 3 beta 3 have been isolated and subjected to restriction enzyme, hybridization, and electron microscope heteroduplex analysis. Plasmids carrying extensive amounts of bacterial deoxyribonucleic acid were produced even though they were obtained by selection for transfer of lac, which is closely linked to F in the parental Hfr strains. Seven plasmids were type II Flac+ proC+ purE+ plasmids, and one was a type I Flac+ proC+ plasmid. Five of the Flac+ proC+ purE+ plasmids contain approximately 284 kilobases of bacterial deoxyribonucleic acid, which is identical for all five within the resolution of the restriction enzyme analysis. Theses results indicate that type II F' plasmids are the predominant tra+ F' type from this region of the Escherichia coli K-12 chromosome and that the recombination events leading to formation of these plasmids exhibit site specificity.


Detection of malignant ovarian neoplasms: a review of the literature. I. Detection of the patient at risk; clinical, radiological and cytological detection.
Risk factors for epithelial ovarian cancer are summarized in Table 1. Calculation of ovulation-years appears to be a potentially useful and practical method for identification of the high-risk individual. Risk factors for nonepithelial ovarian cancer are largely unknown, and consequently clinical diagnosis is stressed in the early detection of these tumors. Patients with Peutz-Jeghers syndrome or ovarian dysgenesis are significantly at risk and require at least regular pelvic examination. Of course, individuals with sexual precocity are at high risk for sex cord/stromal or germ cell malignancies. Individuals with a family history of Sertoli-Leydig cell tumors and benign thyroid disease also deserve close observation. Early clinical detection requires a sensitivity to presenting symptomatology (e.g., diffuse abdominopelvic complaints) as well as the skill and knowledge needed to recognize and appropriately manage adnexal masses. Harbingers of ovarian malignancy in the elderly woman, including unexplained hypercalcemia, new onset dermatomyositis, and cerebellar degeneration, should motivate thorough gynecologic evaluation. While radionuclide ovarian imaging for detection of early epithelial cancers of the ovary may become more generally available in the future, ultrasound imaging of the postmenopausal ovary, and peritoneal cytology may be of immediate value in screening high-risk women.


[Conservative treatment of open incomplete radial fracture in an adult horse].
A non-displaced radialfracture of a horse was,diagnosed. The horse had an open fracture resulting from external trauma. A diagnosis was made on radiographs taken 48h after trauma. The horse was treated conservatively by box rest and Robert-Jones bandages. After 7 days the wound was opened to let the wound drainage necrotic material and small sequesters and was washed every other day. After 7 weeks, radiographs showed complete consolidation. Four months after the injury the horse was back to work at his former level and is still working two years after the incident.


[Clinical and histologic analysis of mucous membrane lesions associated with dental restoration].
Fifteen cases of mucous membrane lesions associated with dental restorations were reported. Eleven cases appeared as lichen planus-like lesions clinically, three leukoplakia like lesions and one erythema with ulceration. Biopsies were taken in six cases, five of them were lichen planus, histologically like and epithelial dysplasia was present in one case. All lesions disappeared or improved after the amalgam restorations were changed. Diagnosis and differential diagnosis were discussed.


Different roles of electromagnetic field experts when giving policy advice: an expert consultation.
The overall evidence for adverse health effects of electromagnetic fields (EMF) at levels of exposure normally experienced by the public is generally considered weak. However, whether long-term health effects arise remains uncertain and scientific policy advice is therefore given against a background of uncertainty. Several theories exist about different roles that experts may take when they provide advice on complex issues such as EMF. To provide empirical evidence for these theories, we conducted an expert consultation with as main research question: What are the different roles of EMF experts when they provide policy advice? Q methodology was used to empirically test theoretical notions on the existence and determinants of different expert roles and to analyze which roles actually play out in the domain of EMF. Experts were selected based on a structured nominee process. In total 32 international EMF experts participated. Responses were analyzed using Principal Component Analysis and for the open questions we used Atlas.ti. Four expert roles were found. Most striking differences between the four roles are whether experts consider current EMF policies adequate or not, whether additional -precautionary- measures are needed, and how experts view their position vis-à-vis policymakers and/or other stakeholders. This empirical study provides support for the so far mainly theoretical debate about the existence of different roles of experts when they give policy advice. The experts' assessment of the degree of uncertainty of the issue turned out to be highly associated with their role. We argue that part of the controversy that exists in the debate regarding scientific policy advice on EMF is about different values and roles.


Long-term persistence of HCV NS5A resistance-associated substitutions after treatment with the HCV NS5A inhibitor, ledipasvir, without sofosbuvir.
Data on persistence of NS5A resistance-associated substitutions (RASs) may have implications for resistance testing approaches and selection of initial and retreatment strategies. Long-term persistence of NS5A RASs in HCV genotype (GT) 1 infected subjects (n=76) who did not achieve sustained virological response after receiving ledipasvir (LDV) without sofosbuvir (SOF) and were subsequently enrolled in an ongoing 3-year follow-up registry study was investigated by population or deep sequencing. Of the 76 subjects enrolled, 67 and 9 subjects had GT1a and GT1b infection, respectively. At pretreatment, NS5A RASs were detected in 14% of subjects (11/76) by population sequencing, with three subjects having >1 RAS. All RASs that were detected at pretreatment persisted and were observed at the 96 week visit in the follow-up study (FU96). For the remaining subjects with no detectable RASs at pretreatment, RASs were detected in 98% (63/64) of subjects at virological failure in the parent study and persisted at detectable levels through FU96 in 86% of subjects by deep sequencing (1% cutoff). However, a decline in the quasispecies frequency of most RASs and the number of RASs per subject was observed over time. Phenotypic analysis demonstrated that the majority of NS5A RASs confer similar levels of resistance to LDV and daclatasvir. The majority of NS5A RASs can persist at detectable levels for >96 weeks post-treatment in subjects who failed treatment with regimens containing an NS5A inhibitor without SOF, suggesting relatively high fitness of NS5A RASs even in the absence of drug pressure.


PopFly: the Drosophila population genomics browser.
The recent compilation of over 1100 worldwide wild-derived Drosophila melanogaster genome sequences reassembled using a standardized pipeline provides a unique resource for population genomic studies (Drosophila Genome Nexus, DGN). A visual display of the estimated metrics describing genome-wide variation and selection patterns would allow gaining a global view and understanding of the evolutionary forces shaping genome variation. Here, we present PopFly, a population genomics-oriented genome browser, based on JBrowse software, that contains a complete inventory of population genomic parameters estimated from DGN data. This browser is designed for the automatic analysis and display of genetic variation data within and between populations along the D. melanogaster genome. PopFly allows the visualization and retrieval of functional annotations, estimates of nucleotide diversity metrics, linkage disequilibrium statistics, recombination rates, a battery of neutrality tests, and population differentiation parameters at different window sizes through the euchromatic chromosomes. PopFly is open and freely available at site http://popfly.uab.cat . email@example.com or firstname.lastname@example.com.


In vivo and in vitro biotransformation of theobromine by phenobarbital- and 3-methylcholanthrene-inducible cytochrome P-450 monooxygenases in rat liver. Role of thiol compounds.
A new in vitro method was developed and applied to establish the role of the hepatic cytochrome P-450 monooxygenases in theobromine biotransformation by control and phenobarbital (PB)- and 3-methylcholanthrene (3MC)-induced Sprague-Dawley rats. In vivo theobromine metabolite formation and pharmacokinetic parameters were also determined to serve as a comparison for in vitro studies. In vivo, the major urinary metabolite was 6-amino-5-[N-methylformylamino]-1-methyluracil (3,7DAU) with lesser amounts of 3,7-dimethyluric acid (3,7DMU), 3-methylxanthine, 7-methylxanthine, 7-methyluric acid, and traces of dimethylallantoin (DMA). Following induction with 3MC, but not PB, selective increases occurred in the urinary excretion of 3,7DAU, indicating that a 3MC-inducible cytochrome P-450 isozyme plays a significant role in this metabolic pathway. Both PB and 3MC induction increased slightly urinary elimination of DMA, a minor metabolite. Pharmacokinetic studies after a single oral dose of 5 mg/kg theobromine revealed a marked effect of 3MC treatment on theobromine elimination, as evidenced by a 59% decrease in theobromine t1/2, a 75% decrease in AUC, and a 284% increase in clearance. By contrast, PB had no effect. Fecal 14C elimination accounted for approximately 5% of the administered theobromine dose, and biliary excretion studies revealed the presence of 3,7DMU, DMA, 3,7DAU, and unchanged theobromine. Studies in vitro indicated that 3,7DMU was the major theobromine metabolite produced by liver microsomes. Conversion rates in PB- and 3MC-induced rats were 2- and 11-fold higher, respectively, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)


A strategy for intensive production of molybdenum-99 isotopes for nuclear medicine using CANDU reactors.
Technetium-99m is an important medical isotope utilized worldwide in nuclear medicine and is produced from the decay of its parent isotope, molybdenum-99. The online fueling capability and compact fuel of the CANDU(®)(1) reactor allows for the potential production of large quantities of (99)Mo. This paper proposes (99)Mo production strategies using modified target fuel bundles loaded into CANDU fuel channels. Using a small group of channels a yield of 89-113% of the weekly world demand for (99)Mo can be obtained.


Cord blood lymphocyte transformation responses to Legionella pneumophila.
Cord blood lymphocytes were obtained from 94 neonates for transformation assays with sonicated and partially Legionella antigens and phytohemagglutinin. The Legionella antigens gave mean stimulation indices (SI) of approximately three times the background. The nonspecific mitogen phytohemagglutinin gave mean SI of 23 times the background. There was some minor nonspecific stimulation of cord blood lymphocytes by Legionella antigens but not enough to account for the SI seen in patients with Legionnaires' disease (48 +/- 14).


Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses.
Heat shock proteins are abundant soluble intracellular proteins, present in all cells. Members of the heat shock protein family bind peptides including antigenic peptides generated within cells. Heat shock proteins also interact with antigen presenting cells through CD91 and other receptors, eliciting a cascade of events including re-presentation of heat shock protein-chaperoned peptides by MHC, translocation of NF kappa B into the nuclei and maturation of dendritic cells. These consequences point to a key role of heat shock proteins in fundamental immunological phenomena such as activation of antigen presenting cells, indirect presentation (or cross-priming), and chaperoning of peptides during antigen presentation. Heat shock proteins appear to have been involved in innate immune responses since the emergence of phagocytes in early multicellular organisms and to have been commandeered for adaptive immune responses with the advent of specificity. These properties of heat shock proteins also allow them to be used for immunotherapy of cancers and infections in novel ways.


Temporal dynamics of the knowledge-mediated visual disambiguation process in humans: a magnetoencephalography study.
Disambiguation of a noisy visual scene with prior knowledge is an indispensable task of the visual system. To adequately adapt to a dynamically changing visual environment full of noisy visual scenes, the implementation of knowledge-mediated disambiguation in the brain is imperative and essential for proceeding as fast as possible under the limited capacity of visual image processing. However, the temporal profile of the disambiguation process has not yet been fully elucidated in the brain. The present study attempted to determine how quickly knowledge-mediated disambiguation began to proceed along visual areas after the onset of a two-tone ambiguous image using magnetoencephalography with high temporal resolution. Using the predictive coding framework, we focused on activity reduction for the two-tone ambiguous image as an index of the implementation of disambiguation. Source analysis revealed that a significant activity reduction was observed in the lateral occipital area at approximately 120 ms after the onset of the ambiguous image, but not in preceding activity (about 115 ms) in the cuneus when participants perceptually disambiguated the ambiguous image with prior knowledge. These results suggested that knowledge-mediated disambiguation may be implemented as early as approximately 120 ms following an ambiguous visual scene, at least in the lateral occipital area, and provided an insight into the temporal profile of the disambiguation process of a noisy visual scene with prior knowledge.


Unusually Giant Sublingual Epidermoid Cyst: A Case Report.
Epidermoid cysts are rare, slow‑growing, benign, developmental cysts, which are derived from abnormally situated ectodermal tissue. Epidermoid cysts of the floor of the mouth represent <0.01% of all oral cysts. So far, only a few cases have been reported. Hereby, we present a case of a giant sublingual epidermoid cyst, which was completely asymptomatic upon presentation. However, due to its large size, it pushed the epiglottis posteriorly and created difficulty during intubation. The patient developed respiratory distress after its surgical excision and extubation, requiring tracheostomy post operatively. The patient recovered well and a successful weaning of tracheostomy was performed, giving the patient a healthy life. Epidermoid cyst is a rare differential diagnosis of sublingual swelling that should be kept in mind for large asymptomatic swellings in this region. The only symptom it can cause might be respiratory distress due to its large size. This can happen not only pre-operatively but also post-operatively and the surgeon should be ready for immediate tracheostomy.


E-PSMA: the EANM standardized reporting guidelines v1.0 for PSMA-PET.
The development of consensus guidelines for interpretation of Prostate-Specific Membrane Antigen (PSMA)-Positron Emission Tomography (PET) is needed to provide more consistent reports in clinical practice. The standardization of PSMA-PET interpretation may also contribute to increasing the data reproducibility within clinical trials. Finally, guidelines in PSMA-PET interpretation are needed to communicate the exact location of findings to referring physicians, to support clinician therapeutic management decisions. A panel of worldwide experts in PSMA-PET was established. Panelists were selected based on their expertise and publication record in the diagnosis or treatment of PCa, in their involvement in clinical guidelines and according to their expertise in the clinical application of radiolabeled PSMA inhibitors. Panelists were actively involved in all stages of a modified, nonanonymous, Delphi consensus process. According to the findings obtained by modified Delphi consensus process, panelist recommendations were implemented in a structured report for PSMA-PET. The E-PSMA standardized reporting guidelines, a document supported by the European Association of Nuclear Medicine (EANM), provide consensus statements among a panel of experts in PSMA-PET imaging, to develop a structured report for PSMA-PET in prostate cancer and to harmonize diagnostic interpretation criteria.


Financial hardship and risk of suicide among U.S. Army personnel.
Financial stress has been frequently identified as a risk factor for suicidal behavior, both in military and civilian groups. However, it remains unclear to what degree financial stress may be associated independently with suicide behavior when accounting for other risk factors. This study examined data on suicide and suicide attempt cases in the Department of Defense Suicide Event Report compared with service members who did not have recent suicide behavior. The resulting multinomial regression analysis found that financial distress had a weak association with suicide, and its relationship to suicide attempts was not statistically significant. Compared with financial distress, relationship problems and substance abuse history appeared to have much stronger associations with suicidal behavior, as did having a diagnosis of a mood disorder, such as major depressive disorder. The major conclusion from these data are that although financial distress may be a risk factor for suicidal behavior, the relationship is likely indirect and considerably less substantial than previously suspected. In addition, its relative influence is significantly less than other identified risk factors. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Vasectomy: potential links to an increased risk of aggressive prostate cancer?
Several studies have found associations between aggressive prostate cancer (PC) and having a vasectomy. However, findings from two very recent meta-analyses have found that this is not the case. Therefore, the data are mixed. Herein, we detail the controversy between vasectomy and PC risk, particularly aggressive PC, by shedding some light on the molecular pathways, potential risk factors and suggested links for those considering vasectomy and medical professionals who perform it. We conclude by supporting the American Urological Association's position that there is no need to discuss potential prostate cancer risks with patients considering vasectomy given reasonably strong data finding no link between vasectomy and prostate cancer risk.


The effects of repetitive transcranial magnetic stimulation and aerobic exercise on cognition, balance and functional brain networks in patients with Alzheimer's disease.
The purpose of this study was to investigate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) and aerobic exercises (AE) in addition to the pharmacological therapy (PT) in Alzheimer's Disease (AD). Twenty-seven patients with AD aged ≥ 60 years were included in the study and divided into 3 groups (rTMS, AE and control). All groups received PT. rTMS group (n = 10) received 20 Hz rTMS over dorsolateral prefrontal cortex (dlPFC) bilaterally and AE group (n = 9) received the structured moderate-intensity AE for 5 consecutive days/week over 2 weeks. Control group (n = 8) only received PT. Cognition, balance, mobility, quality of life (QoL), and resting state functional brain activity were evaluated one week before and one week after the interventions. (ClinicalTrials.gov ID:NCT05102045). Significant improvements were found in executive functions, behavior, and QoL in the rTMS group, in balance and mobility in the AE group, and in the visual memory and behavior in the control group (p < 0.05). Significant differences were found in the behavior in favor of the rTMS group, and balance in favor of the AE group (p < 0.05). There was a significant increase in activation on middle temporal gyrus, intra calcarine, central opercular cortex, superior parietal lobule, and paracingulate cortex in Default Mode Network (DMN) in the rTMS group (p < 0.05). High-frequency rTMS over bilateral dlPFC may improve executive functions and behavior and lead to increased activation in DMN, structured moderate-intensity AE may improve balance and mobility, and PT may improve memory and behaviour compared to pretreatment in AD.


Metabolomic Approaches Reveal the Role of CAR in Energy Metabolism.
The constitutive androstane receptor (CAR; NR1I3) contributes important regulatory roles in biotransformation, xenobiotic transport function, energy metabolism and lipid homeostasis. In this investigation, global serum and liver tissue metabolomes were assessed analytically in wild type and CAR-null transgenic mice using NMR, GC-MS and UPLC-MS/MS-based metabolomics. Significantly, CAR activation increased serum levels of fatty acids, lactate, ketone bodies and tricarboxylic acid cycle products, whereas levels of phosphatidylcholine, sphingomyelin, amino acids and liver glucose were decreased following short-term activation of CAR. Mechanistically, quantitative mRNA analysis demonstrated significantly decreased expression of key gluconeogenic pathways, and increased expression of glucose utilization pathways, changes likely resulting from down-regulation of the hepatic glucose sensor and bidirectional transporter, Glut2. Short-term CAR activation also resulted in enhanced fatty acid synthesis and impaired β-oxidation. In summary, CAR contributes an expansive role regulating energy metabolism, significantly impacting glucose and monocarboxylic acid utilization, fatty acid metabolism and lipid homeostasis, through receptor-mediated regulation of several genes in multiple associated pathways.


The physical environment as a fall risk factor in older adults: Systematic review and meta-analysis of cross-sectional and cohort studies.
Evidence that the physical environment is a fall risk factor in older adults is inconsistent. The study evaluated and summarised evidence of the physical environment as a fall risk factor. Eight databases (1985-2006) were searched. Investigators evaluated quality of two categories (cross-sectional and cohort) of studies, extracted and analysed data. Cross-sectional: falls occur in a variety of environments; gait aids were present in approximately 30% of falls. Home hazards increased fall risk (odds ratio (OR) = 1.15; 95% confidence interval (CI): 0.97-1.36) although not significantly. When only the high quality studies were included, the OR = 1.38 (95% CI: 1.03-1.87), which was statistically significant. Use of mobility aids significantly increased fall risk in community (OR = 2.07; 95% CI: 1.59-2.71) and institutional (OR = 1.77; 95% CI: 1.66-1.89) settings. Home hazards appear to be a significant risk factor in older community-dwelling adults, although they may present the greatest risk for persons who fall repeatedly. Future research should examine relationships between mobility impairments, use of mobility aids and falls.


Distribution of G-proteins in rat liver plasma-membrane domains and endocytic pathways.
1. The distribution of the alpha- and beta-subunits of nucleotide-binding G-proteins among rat liver sinusoidal, lateral and canalicular plasma membranes, endosomes, Golgi membranes and lysosomes was investigated. 2. Pertussis-toxin-catalysed ADP-ribosylation identified a 41 kDa inhibitory alpha-subunit in all liver plasma-membrane functional domains as well as in endosomes. An antibody to a synthetic peptide corresponding to a C-terminal sequence of the inhibitory alpha-subunit also identified the 41 kDa polypeptide in all plasma-membrane domains, in 'early' and 'late' endosomes and in Golgi membranes; this polypeptide was not detected in lysosomes. The antibody-binding studies showed that bile-canalicular plasma membranes had the highest content of the inhibitory alpha-subunit. 3. Immunofluorescent microscopy confirmed the presence of the inhibitory alpha-subunit in all regions of the hepatocyte's cell surface. 4. An antibody recognizing the beta-subunit showed that a 36 kDa polypeptide was present in all plasma membranes and in 'early' and 'late' endosomes; it was not detected in lysosomes. The relative distribution among the fractions of this polypeptide was similar to the distribution of the inhibitory alpha-subunit. 5. The presence of high levels of the G-protein inhibitory alpha-subunit in bile-canalicular plasma membranes was confirmed by demonstration of its co-fractionation with marker enzymes in Nycodenz gradients and by free-flow electrophoresis. The significance of this location is discussed.


Recent advances in understanding schizophrenia.
Schizophrenia is a highly disabling disorder whose causes remain to be better understood, and treatments have to be improved. However, several recent advances have been made in diagnosis, etiopathology, and treatment. Whereas reliability of diagnosis has improved with operational criteria, including Diagnostic and Statistical Manual of Mental Disorders, (DSM) Fifth Edition, validity of the disease boundaries remains unclear because of substantive overlaps with other psychotic disorders. Recent emphasis on dimensional approaches and translational bio-behavioral research domain criteria may eventually help move toward a neuroscience-based definition of schizophrenia. The etiology of schizophrenia is now thought to be multifactorial, with multiple small-effect and fewer large-effect susceptibility genes interacting with several environmental factors. These factors may lead to developmentally mediated alterations in neuroplasticity, manifesting in a cascade of neurotransmitter and circuit dysfunctions and impaired connectivity with an onset around early adolescence. Such etiopathological understanding has motivated a renewed search for novel pharmacological as well as psychotherapeutic targets. Addressing the core features of the illness, such as cognitive deficits and negative symptoms, and developing hypothesis-driven early interventions and preventive strategies are high-priority goals for the field. Schizophrenia is a severe, chronic mental disorder and is among the most disabling disorders in all of medicine. It is estimated by the National Institute of Mental Health (NIMH) that 2.4 million people over the age of 18 in the US suffer from schizophrenia. This illness typically begins in adolescence and derails the formative goals of school, family, and work, leading to considerable suffering and disability and reduced life expectancy by about 20 years. Treatment outcomes are variable, and some people are successfully treated and reintegrated (i.e. go back to work). Despite the effort of many experts in the field, however, schizophrenia remains a chronic relapsing and remitting disorder associated with significant impairments in social and vocational functioning and a shortened lifespan. Comprehensive treatment entails a multi-modal approach, including psychopharmacology, psychosocial interventions, and assistance with housing and financial sustenance. Research to date suggests a network of genetic, neural, behavioral, and environmental factors to be responsible for its development and course. This article aims to summarize and explain recent advancements in research on schizophrenia, to suggest how these recent discoveries may lead to a better understanding and possible further development of effective therapies, and to highlight the paradigm shifts that have taken place in our understanding of the diagnosis, etiopathology, and treatment.


Recurrent concussion and risk of depression in retired professional football players.
The purpose of our study was to investigate the association between prior head injury and the likelihood of being diagnosed with clinical depression among retired professional football players with prior head injury exposure. A general health questionnaire, including information about prior injuries, the SF-36 (Short Form 36), and other markers for depression, was completed by 2552 retired professional football players with an average age of 53.8 (+/-13.4) yr and an average professional football-playing career of 6.6 (+/-3.6) yr. A second questionnaire focusing on mild cognitive impairment (MCI)-related issues was completed by a subset of 758 retired professional football players (50 yr and older). Two hundred sixty-nine (11.1%) of all respondents reported having prior or current diagnosis of clinical depression. There was an association between recurrent concussion and diagnosis of lifetime depression (chi2=71.21, df=2, P<0.005), suggesting that the prevalence increases with increasing concussion history. Compared with retired players with no history of concussion, retired players reporting three or more previous concussions (24.4%) were three times more likely to be diagnosed with depression; those with a history of one or two previous concussions (36.3%) were 1.5 times more likely to be diagnosed with depression. The analyses controlled for age, number of years since retirement, number of years played, physical component score on the SF-36, and diagnosed comorbidities such as osteoarthritis, coronary heart disease, stroke, cancer, and diabetes. Our findings suggest a possible link between recurrent sport-related concussion and increased risk of clinical depression. The findings emphasize the importance of understanding potential neurological consequences of recurrent concussion.