Been there before? Examining "familiarity" as a moderator for discriminating between true and false intentions.
Prospection is thinking about possible future states of the world. Commitment to perform a future action-commonly referred to as intention-is a specific type of prospection. This knowledge is relevant when trying to assess whether a stated intention is a lie or the truth. An important observation is that thinking of, and committing to, future actions often evoke vivid and detailed mental images. One factor that affects how specific a person experiences these simulations is location-familiarity. The purpose of this study was to examine to what extent location-familiarity moderates how liars and truth tellers describe a mental image in an investigative interview. Liars were instructed to plan a criminal act and truth tellers were instructed to plan a non-criminal act. Before they could carry out these acts, the participants were intercepted and interviewed about the mental images they may have had experienced in this planning phase. Truth tellers told the truth whereas liars used a cover story to mask their criminal intentions. As predicted, the results showed that the truth tellers reported a mental image significantly more often than the liars. If a mental image was reported, the content of the descriptions did not differ between liars and truth tellers. In a post interview questionnaire, the participants rated the vividness (i.e., content and clarity) of their mental images. The ratings revealed that the truth tellers had experienced their mental images more vividly during the planning phase than the liars. In conclusion, this study indicates that both prototypical and specific representations play a role in prospection. Although location-familiarity did not moderate how liars and truth tellers describe their mental images of the future, this study allows some interesting insights into human future thinking. How these findings can be helpful for distinguishing between true and false intentions will be discussed.


BACE inhibition-dependent repair of Alzheimer's pathophysiology.
Amyloid-β (Aβ) is thought to play an essential pathogenic role in Alzheimer´s disease (AD). A key enzyme involved in the generation of Aβ is the β-secretase BACE, for which powerful inhibitors have been developed and are currently in use in human clinical trials. However, although BACE inhibition can reduce cerebral Aβ levels, whether it also can ameliorate neural circuit and memory impairments remains unclear. Using histochemistry, in vivo Ca2+ imaging, and behavioral analyses in a mouse model of AD, we demonstrate that along with reducing prefibrillary Aβ surrounding plaques, the inhibition of BACE activity can rescue neuronal hyperactivity, impaired long-range circuit function, and memory defects. The functional neuronal impairments reappeared after infusion of soluble Aβ, mechanistically linking Aβ pathology to neuronal and cognitive dysfunction. These data highlight the potential benefits of BACE inhibition for the effective treatment of a wide range of AD-like pathophysiological and cognitive impairments.


Effect of Physical Load on Aerobic Exercise Performance during Heat Stress.
This study aimed to investigate the effect of increasing external loads on 5-km treadmill time trial (TT) performance in 20°C and 40°C environmental conditions and to construct an ecologically relevant performance prediction decision aid. Twenty-six male and four female volunteers (age, 23.5 ± 6.9 yr; weight, 76.0 ± 8.9 kg; height, 1.75 ± 0.07 m; V˙O2peak, 50.7 ± 4.5 mL·kg·min) participated in a counterbalanced, mixed-model design, with each subject assigned to a load group (20%, 30%, or 50% body mass (BM); n = 10 per group). Volunteers performed three, self-paced 5-km familiarization TT (treadmill) without external load. Each volunteer then performed a 5-km TT in each environment with loads of either 20% (n = 10), 30% (n = 10), or 50% (n = 10) of BM. 1) Loads of (20%, 30%, and 50% of BM) impaired 5-km TT performance compared with that when unloaded (P < 0.05); 2) the time penalties of the 20% and 30% load were <50% load (P < 0.05); 3) in all trials, the addition of heat exposure reduced 5-km TT performance beyond the penalty of load itself (P < 0.05); and 4) the combination of heat and 50% load resulted in a substantial penalty such that continuous work was not sustainable for all of the volunteers. Relative to prediction models using fixed or constant workload exercise trials, an ecologically valid decision aid was developed from self-paced data, in which pace (km·h) can be predicted for individual levels of heat, load, or heat + load in combination.


Early use of beta-blockers attenuates systemic inflammatory response and lung oxygenation impairment after distal type acute aortic dissection.
We have reported that serum C-reactive protein (CRP) elevation is an independent predictor of lung oxygenation impairment (LOI) after distal type acute aortic dissection (AAD). Systemic activation of the inflammatory system after aortic injury may play a role in the development of LOI. The aim of this study is to clarify the effect of beta-blockers on systemic inflammation and the development of LOI after distal type AAD. A total of 49 patients, who were admitted with distal type AAD and treated conservatively, were examined. White blood cell (WBC) count, serum CRP level, and arterial blood gases were measured serially. Forty patients received beta-blocker treatment within 24 h of the onset, while 9 patients received no beta-blocker treatment. Maximum WBC count, maximum CRP level, lowest PaO(2)/FiO(2) (P/F) ratio, and patient background were compared between the two groups. There was no difference between the groups according to age, sex, coronary risk factors, blood pressure, serum level of CRP, WBC count, and oxygenation index on admission. Beta-blocker treatment was associated with lower maximum WBC count (P = 0.0028) and lower maximum serum CRP level (P = 0.0004). The minimum P/F ratio was higher in patients with beta-blocker treatment than in those without (P = 0.0076). Multivariate analysis revealed that administration of a beta-blocker was an independent negative determinant of LOI (P/F ratio < or = 200 mmHg). In conclusion, early use of beta-blockers prevented excessive inflammation and LOI after distal type AAD, suggesting a pleiotropic effect of beta-blockers on the inflammatory response after AAD.


Pharmacological actions of diaspirins, potential antisickling agents: analgesic and anti-inflammatory effects.
Three aspirin analogs, dibromoaspirin, bis(3,5-dibromosalicyl) succinate and bis(3,5-dibromosalicyl) fumarate, potential antisickling agents, were compared with acetylsalicylic acid (aspirin) for their analgesic, body temperature and anti-inflammatory effects in the laboratory mouse and rat. In the analgesic assay, using the "writhing method", only a 200 mg/kg dose of the diaspirin succinate significantly reduced the writhing response induced by phenylacetic acid. Only a dose of 800 mg/kg of acetylsalicylic acid significantly decreased writhing. These analog compounds had only slight hypothermic effects, the reduction in body temperature not being appreciable. On the other hand, they were effective anti-inflammatory agents, comparable to aspirin; a dose of 200 mg/kg very significantly reduced the paw edema due to injected carrageenan.


Multiple-frequency measurement based on serial photonic channelization using optical wavelength scanning.
A serial photonic channelized radio frequency (RF) measurement scheme is proposed and experimentally demonstrated. This scheme can be used for instantaneous multiple-frequency measurement and capturing key parameters of linear frequency modulation signals. Based on high-speed wavelength scanning, this photonic RF channelizer works serially in time domain, and each wavelength labels a certain RF channel. With only one low-bandwidth photodetector (PD), we can implement multiple channel RF frequency measurements, which have a much simpler structure compared with parallel channelized schemes using broadband filter-bank and multiple PDs.


PEGylation as a tool for the biomedical engineering of surface modified microparticles.
Microparticles are of considerable interest for drug delivery, vaccination and diagnostic imaging. In order to obtain microparticles with long circulation times, or to provide the prerequisite for tissue specific targeting through decoration with suitable ligands, their surfaces need to be modified such that they become repellent to the adsorption of opsonic proteins and resistant to unspecific phagocytosis. The currently most considered strategy relies on the immobilisation of a poly(ethylene glycol) (PEG) corona onto the microparticles' surface. In the first chapter of this review, we discuss the unique physicochemical properties of PEG, which make it the polymer of choice to render the surfaces of microparticles repellent to the adsorption of proteins and resistant to cellular recognition. Furthermore, we present various technologies for the preparation of microparticles with PEGylated surfaces. Another aspect is the decoration of the PEGylated surfaces with suitable ligands for cell specific recognition and targeting. Finally, we review miscellaneous applications of PEGylated microparticles, mainly focusing on the fields of drug delivery, targeting and vaccination. Although still in its infancy, the PEGylation of microparticles holds promise towards future biomedical applications.


Radiation Protection and Mitigation by Natural Antioxidants and Flavonoids: Implications to Radiotherapy and Radiation Disasters.
Nowadays, ionizing radiations are used for various medical and terroristic aims. These purposes involve exposure to ionizing radiations. Hence, people are at risk for acute or late effects. Annually, millions of cancer patients undergo radiotherapy during their course of treatment. Also, some radiological or nuclear events in recent years pose a threat to people, hence the need for radiation mitigation strategies. Amifostine, the first FDA approved radioprotector, has shown some toxicities that limit its usage and efficiency. Due to these side effects, scientists have researched for other agents with less toxicity for better radioprotection and possible mitigation of the lethal effects of ionizing radiations after an accidental exposure. Flavonoids have shown promising results for radioprotection and can be administered in higher doses with less toxicity. Studies for mitigation of ionizing radiation-induced toxicities have concentrated on natural antioxidants. Detoxification of free radicals, management of inflammatory responses and attenuation of apoptosis signaling pathways in radiosensitive organs are the main mechanisms for radiation protection and mitigation with flavonoids and natural antioxidants. However, several studies have proposed that a combination in the form of some antioxidants may alleviate radiation toxicities more effectively in comparison to a single form of antioxidants. In this review, we focus on recent findings about natural radioprotectors and mitigators which are clinically applicable for radiotherapy patients, as well as injured people in possible radiation accidents.


Immune-Mediated Fetal Complete Atrioventricular Block: Can Dexamethasone Therapy Revert the Process?
Fetal complete atrioventricular block (CAVB) is usually autoimmune mediated. The risk of developing CAVB is 2% to 3% in anti-Ro/SS-A seropositive pregnancies and it increases 10 times after previous CAVB in siblings. Despite being a rare complication, CAVB carries a 20% mortality rate and substantial morbidity, as about 65% of newborns will eventually need life-long pacing. Once found, fetal CAVB is almost always irreversible, despite aggressive immunotherapy. This poor outcome prompted some research groups to address this situation. All groups followed anti-Ro/SS-A seropositive pregnancies on a weekly basis during the second trimester of pregnancy and tried to detect first degree atrioventricular block (AVB) using accurate echocardiographic tools, assuming they may characterize the initiation of the immune damage to the A-V conduction system, at which point the process might still be reversible. Some of the groups treated fetuses with first degree AVB with maternal oral fluorinated steroids. We summarized the results of all groups, including our group. We describe a case of a fetus that developed CAVB 6 days after normal sinus rhythm (NSR), who under aggressive dexamethasone therapy gradually reverted to NSR. This fetus had a previous sibling with CAVB. We assumed the immune damage to the conduction system in this small group of fetuses with a previous CAVB sibling may have occurred more quickly than usual. We therefore recommend a twice-weekly follow-up with these fetuses.


Development of a subunit vaccine for infectious pancreatic necrosis virus using a baculovirus insect/larvae system.
Various attempts to develop a vaccine against infectious pancreatic necrosis virus (IPNV) have not yielded consistent results. Thus, at present, no commercial vaccine is available that can be used with confidence to immunize fry of salmon and trout. We generated a cDNA clone of the large genome segment A of an IPNV Sp strain and expressed all structural protein genes in insect cells and larvae using a baculovirus expression system. Green fluorescent protein was also coexpressed as a reporter molecule. High yields of IPNV proteins were obtained and the structural proteins self assembled to form virus-like particles (VLPs). We tested the immunogenicity of the putative VLP antigen in immersion vaccine experiments (two concentrations) in rainbow trout (Oncorhynchus mykiss) fry, and by intraperitoneal immunisation of Atlantic salmon (Salmo salar) pre-smolts using an oil adjuvant formulation. Rainbow trout were challenged by immersion using either the Sp or the VR-299 strain of IPNV two or three weeks post-vaccination, while Atlantic salmon were bath challenged with Sp strain after two months, after parr-smolt transformation. In the rainbow trout fry challenged two weeks post-immunization, cumulative mortality rates three weeks post challenge were 14 % in the fry that had received the highest dose versus 8 % in the control groups. No indication of protection was seen in repeated trials using a lower dose of antigen and challenge three weeks post-immunisation. The cumulative mortality rate of intraperitoneally immunised Atlantic salmon post-smolts four weeks post challenge was lower (56%) than in the control fish (77%), showing a dose-response pattern.


Leptin transport in the central nervous system.
Synthesized and released by the adipose tissue, leptin is the widely studied 167-amino acid hormonal protein product of the obesity gene. Originally leptin was defined in association with satiety and energy balance and claimed to be an anti-obesity factor that functioned via a feedback effect from adipocytes to hypothalamus. There is a growing body of evidence that emphasizes the importance of leptin in the regulation of food intake and body weight in animals and humans, alike. Other research findings point out that it plays a role in the regulation of the metabolism, sexual development, reproduction, hematopoiesis, immunity, gastrointestinal functions, sympathetic activation, and angiogenesis. The aim of this review is to evaluate the relation between leptin and the central nervous system (CNS).


Derivation of coarse-grained potentials via multistate iterative Boltzmann inversion.
In this work, an extension is proposed to the standard iterative Boltzmann inversion (IBI) method used to derive coarse-grained potentials. It is shown that the inclusion of target data from multiple states yields a less state-dependent potential, and is thus better suited to simulate systems over a range of thermodynamic states than the standard IBI method. The inclusion of target data from multiple states forces the algorithm to sample regions of potential phase space that match the radial distribution function at multiple state points, thus producing a derived potential that is more representative of the underlying interactions. It is shown that the algorithm is able to converge to the true potential for a system where the underlying potential is known. It is also shown that potentials derived via the proposed method better predict the behavior of n-alkane chains than those derived via the standard IBI method. Additionally, through the examination of alkane monolayers, it is shown that the relative weight given to each state in the fitting procedure can impact bulk system properties, allowing the potentials to be further tuned in order to match the properties of reference atomistic and/or experimental systems.


Synthesis of essential amino acids from their alpha-keto analogues by perfused rat liver and muscle.
Most essential amino acids can be replaced by their alpha-keto-analogues in the diet. These ketoacids have therefore been proposed as substitutes for dietary protein. In order to determine their fate in tissues of normal animals, isolated rat liver and hindquarter (muscle) preparations were perfused with keto-analogues of valine, leucine, isoleucine, methionine, or phenylalanine. When perfused at 1.5-2.0 mM, all five compounds were utilized rapidly by the liver of 48-h starved rats, at rates varying from 49 to 155 mumol/h per 200g rat. The corresponding amino acids appeared in the medium in significantly increased concentrations. Perfusion with phenylpyruvate also led to the appearance of tyrosine. Urea release was unaltered. Measurement of metabolite concentrations in freeze-clamped liver revealed two abnormalities, particularly at ketoacid concentrations of 5 mM or above: a large increase in alpha-ketoglutarate, and a moderate to marked decrease in tissue glutamine. This decrease was quantitatively sufficient to account for nitrogen appearing in newly synthesized amino acids. Isolated hindquarters of fed rats were perfused with the same ketoacids at concentrations of 1.3-8.0 mM. All were utilized at rates varying from 1.4 to 7.0 mumol/h per g muscle perfused. The corresponding amino acids were released at greatly increased rates. Alanine and glutamate levels fell in some perfusions, but the principal nitrogen donor in muscle was not identified; the content of glutamine in tissue, and its rate of release into the perfusate remained constant.


Optimized strategies to synthesize β-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers.
A new generation of organophosphate (OP) scavengers was obtained by synthesis of β-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of β-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8-10 were obtained from 5-7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8-12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.


Population-specific genotype x genotype x environment interactions in bacterial disease of early life stages of Pacific oyster larvae.
The consequences of emerging marine diseases on the evolutionary trajectories of affected host populations in the marine realm are largely unexplored. Evolution in response to natural selection depends on the genetic variation of the traits under selection and the interaction of these traits with the environment (GxE). However, in the case of diseases, pathogen genotypes add another dimension to this interaction. Therefore, the study of disease resistance needs to be extended to the interaction of host genotype, pathogen genotype and environment (GxGxE). In this study, we used a full-sib breeding design crossing two genetically differentiated populations of the Pacific oyster Crassostrea gigas (Thunberg, 1793), to determine the influence of host genotype, pathogen genotype and temperature on disease resistance. Based on a controlled infection experiment on two early life stages, that is, D-larvae and Pediveliger larvae at elevated and ambient water temperatures, we estimated disease resistance to allopatric and sympatric Vibrio sp. by measuring survival and growth within and between genetically differentiated oyster populations. In both populations, survival was higher upon infection with sympatric Vibrio sp., indicating that disease resistance has a genetic basis and is dependent on host genotype. In addition, we observed a significant GxGxE effect in D-larvae, where contrary to expectations, disease resistance was higher at warm than at cold temperatures. Using thermal reaction norms, we could further show that disease resistance is an environment dependent trait with high plasticity, which indicates the potential for a fast acclimatization to changing environmental conditions. These population-specific reaction norms disappeared in hybrid crosses between both populations which demonstrates that admixture between genetically differentiated populations can influence GxGxE interactions on larger scales.


Evolution of long centromeres in fire ants.
Centromeres are essential for accurate chromosome segregation, yet sequence conservation is low even among closely related species. Centromere drive predicts rapid turnover because some centromeric sequences may compete better than others during female meiosis. In addition to sequence composition, longer centromeres may have a transmission advantage. We report the first observations of extremely long centromeres, covering on average 34 % of the chromosomes, in the red imported fire ant Solenopsis invicta. By comparison, cytological examination of Solenopsis geminata revealed typical small centromeric constrictions. Bioinformatics and molecular analyses identified CenSol, the major centromeric satellite DNA repeat. We found that CenSol sequences are very similar between the two species but the CenSol copy number in S. invicta is much greater than that in S. geminata. In addition, centromere expansion in S. invicta is not correlated with the duplication of CenH3. Comparative analyses revealed that several closely related fire ant species also possess long centromeres. Our results are consistent with a model of simple runaway centromere expansion due to centromere drive. We suggest expanded centromeres may be more prevalent in hymenopteran insects, which use haplodiploid sex determination, than previously considered.


Effect of Intravenous Tenecteplase Dose on Cerebral Reperfusion Before Thrombectomy in Patients With Large Vessel Occlusion Ischemic Stroke: The EXTEND-IA TNK Part 2 Randomized Clinical Trial.
Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P = .89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]). Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. ClinicalTrials.gov Identifier: NCT03340493.


[Intramedullary epidermoid tumor: case report].
A rare case of an epidermoid intramedullary spinal cord tumor, extending from the second to the fourth thoracic vertebra is reported, in a 15 years old girl, surgically treated successfully. The clinical feature, the ethiopatogeny and a literature review will be discussed.


Differences between beige and bg/+ mice in the disruption of plasma proteinase regulation in the tumor-bearing state or following Corynebacterium parvum treatment. Evidence for the involvement of polymorphonuclear leukocyte proteinases.
Mice bearing the B16 melanoma or treated with Corynebacterium parvum develop elevated levels of plasma neutral proteinase activity. Similar experiments carried out with C57BL/6-bg/bg (beige) mice, which are genetically deficient in polymorphonuclear neutrophil (PMN) proteinases, revealed that such mice develop significantly diminished elevation in plasma proteinase activity compared to C57BL/6-bg/+ mice. Lysates of C. parvum elicited PMN from beige mice contained approximately 80% less neutral proteinase activity as did lysates of PMN from bg/+ mice. These results indicate that host cells, such as PMN, may become activated during the tumor progression, or following C. parvum treatment, causing degranulation and a subsequent elevation in plasma proteinase levels. If such an interpretation is correct, then this phenomenon may be the murine corollary to what has been observed in patients with certain inflammatory diseases or tumors.


Waiting for child developmental and rehabilitation services: an overview of issues and needs.
Concern about the length of time that children, young people, and families may have to wait to access assessment, diagnostic, interventional, therapeutic, and supportive child developmental and rehabilitation (CDR) services is widespread, but adequate data collection and research on this issue remain limited. We review key concepts and issues relevant to waiting for CDR services from the published literature, a national workshop devoted to this topic, and international experience. We conclude that gaps in data, evidence, and consensus challenge our ability to address the issue of waiting for CDR services in a systematic way. A program of research coupled with actions based on consensus-building is required. Research priorities include acquiring evidence of the appropriateness and effectiveness of different models of intervention and rehabilitation services, and documenting the experience and expectations of waiting families. Consensus-building processes are critical to identify, categorize, and prioritize 'sentinel' components of CDR service pathways: (1) to reduce the inherent complexity of the field; (2) to create benchmarks for waiting for these respective services; and (3) to develop definitions for wait-time subcomponents in CDR services. Collection of accurate and replicable data on wait times for CDR services can be used to document baseline realities, to monitor and improve system performance, and to conduct comparative and analytic research in the field of CDR services.


The structure of the N-terminal actin-binding domain of human dystrophin and how mutations in this domain may cause Duchenne or Becker muscular dystrophy.
Dystrophin is an essential component of skeletal muscle cells. Its N-terminal domain binds to F-actin and its C terminus binds to the dystrophin-associated glycoprotein (DAG) complex in the membrane. Dystrophin is therefore thought to serve as a link from the actin-based cytoskeleton of the muscle cell through the plasma membrane to the extracellular matrix. Pathogenic mutations in dystrophin result in Duchenne or Becker muscular dystrophy. The crystal structure of the dystrophin actin-binding domain (ABD) has been determined at 2.6 A resolution. The structure is an antiparallel dimer of two ABDs each comprising two calponin homology domains (CH1 and CH2) that are linked by a central alpha helix. The CH domains are both alpha-helical globular folds. Comparisons with the structures of utrophin and fimbrin ABDs reveal that the conformations of the individual CH domains are very similar to those of dystrophin but that the arrangement of the two CH domains within the ABD is altered. The dystrophin dimer reveals a change of 72 degrees in the orientation of one pair of CH1 and CH2 domains (from different monomers) relative to the other pair when compared with the utrophin dimer. The dystrophin monomer is more elongated than the fimbrin ABD. The dystrophin ABD structure reveals a previously uncharacterised arrangement of the CH domains within the ABD. This observation has implications for the mechanism of actin binding by dystrophin and related proteins. Examining the position of three pathogenic missense mutations within the structure suggests that they exert their effects through misfolding of the ABD, rather than through disruption of the binding to F-actin.


Low intraspecific variation of Frog virus 3 with evidence for novel FV3-like isolates in central and northwestern Canada.
Frog virus 3 (FV3) and FV3-like ranaviruses can infect a variety of cold-blooded aquatic species and present a primary threat to amphibians across the globe. Previous studies of FV3-like viruses have largely investigated higher-level phylogenetic distinctions of these pathogens via portions of the conserved major capsid protein (MCP), and the putative virulence gene vIF-2α. Few studies, however, have investigated the spatial distribution of FV3 variants at the population level3-data that can be used to further understand the spatial epidemiology of this disease. In this study, we sequenced the MCP and vIF-2α of 127 FV3-positive amphibians sampled from Canadian water bodies in Ontario, northeastern Alberta, and southern Northwest Territories to explore whether intraspecific genetic variation exists within FV3. There was a lack of variation at the 2 markers across these regions, suggesting that there is a lack of FV3 sequence diversity in Canada, which may hint at a single source of infection that has spread. However, an undocumented variant termed Wood Buffalo ranavirus (WBRV) was detected in samples from 3 sites in Alberta and Northwest Territories that clustered within the FV3-like lineage with 99.3% sequence homology for MCP. For vIF-2α, all sequences were the expected truncated variant except for 6 samples in Ontario. These latter sequences were suggestive of recombination with common midwife toad virus (CMTV). The lack of variation suggests that higher-resolution genome analyses will be required to further explore the spatial spread and intraspecific variation of the disease.


[Course and outcome of arterial hypertension after stroke].
Clinico-hemodynamic features as well as arterial hypertension outcome in 92 patients with hypertensive disease accompanied by atherosclerosis and atherosclerotic hypertension, who had suffered acute stroke in arteria caroticus interna areas 0.5-19 years before were followed up for 6 years. The minimal number of lethal outcomes fell within the first 3 years after stroke when hyperkinetic circulation was seen in all the patients. The lethality increase caused by repeated strokes (4-5 years after the first stroke was connected with gradual development of cardiac muscle pathology manifested by cardiac rhythm disorders or coronary and cardiac insufficiency in the patients with hypertensive disease in conjunction with atherosclerosis. Regressive course of arterial hypertension occurred in the patients with atherosclerotic hypertension 2 years after stroke. The frequency of repeated strokes did not increase in these patients. The lethality caused by cardiac muscle infarction was not increasing in the post-stroke period.


Rapid Anti-tTG-IgA Screening Test for Early Diagnosis of Celiac Disease in Pediatric Populations.
A large number of patients with celiac disease (CD) remain undiagnosed because they do not fulfill the criteria for entry into the conventional diagnostic workflow. This study evaluated the clinical utility of anti-tissue transglutaminase IgA antibody lateral flow immunoassays (anti-tTG-IgA LFIA) in the undiagnosed-CD-based pediatric population and the impact of a gluten-free diet (GFD) on screening-detected CD. A total of 576 volunteers were tested for anti-tTG-IgA. Gluten consumption habits, CD related symptoms, and risk factors for CD development were evaluated. Volunteers testing positive for anti-tTG-IgA were referred to the conventional CD diagnostic workflow, and the impact of the GFD on health-related quality of life (HR-QoL) was measured. Among them, 13 had a positive anti-tTG-IgA LFIA test result: 11 had confirmed CD (1.91%), one refused confirmatory tests, and another is undergoing diagnosis. Regarding the CD prevalence, no significant differences were observed among risk (1.89%) and symptomatic (2.65%) groups and the entire tested population (1.55%). Rapid anti-tTG-IgA LFIAs could be of clinical utility in primary care for the early identification of children with CD unidentified by the conventional diagnostic workflow. It could potentially reduce the costs of undiagnosed CD, avoiding unnecessary referrals to gastroenterologists, reducing diagnosis delays and long-term problems, and improving patients' HR-QoL.


The Peroxisomal Targeting Signal 3 (PTS3) of the Budding Yeast Acyl-CoA Oxidase Is a Signal Patch.
The specificity of import of peroxisomal matrix proteins is dependent on the targeting signals encoded within their amino acid sequences. Two known import signals, peroxisomal targeting signal 1 (PTS1), positioned at the C-termini and PTS2 located close to N-termini of these proteins are recognized by the Pex5p and Pex7p receptors, respectively. However, in several yeast species, including Saccharomyces cerevisiae, proteins exist that are efficiently imported into peroxisomes despite having neither PTS1 nor PTS2 and for which no other import signal has been determined. An example of such a protein is S. cerevisiae acyl-CoA oxidase (AOx) encoded by the POX1 gene. While it is known that its import is driven by its interaction with the N-terminal segment of Pex5p, which is separate from its C-terminal PTS1-recognizing tetratricopeptide domain, to date, no AOx polypeptide region has been implicated as critical for this interaction, and thus would constitute the long-sought PTS3 signal. Using random mutagenesis combined with a two-hybrid screen, we identified single amino acid residues within the AOx polypeptide that are crucial for this interaction and for the peroxisomal import of this protein. Interestingly, while scattered throughout the primary sequence, these amino acids come close to each other within two domains of the folded AOx. Although the role of one or both of these regions as the PTS3 signal is not finally proven, our data indicate that the signal guiding AOx into peroxisomal matrix is not a linear sequence but a signal patch.


Psychological Distress and Attachment Insecurity of Stalked Mothers.
There is a lack of research about intimate partner stalking when victim and stalker have children together. The aim of the current study was to provide knowledge about the mental health status and attachment patterns of mothers stalked by the father of one or more of their children. One hundred ninety six Danish women, recruited via a closed social network for stalked mothers, completed an anonymous online questionnaire concerning their experiences of violence during and after the relationship with the stalker, relationship characteristics, attachment patterns, and psychological distress. Results indicated high exposure to psychological maltreatment during the victim-stalker relationship, harassing and violent stalking behaviors after relationship termination, and high levels of functional disabilities, PTSD (posttraumatic stress disorder), other trauma-related, affective, and somatization symptoms. Furthermore, the women retrospectively reported an increase in attachment insecurity from the time before their relationship with the stalker to the time of study participation (after they experienced relationship violence and/or stalking). Stalking behaviors uniquely contributed to the explanation of the mothers' psychological distress above the effects of relationship violence. Moreover, attachment insecurity appeared to be the strongest predictor of psychological distress. Having children together with their stalker captures women in an ongoing situation of threat and interpersonal traumatization that differs from other forms of stalking in many respects. The present study is the first drawing attention to the experiences and suffering of stalked mothers, a particularly vulnerable group of stalking victims.


Modified Robicsek procedure for pectus excavatum in adult patients.
The aim of this study was to clarify the short-term and mid-term outcomes of the modified Robicsek procedure using polypropylene mesh for adult pectus excavatum patients. Retrospective chart review was performed. Between 2001 and 2012, 46 consecutive adult patients underwent modified Ravitch repair using polypropylene mesh for pectus excavatum at our institution. There were 30 males and 16 females, with a median age of 25.5 (range: from 17 to 60). Potential risk factors for perioperative complications and early failure in pectus repair were analysed with χ(2) test or Fisher's exact test and Mann-Whitney test. Potential risk factors for postoperative mid-term recurrence were analysed using Cox proportional hazard regression model. The postoperative follow-up interval was 7.0 ± 15.1 months (mean ± standard deviation). No mortality and 11 patients (24.0%) of morbidity, including 2 patients with temporary mesh infection, were noted. A lower preoperative %FEV1.0 predicted was a significant factor (P = 0.0088) of morbidity in multivariate analysis. Regarding chest morphology, early failure in 1 patient (2.2%) and mid-term recurrence in 1 patient (2.2%) were seen. Previous pectus repair (P = 0.0324) and severe asymmetry (P = 0.04) were significant factors of early failure in multivariate analysis, while no significant factor for mid-term recurrence was found. Modified Robicsek procedure with a polypropylene mesh is associated with low incidences of early failure and mid-term recurrence. The procedure is recommended for adult pectus excavatum patients, including those with asymmetric or combined deformity as an initial or reoperative procedure.


THE BRAIN LESION OF GOLDTHIOGLUCOSE OBESITY.
The development of hypothalamic lesions due to goldthioglucose are described. The initial extensive necrotic lesion occurs in close to 100 per cent of animals injected with LD(50). Within 2 weeks the necrotic material has been removed and a narrow scar results. After a lapse of several months, the scar is often difficult to visualize, especially in animals that have not developed obesity. The ventromedial nucleus is not the center of the lesion. The nucleus is preserved in some instances, and partially or completely destroyed in others, depending on the extent of the lesion. The more prominent scar in the obese animals correlates with the larger initial lesion necessary for the complete bilateral destruction of the ventromedial nucleus which is known to be a prerequisite for the development of hypothalamic obesity. Thus, contrary to earlier suggestions, goldthioglucose does not localize specifically in the cells of the ventromedial nucleus.


Molecular force transduction by ion channels: diversity and unifying principles.
Cells perceive force through a variety of molecular sensors, of which the mechanosensitive ion channels are the most efficient and act the fastest. These channels apparently evolved to prevent osmotic lysis of the cell as a result of metabolite accumulation and/or external changes in osmolarity. From this simple beginning, nature developed specific mechanosensitive enzymes that allow us to hear, maintain balance, feel touch and regulate many systemic variables, such as blood pressure. For a channel to be mechanosensitive it needs to respond to mechanical stresses by changing its shape between the closed and open states. In that way, forces within the lipid bilayer or within a protein link can do work on the channel and stabilize its state. Ion channels have the highest turnover rates of all enzymes, and they can act as both sensors and effectors, providing the necessary fluxes to relieve osmotic pressure, shift the membrane potential or initiate chemical signaling. In this Commentary, we focus on the common mechanisms by which mechanical forces and the local environment can regulate membrane protein structure, and more specifically, mechanosensitive ion channels.


Patterns of genetic diversity at the nine forensically approved STR loci in the Indian populations.
Genetic diversity at the nine short tandem repeat (STR) loci, which are universally approved and widely used for forensic investigations, has been studied among nine Indian populations with diverse ethnic, linguistic, and geographic backgrounds. The nine STR loci were profiled on 902 individuals using fluorescent detection methods on an ABI377 System, with the aid of an Amp-F1 Profiler Plus Kit. The studied populations include two upper castes, Brahmin and Kayastha; a tribe, Garo, from West Bengal; a Hindu caste, Meitei, with historical links to Bengal Brahmins; a migrant group of Muslims; three tribal groups, Naga, Kuki and Hmar, from Manipur in northeast India; and a middle-ranking caste, Golla, who are seminomadic herders from Andhra Pradesh. Gene diversity analysis suggests that the average heterozygosity is uniformly high (>0.8) in the studied populations, with the coefficient of gene differentiation at 0.050 +/- 0.0054. Both neighbor-joining (NJ) and unweighted pair group method with arithmetic mean (UPGMA) trees based on DA distances bring out distinct clusters that are consistent with ethnic, linguistic, and/or geographic backgrounds of the populations. The fit of the Harpending and Ward model of regression of average heterozygosity on the gene frequency centroid is found to be good, and the observed outliers are consistent with the population structure and history of the studied populations. Our study suggests that the nine STR loci, used so far mostly for forensic investigations, can be used fruitfully for microevolutionary studies as well, and for reconstructing the phylogenetic history of human populations, at least at the local level.


Metamaterials with custom emissivity polarization in the near-infrared.
Metamaterials have been previously studied for their ability to tailor the dispersive infrared (IR) emissivity of a surface. Here, we investigate metamaterial coatings based on an electromagnetic band-gap surface for use as near-IR emitters with custom polarization selectivity. A genetic algorithm is successfully employed to optimize the metamaterial structures to exhibit custom linear, circular, and elliptical polarization. A study is also conducted on a bi-anisotropic slab, showing that anisotropic chirality is required in the metamaterial structure in order to achieve circular or elliptical emissivity polarization.


Case study of the attitudes and values of nursing students toward caring for older adults.
Given the aging population and the complex needs of older adults, there is considerable need for additional gerontological nurses. This pilot study explored fourth-year nursing students' attitudes and values toward caring for older adults and the influence of their experiences with older adults on these attitudes and values. Using Yin's exploratory case study design, 51 fourth-year nursing students constituted the single case. An initial quantitative survey placed students in three embedded units of analysis: neutral, pro-aged, and anti-aged bias toward older adults. Using purposeful sampling from each of the embedded units, 9 students were interviewed. Four main values (respect, caring, independence, and wisdom and experience) and five attitudes (enjoy older adults, see older adults as normal, feel sorry for older adults, are frustrated by older adults, and dislike gerontological nursing) were identified. The authors' findings have important implications for education and practice.


Triclocarban enhances short-chain fatty acids production from anaerobic fermentation of waste activated sludge.
Triclocarban (TCC), one typical antibacterial agent being widely used in various applications, was found to be present in waste activated sludge at significant levels. To date, however, its effect on anaerobic fermentation of sludge has not been investigated. This work therefore aims to fill this knowledge gap. Experimental results showed that when TCC content in sludge increased from 26.7 ± 5.3 to 520.5 ± 12.6 mg per kilogram total suspended solids, the maximum concentration of short-chain fatty acids (SCFA) increased from 32.6 ± 2.5 to 228.2 ± 3.6 (without pH control) and from 211.7 ± 2.4 to 378.3 ± 3.2 mg COD/g VSS (initial pH 10), respectively. The large promotion of acetic acid was found to be the major reason for the enhancement of total SCFA production. Although a significant level of TCC was degraded in the fermentation process, SCFA was neither produced from TCC nor affected by its major intermediates at the relevant levels. It was found that TCC facilitated solubilization, acidogenesis, acetogenesis, and homoacetogenesis processes but inhibited methanogenesis process. Microbial analysis revealed that the increase of TCC increased the microbial community diversity, the abundances of SCFA (especially acetic acid) producers, and the activities of key enzymes relevant to acetic acid production.


Accuracy of artificial intelligence CT quantification in predicting COVID-19 subjects' prognosis.
Artificial intelligence (AI)-aided analysis of chest CT expedites the quantification of abnormalities and may facilitate the diagnosis and assessment of the prognosis of subjects with COVID-19. This study investigates the performance of an AI-aided quantification model in predicting the clinical outcomes of hospitalized subjects with COVID-19 and compares it with radiologists' performance. A total of 90 subjects with COVID-19 (men, n = 59 [65.6%]; age, 52.9±16.7 years) were recruited in this cross-sectional study. Quantification of the total and compromised lung parenchyma was performed by two expert radiologists using a volumetric image analysis software and compared against an AI-assisted package consisting of a modified U-Net model for segmenting COVID-19 lesions and an off-the-shelf U-Net model augmented with COVID-19 data for segmenting lung volume. The fraction of compromised lung parenchyma (%CL) was calculated. Based on clinical results, the subjects were divided into two categories: critical (n = 45) and noncritical (n = 45). All admission data were compared between the two groups. There was an excellent agreement between the radiologist-obtained and AI-assisted measurements (intraclass correlation coefficient = 0.88, P < 0.001). Both the AI-assisted and radiologist-obtained %CLs were significantly higher in the critical subjects (P = 0.009 and 0.02, respectively) than in the noncritical subjects. In the multivariate logistic regression analysis to distinguish the critical subjects, an AI-assisted %CL ≥35% (odds ratio [OR] = 17.0), oxygen saturation level of <88% (OR = 33.6), immunocompromised condition (OR = 8.1), and other comorbidities (OR = 15.2) independently remained as significant variables in the models. Our proposed model obtained an accuracy of 83.9%, a sensitivity of 79.1%, and a specificity of 88.6% in predicting critical outcomes. AI-assisted measurements are similar to quantitative radiologist-obtained measurements in determining lung involvement in COVID-19 subjects.


Ambroxol-Enhanced Frequency and Amplitude of Beating Cilia Controlled by a Voltage-Gated Ca2+ Channel, Cav1.2, via pHi Increase and [Cl-]i Decrease in the Lung Airway Epithelial Cells of Mice.
Ambroxol (ABX), a frequently prescribed secretolytic agent which enhances the ciliary beat frequency (CBF) and ciliary bend angle (CBA, an index of amplitude) by 30%, activates a voltage-dependent Ca2+ channel (CaV1.2) and a small transient Ca2+ release in the ciliated lung airway epithelial cells (c-LAECs) of mice. The activation of CaV1.2 alone enhanced the CBF and CBA by 20%, mediated by a pHi increasei and a [Cl-]i decrease in the c-LAECs. The increase in pHi, which was induced by the activation of the Na+-HCO3- cotransporter (NBC), enhanced the CBF (by 30%) and CBA (by 15-20%), and a decrease in [Cl-]i, which was induced by the Cl- release via anoctamine 1 (ANO1), enhanced the CBA (by 10-15%). While a Ca2+-free solution or nifedipine (an inhibitor of CaV1.2) inhibited 70% of the CBF and CBA enhancement using ABX, CaV1.2 enhanced most of the CBF and CBA increases using ABX. The activation of the CaV1.2 existing in the cilia stimulates the NBC to increase pHi and ANO1 to decrease the [Cl-]i in the c-LAECs. In conclusion, the pHi increase and the [Cl-]i decrease enhanced the CBF and CBA in the ABX-stimulated c-LAECs.


A Learning Scheme for EMG Based Decoding of Dexterous, In-Hand Manipulation Motions.
Electromyography (EMG) based interfaces are the most common solutions for the control of robotic, orthotic, prosthetic, assistive, and rehabilitation devices, translating myoelectric activations into meaningful actions. Over the last years, a lot of emphasis has been put into the EMG based decoding of human intention, but very few studies have been carried out focusing on the continuous decoding of human motion. In this work, we present a learning scheme for the EMG based decoding of object motions in dexterous, in-hand manipulation tasks. We also study the contribution of different muscles while performing these tasks and the effect of the gender and hand size in the overall decoding accuracy. To do that, we use EMG signals derived from 16 muscle sites (8 on the hand and 8 on the forearm) from 11 different subjects and an optical motion capture system that records the object motion. The object motion decoding is formulated as a regression problem using the Random Forests methodology. Regarding feature selection, we use the following time-domain features: root mean square, waveform length and zero crossings. A 10-fold cross validation procedure is used for model assessment purposes and the feature variable importance values are calculated for each feature. This study shows that subject specific, hand specific, and object specific decoding models offer better decoding accuracy that the generic models.


Respiratory syncytial virus infection in C57BL/6 mice: clearance of virus from the lungs with virus-specific cytotoxic T cells.
We describe respiratory syncytial virus (RSV)-specific cytotoxic T-cell (CTL) lines and clones developed from the spleens of C57BL/6 and BALB/c mice. Line 7 and clones derived from it were H-2Kb restricted, whereas line 12 had both Kb and Db components. Both lines, and all the clones except one, could lyse targets infected with either strain A or strain B RSV. Line 7 or 7-11E1 cells (8 x 10(6) to 10 x 10(6) given intravenously cleared RSV from the lungs of infected mice. There was no morbidity or mortality in any of the infected mice whether or not they received T cells. The C57BL/6 mouse is a useful model system in which to study the role of the CTL response in protective immunity to RSV. CTL lines and clones can mediate clearance of RSV from the lungs of normal mice without producing any associated morbidity.


Fetal cell microchimerism: a protective role in autoimmune thyroid diseases.
The physiological persistence of fetal cells in the circulation and tissue of a previously pregnant woman is called fetal cell microchimerism (FCM). It has been hypothesized to play a role in systemic autoimmune disease; however, only limited data are available regarding its role in autoimmune thyroid disease (AITD). Circulating FCM was analyzed in a large series of previously pregnant women with Graves' disease (GD), Hashimoto's thyroiditis (HT), or no disease (healthy controls (HCs)). To exclude the possible bias related to placental factors, the polymorphic pattern of human leukocyte antigen-G (HLA-G) gene, which is known to be involved in the tolerance of fetal cells by the maternal immune system, was investigated. FCM was evaluated by PCR in the peripheral blood, and the Y chromosome was identified by fluorescence in situ hybridization in some GD tissues. HLA-G polymorphism typing was assessed by real-time PCR. FCM was significantly more frequent in HC (63.6%) than in GD (33.3%) or HT (27.8%) women (P=0.0004 and P=0.001 respectively). A quantitative analysis confirmed that circulating male DNA was more abundant in HC than it was in GD or HT. Microchimeric cells were documented in vessels and in thyroid follicles. In neither GD/HT patients nor HC women was the HLA-G typing different between FCM-positive and FCM-negative cases. The higher prevalence of FCM in HC as compared to GD and HT patients suggests that it plays a possible protective role in autoimmune thyroid disorders. Placental factors have been excluded as determinants of the differences found. The vascular and tissue localization of microchimeric cells further highlights the ability of those cells to migrate to damaged tissues.


Structure-function analysis of the dolichyl phosphate-mannose: protein O-mannosyltransferase ScPmt1p.
Protein O-mannosylation is an essential protein modification. It is initiated at the endoplasmic reticulum by a family of dolichyl phosphate-mannose:protein O-mannosyltransferases (Pmts), which is evolutionarily conserved from yeast to humans. Saccharomyces cerevisiae Pmt1p is an integral membrane protein of the endoplasmic reticulum. ScPmt1p forms a complex with ScPmt2p that is required for maximum transferase activity. Recently, we proposed a seven-transmembrane structural model for ScPmt1p. A large, hydrophilic, endoplasmic reticulum-oriented segment is flanked by five amino-terminal and two carboxyl-terminal membrane-spanning domains. Based on this model, a structure-function analysis of ScPmt1p was performed. Deletion mutagenesis identified the N-terminal third of the transferase as being essential for the formation of a functional ScPmt1p-ScPmt2p complex. Deletion of the central hydrophilic loop eliminates mannosyltransferase activity, but not ScPmt1p-ScPmt2p interactions. Alignment of all fully characterized PMT family members revealed that this central loop region contains three highly conserved peptide motifs, which can be considered as signatures of the PMT family. In addition, a number of invariant amino acid residues were identified throughout the entire protein sequence. In order to evaluate the functional significance of these conserved residues site-directed mutagenesis was performed. We show that several amino acid substitutions in the conserved motifs significantly reduce ScPmt1p activity. Further, the invariant residues Arg-64, Glu-78, Arg-138, and Leu-408 are essential for ScPmt1p function. In particular, Arg-138 is crucial for ScPmt1p-ScPmt2p complex formation.


Diagnosis and classification of severe combined immunodeficiency disease.
The failure to demonstrate normal humoral and cell-mediated immunity (CMI) in patients diagnosed as SCID is seen to reflect the varied pathogenesis of this syndrome. Two major groups of patients have been described, those with or without an associated absence of the enzyme ADA. The heterogeneity of the syndrome is expressed in variable inheritance patterns (particularly defined X-linked or autosomal recessive modes of inheritance), differing clinical presentations, and significant variability in laboratory findings. Some of this heterogeneity of laboratory findings may in fact be contributed to by the high incidence of infection or engraftment of maternal cells in utero. Common to all, however, is the profound deficiency of functional attributes of humoral and cell-mediated immunity. Insight into the biology of this immunodeficiency has advanced steadily in the last decade. Although initially hypothesized to represent a primary lymphoid stem-cell defect, newer technologies to identify and enumerate lymphocyte subpopulations and precursor lymphocytes have revealed the complexity of the disorder. This complexity may now be attributable to a number of abnormalities in the quantitative and qualitative differentiation of these lymphoid stem cells. Functional differentiation of lymphocytes is the result of a progressive and orderly sequence of events. In SCID, lymphocytes of both lineages may be arrested at specific and identifiable stages of maturation, leading to a deficiency of cell-mediated and humoral immunity. In many patients with SCID, the combined immune deficiency may be linked solely to a failure in the stepwise progression of T-cell differentiation.


Dispensing with marriage: Marital and partnership trends in rural KwaZulu-Natal, South Africa 2000-2006.
This paper describes marriage and partnership patterns and trends in rural KwaZulu-Natal, South Africa from 2000-2006. The study is based on longitudinal, population-based data collected by the Africa Centre demographic surveillance system. We consider whether the high rates of non-marriage among Africans in South Africa reported in the 1980s were reversed following the political transformation underway by the 1990s. Our findings show that marriage has continued to decline with a small increase in cohabitation among unmarried couples, particularly in more urbanised areas. Comparing surveillance and census data, we highlight problems with the use of the 'living together' marital status category in a highly mobile population.


Networking in the endoplasmic reticulum.
The network of the ER (endoplasmic reticulum) is set up by cytoskeletal control of the movement and remodelling of polygonal rings of tubules, bundles of tubules and cisternal regions. We have developed a new image analysis tool, persistency mapping, to understand the framework upon which the plant ER remodels. With this new tool, we have explored the network nodes, called anchor/growth sites, that may anchor the network by attachment to the plasma membrane. We have determined how the polygonal ring structure depends on myosin XI-K for 'opening' and 'closing'. With latrunculin B treatment, we have investigated the involvement of actin in the elongation and persistency of the tubules. We also show how the cytoskeleton is involved in directional diffusion within the membrane. This observation may lead to an answer to the question of what function this network structure serves in the cell. We propose that the ER acts as a trafficking network, delivering lipid, protein, calcium and signalling molecules to different regions of the cell. It does so by directional reduced dimensional diffusion. The ER network of tubules restricts the dimensionality of diffusion to near one-dimensional, whereas the cisternae reduce it to near two-dimensional. The cytoskeleton does not drive the diffusion, but participates by providing directionality to the diffusion.


Circular RNA EFR3A promotes nasopharyngeal carcinoma progression through modulating the miR-654-3p/EFR3A axis.
Nasopharyngeal carcinoma (NPC) originates from the nasopharyngeal epithelium. hsa_circ_0135761 (circEFR3A), a newly identified circRNA, presented elevation in NPC via high-throughput sequencing. This study aimed to clarify the molecular mechanism of circEFR3A in the carcinogenesis of NPC. Based on RT-qPCR, subcellular fractionation, RNase R digestion and actinomycin D assays, we evaluated circEFR3A expression characteristics in NPC cells. We found that the circEFR3A was located in the cytoplasm of NPC cells, presented upregulation and stably expressed in NPC cells. Loss-of-function assays clarified the effects of circEFR3A on NPC cell malignant behaviors. The results demonstrated that circEFR3A knockdown facilitated NPC cell apoptosis but repressed NPC cell proliferation and migration. Furthermore, the regulatory mechanism of circEFR3A in NPC was explored. Bioinformatics and mechanism experiments revealed that cicrEFR3A positively modulated EFR3A by competitively binding with miR-654-3p in NPC cells. Additionally, rescue assays showed that the suppressive effects of cicrEFR3A knockdown on NPC cell proliferation, migration and apoptosis were countervailed by EFR3A upregulation. Xenograft tumor-bearing mouse models were established to investigate the role of cicrEFR3A in NPC tumorigenesis in vivo, and the results indicated that circEFR3A silencing suppressed tumor growth in mice. In conclusion, circEFR3A is highly expressed and functions as an oncogene in NPC progression. circEFR3A facilitates NPC cell proliferation and migration by binding to miR-654-3p to upregulate EFR3A, providing a potential new direction for seeking therapeutic plans for NPC.


Meta-analysis: effect of patient self-testing and self-management of long-term anticoagulation on major clinical outcomes.
Anticoagulation with vitamin K antagonists reduces major thromboembolic complications in at-risk patients. With portable monitoring devices, patients can conduct their own international normalized ratio testing and dose adjustment at home. To determine whether patient self-testing (PST), alone or in combination with self-adjustment of doses (patient self-management [PSM]), is associated with a reduction in thromboembolic complications and all-cause mortality without an increase in major bleeding events compared with usual care. MEDLINE and the Cochrane Central Register of Controlled Trials. Studies published in English from 1966 to October 2010 that enrolled outpatient adults receiving long-term (>3 months) oral anticoagulant therapy and that compared PST or PSM with care in a physician's office or an anticoagulation clinic were included. Two investigators reviewed each article. Three investigators extracted data from articles that met inclusion criteria by using standardized data abstraction forms. Studies were assessed for quality, and the overall strength of evidence was rated for each clinical outcome. Twenty-two trials, with a total of 8413 patients, were included. In one half of the trials, fewer than 50% of potentially eligible persons successfully completed the training and agreed to be randomly assigned. Patients randomly assigned to PST or PSM had lower total mortality (Peto odds ratio [OR], 0.74 [95% CI, 0.63 to 0.87]), lower risk for major thromboembolism (Peto OR, 0.58 [CI, 0.45 to 0.75]), and no increased risk for a major bleeding event (Peto OR, 0.89 [CI, 0.75 to 1.05]). The strength of evidence was moderate for the bleeding and thromboembolism outcomes but low for mortality. Eight of 11 trials reported that patient satisfaction, quality of life, or both was better with PST or PSM than with usual care. In one half of the trials, fewer than 50% of the potentially eligible patients were randomly assigned. Only 5 trials were considered high quality, and only 2 were conducted in the United States. No studies addressed whether PST or PSM is safe during the high-risk initiation phase. Compared with usual care, PST with or without PSM is associated with significantly fewer deaths and thromboembolic events, without increased risk for a serious bleeding event, for a highly selected group of motivated adult patients requiring long-term anticoagulation with vitamin K antagonists. Whether this care model is cost-effective and can be implemented successfully in typical U.S. health care settings requires further study. U.S. Department of Veterans Affairs Health Services Research and Development Service.


Smartphone-Based Remote Monitoring Solution for Heart Failure Patients.
The hospitalisation of patients with Heart Failure (HF) represents an increasing problem for the healthcare system with more than 26 million worldwide suffering from this disease. Predictions demonstrate that the total health expenditure will increase by 127% in 2030. In Portugal, demographic changes caused by an ageing population are associated with an increase in HF incidence rate, forecasting 479.921 Heart Failure patients by 2035. In this paper, we present the smartBEAT solution that was developed to monitor Heart Failure patients so that physicians can early detect HF decompensation and prevent HF hospitalisations. SmartBEAT collects data from several sensors: weigh scale, blood pressures, physical activity bracelet - and transmits to the cloud where a decision support algorithm helps to detect acute episodes early. The system was evaluated during a pilot phase for two weeks with nine seniors, and later for 1-3 months with 38 seniors HF patients. Adherence to the evaluation protocol was high, and perceptions on wellbeing and control over the disease were considered positive. Moreover, healthcare professionals were overwhelmed with the patients' high adherence and found the usability of the portal high, and providing interesting information about patients' health status.


Roles of Children and Adolescents in COVID-19 Transmission in the Community: A Retrospective Analysis of Nationwide Data in Japan.
Background: Roles of children and adolescents in spreading coronavirus disease 2019 (COVID-19) in the community is not fully understood. Methods: We analyzed the data of 7,758 children and adolescents with COVID-19 and characteristics of secondary transmission generated by these cases using case information published by local governments. Ratio of pediatric and adolescent cases generating secondary transmission was calculated for various social settings. Results: The incidence of COVID-19 was 24.8 cases per 105 population aged between 0 and 9 years, and 59.2 among those aged between 10 and 19 years, which was lower than that among individuals of all age groups (79.6 per 105 population) between January 15 and October 31, 2020. The proportion of cases generating secondary cases was 8.3% among infants and young children in nursery schools and kindergartens, 16% among children and adolescents attending primary schools, 34% among those attending junior high schools, 43% among those attending high schools, 31% among those attending professional training colleges, and 24% in those attending universities. Households were the most common setting for secondary transmission. Conclusion: The risk of generating secondary cases might be limited among pediatric and adolescent cases with COVID-19, especially in settings outside households. Effectiveness of traditional mitigation measures (e.g., school closures) to suppress COVID-19 transmissions should be carefully evaluated.


The efficacy of perioperative antibiotic therapy in adenotonsillectomy children.
To evaluate the role of perioperative antibiotics use in children after adenotonsillectomy. SPSS 27.0 was used for statistical analysis. Two independent samples mean T test was used to evaluate the throat pain scores consecutive 3 days after the surgery, the time to resume to normal diet, and the wound healing time. Logistic regression analysis was used to evaluate the independent risk factors of the two groups. The generalized estimation model was used to evaluate the correlation between age and postoperative pain scores, and the relationship between different tonsillar bed gradings and postoperative pain scores. The pain scores were 5.83 ± 1.879, 5.20 ± 1.933, and 4.02 ± 1.936 in the observation group; and 6.83 ± 1.892, 6.17 ± 2.001, and 5.29 ± 2.068 in the control group on days 1-3 after surgery, respectively. The time of pain disappearance was 6.24 ± 2.121 days in the observation group and 7.73 ± 2.210 days in the control group. The wound repair time was 18.66 ± 2.200 days in the observation group and 18.70 ± 2.468 days in the control group. Logistic regression analysis showed that fever was an independent risk factor for the two groups and was negatively correlated (B = - 1.237, P < 0.001, OR = 0.290). Generalized estimation model showed that there was a positive correlation between age and pain scores (P < 0.001), and with the increasing grading of tonsillar bed, the higher the pain scores was (P < 0.001). Perioperative use of antibiotics in children with adenotonsillectomy can effectively reduce postoperative fever, throat pain symptoms, and shorten the pain time. With the increasing of tonsillar bed grading, perioperative antibiotic therapy was more necessary.


Decreased growth rate of P. falciparum blood stage parasitemia with age in a holoendemic population.
In malaria holoendemic settings, decreased parasitemia and clinical disease is associated with age and cumulative exposure. The relative contribution of acquired immunity against various stages of the parasite life cycle is not well understood. In particular, it is not known whether changes in infection dynamics can be best explained by decreasing rates of infection, or by decreased growth rates of parasites in blood. Here, we analyze the dynamics of Plasmodium falciparum infection after treatment in a cohort of 197 healthy study participants of different ages. We use both polymerase chain reaction (PCR) and microscopy detection of parasitemia in order to understand parasite growth rates and infection rates over time. The more sensitive PCR assay detects parasites earlier than microscopy, and demonstrates a higher overall prevalence of infection than microscopy alone. The delay between PCR and microscopy detection is significantly longer in adults compared with children, consistent with slower parasite growth with age. We estimated the parasite multiplication rate from delay to PCR and microscopy detections of parasitemia. We find that both the delay between PCR and microscopy infection as well as the differing reinfection dynamics in different age groups are best explained by a slowing of parasite growth with age.


Clinical, Epidemiological, and Etiological Changes in Erythema Nodosum.
Erythema nodosum (EN) is the most common type of panniculitis, commonly secondary to infectious diseases. To elucidate the causative factors and the clinical presentation of patients with EN (2004-2014) and to compare their data to those reported in a previous study. A retrospective study was conducted of all patients diagnosed with EN who were hospitalized at Soroka University Medical Center (2004-2014). The clinical, demographic, and laboratory characteristics of the patients were compared to those in a cohort of patients diagnosed with EN from 1973-1982. The study comprised 45 patients with a diagnosis of EN. The most common symptoms of patients hospitalized with EN were arthritis or arthralgia (27% of patients). Patients with EN, compared to those reported in 1987, has significantly lower rates of fever (18% vs. 62% P < 0.001), streptococcal infection (16% vs. 44%, P = 0.003), and joint involvement (27% vs. 66%, P < 0.001). In addition, fewer patients had idiopathic causes of EN (9% vs. 32%, P = 0.006). In the past decades, clinical, epidemiological, and etiological changes have occurred in EN patients. The lowering in rate of fever, streptococcal infection, and joint involvement in patients with EN are probably explained by improvements in socioeconomic conditions. The significantly decreasing rate of idiopathic causes of EN is possibly due to the greater diagnostic accuracy of modern medicine. The results of the present study demonstrate the impact of improvements in socioeconomic conditions and access to healthcare on disease presentation.


Cardiovascular risk reduction with once-weekly semaglutide in subjects with type 2 diabetes: a post hoc analysis of gender, age, and baseline CV risk profile in the SUSTAIN 6 trial.
The SUSTAIN 6 trial demonstrated that once-weekly semaglutide (0.5 and 1.0 mg) significantly reduced major adverse cardiovascular (CV) events (MACE) vs placebo in subjects with type 2 diabetes (T2D) and high CV risk. The effects of gender, age and baseline CV risk on outcomes are important considerations for further study. Subjects were grouped according to gender, age (50-65 years and > 65 years), and CV risk profile at baseline (prior myocardial infarction [MI] or stroke vs no prior MI or stroke, and established CV disease [CVD] vs CV risk factors alone, including subjects with chronic kidney disease). Time to MACE and its individual components (CV death, nonfatal MI, nonfatal stroke), hospitalization for unstable angina or heart failure, and revascularization (coronary and peripheral) were analyzed for all subgroups. Additional analyses were performed for gender and age to investigate change from baseline in HbA1c and body weight, as well as tolerability. A total of 3297 subjects were included. The majority of subjects (60.7%) were male; 43% were > 65 years of age; 41.5% had a history of MI or stroke; and 76.8% had established CVD. Compared with placebo, semaglutide reduced the risk of the first occurrence of MACE and each MACE component consistently across all subgroups (gender, age, and baseline CV risk profile). Revascularizations, HbA1c and body weight were also reduced consistently across all subgroups compared with placebo. Gastrointestinal adverse events in all treatment groups were more common among women than men, but rates of premature treatment discontinuation were similar for both genders. In this post hoc analysis of SUSTAIN 6, once-weekly semaglutide vs placebo reduced the risk of MACE in all subjects included in the trial, regardless of gender, age, or baseline CV risk profile. Trial registry Clinicaltrials.gov, Identifying number: NCT01720446, Date of registration: October 29, 2012.


The Women's Health Initiative Estrogen-alone Trial had differential disease and medical expenditure consequences across age groups.
The Women's Health Initiative (WHI) randomized trial identified age differences in the benefit-risk profile of estrogen-alone (ET) use. The impact of WHI trial on disease-associated medical expenditures attributable to subsequent decreased ET utilization has, however, not been measured. Therefore, the objective of this analysis was to quantify the age-specific disease-associated medical expenditures attributable to reduced ET utilization after the WHI Hormone Therapy (HT) trials. Population-level disease counts and associated expenditures between 2003 and 2015 were compared between an observed ET-user population versus a hypothetical ET-user population assuming absence of the WHI HT trials, constructed by extrapolating ET utilization rates from 1996 to 2002 assuming pre-WHI HT rates would have continued without publication of the WHI HT trial data (2002-2004). Analyses were stratified by age (50-59, 60-69, and 70-79 years). Input data were extracted from Medical Expenditure Panel Survey and the literature. The primary outcomes were: ET utilization, chronic diseases (breast cancer, stroke, coronary heart disease, colorectal cancer, pulmonary embolism, and hip fracture) and disease-associated direct medical expenditures. Over 13 years, the decline in ET utilization was associated with $4.1 billion expenditure for excess chronic diseases (37,549 excess events) among women in their 50s, compared to savings of $1.5 billion and $4.4 billion for diseases averted by lower ET utilization among women in their 60s (13,495 fewer events) and 70s (40,792 fewer events), respectively. The decline in ET utilization had differential disease and expenditure consequences by age groups in the United States. These results are limited by the lack of inclusion of vasomotor symptom benefit and costs of alternative medications for these symptoms in the analysis.


Herpes Zoster and Subsequent Cancer Risk: A Nationwide Population-Based Cohort Study in Korea.
It is well known that an immunosuppressed status such as cancer is a risk factor for herpes zoster (HZ), but little is known about whether HZ affects cancer development. This study aimed to investigate the association between HZ and subsequent cancer risk by cancer type. We conducted a nationwide retrospective cohort study using the Korean National Health Insurance claims database. The study enrolled 1,568,818 patients: 784,409 diagnosed with HZ between 2010 and 2015 were included in the HZ group, and 784,409 matched controls without HZ were included in the non-HZ group, with 1:1 exact matching for age, sex, and index year. Hazard ratios (HRs) were calculated for the risk of cancers based on anatomical site according to the HZ status using the Cox proportional hazards regression models. During a mean follow-up period of 6 years, 22,235 and 22,316 patients in the HZ group and the non-HZ group, respectively, developed cancer (incidence rate: 7.6 vs. 7.7 per 1,000 person-years). After adjusting for age, sex, and comorbidities, the overall risk of cancers was slightly decreased in the HZ group compared with the non-HZ group (HR, 0.999; 95% confidence interval [CI], 0.98-1.02). In post hoc analyses on organ site, the HZ group had significantly increased risk of hematologic malignancies, including multiple myeloma (HR, 1.63; 95% CI, 1.37-1.95), leukemia (HR, 1.20; 95% CI, 1.03-1.39), and lymphoma (HR, 1.15; 95% CI, 1.02-1.30) compared with the non-HZ group. Conversely, the risk of cancers in the liver (HR, 0.87; 95% CI, 0.82-0.93) and larynx (HR, 0.73; 95% CI, 0.58-0.92) were significantly decreased in the HZ group compared with the non-HZ group. Although the risk of developing some hematological cancers increased in patients with HZ, solid cancers including liver and laryngeal cancers showed a negative association with HZ.


Overview of Flaxseed Patent Applications for the Reduction of Cholesterol Levels.
Flaxseed is becoming an increasingly widely used food ingredient. The rising interest of the food industry in this nutraceutical is primarily because of functional nutrients, such as alpha-linolenic acid and lignans, which have health benefits due to their lipid-lowering properties. The objective of this study was to provide an overview of the patenting of flaxseed products with cholesterol-lowering effects. Patent applications filed by country of origin were retrieved from the Derwent Innovations Index®database. A total of 307 patent documents were identified, of which 184 claim the use of flaxseed or parts of the flax plant in the product formulation, for their lipid-lowering effect when consumed by humans. A few of the patent applications contain claims for new products based on flaxseed in isolation, including the preparation of foods designed to inhibit the production of cholesterol. Most of the claims were for flaxseed in the form of oil and in association with other lipid-lowering compounds, mainly for the food industry, in the form of dietary supplements or baked products designed to raise their high-density lipoprotein content, and for treating heart problems. China and the United States are the leading countries of flax-related applications. These results may have important implications for the production of functional food products that meet specific societal demands.


Permeability of a nuclear membrane: changes during normal development and changes induced by growth hormone.
The ion permeability of the nuclear membrane envelope of salivary gland cells (of the midge Chironomus thummi) undergoes changes during development. Following the early fourth instar stage, permeability falls to about one-fifth of its base value over a period of 3 to 5 days of development of the animal, and then rises again over the next 2 to 4 days. The falling phase of the change can be reproduced within 1 hour by injections of the growth hormone ecdyson.


Determinants of Completion and Use of Psychiatric Advance Statements in Mental Health Care in the Netherlands.
Crisis plans are a type of psychiatric advance statement (PAS) that describe how to recognize early signs of a psychiatric crisis and how to handle crisis situations. Although PASs may help reduce the occurrence of crises, their implementation in clinical practice is problematic. This study examined patient and clinician characteristics associated with successful completion of a crisis plan and determined how often a plan was consulted in a crisis situation. Participants were 139 crisis-prone outpatients and their clinicians recruited in the context of a randomized controlled trial in the Netherlands studying the effects of crisis plans. Multivariate logistic regression analyses examined associations between patient and clinician characteristics and completion of a crisis plan. Descriptive and univariate statistics were used to determine subsequent use of crisis plans. Of the 139 patients, 64% completed a crisis plan. Higher completion rates were associated with a better clinician-rated working alliance, a lower education level of the patient, and fewer years of professional experience of the clinician. Of the 89 patients who completed a crisis plan, 38 later experienced a crisis, and plans were consulted for a third of these patients (34%). For those whose crisis involved involuntary admission, a smaller proportion had their plans consulted, compared with those whose crisis involved an outpatient emergency visit or voluntary admission. PAS completion was associated not only with patient and clinician characteristics but also with a positive working alliance. PAS use did not occur in all cases, especially not when patients were involuntarily admitted.


Signaling through myosin light chain kinase in smooth muscles.
Ca(2+)/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates smooth muscle myosin regulatory light chain (RLC) to initiate contraction. We used a tamoxifen-activated, smooth muscle-specific inactivation of MLCK expression in adult mice to determine whether MLCK was differentially limiting in distinct smooth muscles. A 50% decrease in MLCK in urinary bladder smooth muscle had no effect on RLC phosphorylation or on contractile responses, whereas an 80% decrease resulted in only a 20% decrease in RLC phosphorylation and contractile responses to the muscarinic agonist carbachol. Phosphorylation of the myosin light chain phosphatase regulatory subunit MYPT1 at Thr-696 and Thr-853 and the inhibitor protein CPI-17 were also stimulated with carbachol. These results are consistent with the previous findings that activation of a small fraction of MLCK by limiting amounts of free Ca(2+)/calmodulin combined with myosin light chain phosphatase inhibition is sufficient for robust RLC phosphorylation and contractile responses in bladder smooth muscle. In contrast, a 50% decrease in MLCK in aortic smooth muscle resulted in 40% inhibition of RLC phosphorylation and aorta contractile responses, whereas a 90% decrease profoundly inhibited both responses. Thus, MLCK content is limiting for contraction in aortic smooth muscle. Phosphorylation of CPI-17 and MYPT1 at Thr-696 and Thr-853 were also stimulated with phenylephrine but significantly less than in bladder tissue. These results indicate differential contributions of MLCK to signaling. Limiting MLCK activity combined with modest Ca(2+) sensitization responses provide insights into how haploinsufficiency of MLCK may result in contractile dysfunction in vivo, leading to dissections of human thoracic aorta.


Tumor Microenvironment Responsive CD8+ T Cells and Myeloid-Derived Suppressor Cells to Trigger CD73 Inhibitor AB680-Based Synergistic Therapy for Pancreatic Cancer.
CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8+ T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8+ T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC.


Polarization properties of fluorescent BSA protected Au25 nanoclusters.
BSA protected gold nanoclusters (Au25) are attracting a great deal of attention due to their unique spectroscopic properties and possible use in biophysical applications. Although there are reports on synthetic strategies, spectroscopy and applications, little is known about their polarization behavior. In this study, we synthesized the BSA protected Au25 nanoclusters and studied their steady state and time resolved fluorescence properties including polarization behavior in different solvents: glycerol, propylene glycol and water. We demonstrated that the nanocluster absorption spectrum can be separated from the extinction spectrum by subtraction of Rayleigh scattering. The nanocluster absorption spectrum is well approximated by three Gaussian components. By a comparison of the emissions from BSA Au25 clusters and rhodamine B in water, we estimated the quantum yield of nanoclusters to be higher than 0.06. The fluorescence lifetime of BSA Au25 clusters is long and heterogeneous with an average value of 1.84 μs. In glycerol at -20 °C the anisotropy is high, reaching a value of 0.35. However, the excitation anisotropy strongly depends on the excitation wavelengths indicating a significant overlap of the different transition moments. The anisotropy decay in water reveals a correlation time below 0.2 μs. In propylene glycol the measured correlation time is longer and the initial anisotropy depends on the excitation wavelength. BSA Au25 clusters, due to long lifetime and high polarization, can potentially be used in studying large macromolecules such as protein complexes with large molecular weight.


Evaluation of record linkage of two large administrative databases in a middle income country: stillbirths and notifications of dengue during pregnancy in Brazil.
Due to the increasing availability of individual-level information across different electronic datasets, record linkage has become an efficient and important research tool. High quality linkage is essential for producing robust results. The objective of this study was to describe the process of preparing and linking national Brazilian datasets, and to compare the accuracy of different linkage methods for assessing the risk of stillbirth due to dengue in pregnancy. We linked mothers and stillbirths in two routinely collected datasets from Brazil for 2009-2010: for dengue in pregnancy, notifications of infectious diseases (SINAN); for stillbirths, mortality (SIM). Since there was no unique identifier, we used probabilistic linkage based on maternal name, age and municipality. We compared two probabilistic approaches, each with two thresholds: 1) a bespoke linkage algorithm; 2) a standard linkage software widely used in Brazil (ReclinkIII), and used manual review to identify further links. Sensitivity and positive predictive value (PPV) were estimated using a subset of gold-standard data created through manual review. We examined the characteristics of false-matches and missed-matches to identify any sources of bias. From records of 678,999 dengue cases and 62,373 stillbirths, the gold-standard linkage identified 191 cases. The bespoke linkage algorithm with a conservative threshold produced 131 links, with sensitivity = 64.4% (68 missed-matches) and PPV = 92.5% (8 false-matches). Manual review of uncertain links identified an additional 37 links, increasing sensitivity to 83.7%. The bespoke algorithm with a relaxed threshold identified 132 true matches (sensitivity = 69.1%), but introduced 61 false-matches (PPV = 68.4%). ReclinkIII produced lower sensitivity and PPV than the bespoke linkage algorithm. Linkage error was not associated with any recorded study variables. Despite a lack of unique identifiers for linking mothers and stillbirths, we demonstrate a high standard of linkage of large routine databases from a middle income country. Probabilistic linkage and manual review were essential for accurately identifying cases for a case-control study, but this approach may not be feasible for larger databases or for linkage of more common outcomes.


[Clinical, genetic and molecular studies on autosomal dominant polycystic kidney disease].
Two genes causing autosomal dominant polycystic kidney disease (ADPKD), PKD1 and PKD2, have been described. In the present work we study, by means of linkage analysis, the genetic heterogeneity in our population as well as the clinical differences between PKD1 and PKD2. 316 subjects belonging to 49 unrelated ADPKD families have been studied by means of 3 microsatellites for PKD1 and 3 for PKD2 to differentiate if they have ADPKD type 1 or 2. The techniques used to analyze the microsatellites have been the chemiluminescence and the silver satining techniques. All the subjects underwent a complete physical examination and a sonographic scan. Clinical and molecular results have been correlated. Genetic heterogeneity has been proved, with 85% of families linked to PKD1 and 15% to PKD2. The disease is more severe in PKD1, with an earlier age at diagnosis (27.4 vs. 41.4 years; p = 0.0002), a younger age at the onset of end stage renal disease (53.4 vs. 72.7 years, p < 0.00001), and earlier age at diagnosis of hypertension (34.8 vs. 49.7 years; p = 0.001) and a higher prevalence of hypertension for all groups of age. In both forms of ADPKD there were families showing anticipation (8/44 for PKD1 and 2/5 for PKD2) but this was not a widespread phenomenon. Our data do not support the phenomenon of genetic imprinting for this disease. In the population of Catalonia, Spain, PKD1 accounts for 85% of families with autosomal dominant polycystic kidney disease and PKD2 accounts for the remaining 15%. PKD1 form is more severe than PKD2.


Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).
To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy. High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4. For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death. A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.


Orally administered branaplam does not impact neurogenesis in juvenile mice, rats, and dogs.
Branaplam is a therapeutic agent currently in clinical development for the treatment of infants with type 1 spinal muscular atrophy (SMA). Since preclinical studies showed that branaplam had cell-cycle arrest effects, we sought to determine whether branaplam may affect postnatal cerebellar development and brain neurogenesis. Here, we describe a novel approach for developmental neurotoxicity testing (DNT) of a central nervous system (CNS) active drug. The effects of orally administered branaplam were evaluated in the SMA neonatal mouse model (SMNΔ7), and in juvenile Wistar Hannover rats and Beagle dogs. Histopathological examination and complementary immunohistochemical studies focused on areas of neurogenesis in the cerebellum (mice, rats, and dogs), and the subventricular zone of the striatum and dentate gyrus (rats and dogs) using antibodies directed against Ki67, phosphorylated histone H3, cleaved caspase-3, and glial fibrillary acidic protein. Additionally, image-analysis based quantification of calbindin-D28k and Ki67 was performed in rats and dogs. The patterns of cell proliferation and apoptosis, and neural migration and innervation in the cerebellum and other brain regions of active adult neurogenesis did not differ between branaplam- and control-treated animals. Quantitative image analysis did not reveal any changes in calbindin-D28k and Ki67 expression in rats and dogs. The data show that orally administered branaplam has no impact on neurogenesis in juvenile animals. Application of selected immunohistochemical stainings in combination with quantitative image analysis on a few critical areas of postnatal CNS development offer a reliable approach to assess DNT of CNS-active drug candidates in juvenile animal toxicity studies.


Sexual behaviors relevant to HIV transmission in a rural African population. How much can a KAP survey tell us?
KAP surveys have been proposed as a means to gather quantitative information on AIDS-related sexual behaviors, but the validity of survey results has not been tested. The validity of data gathered during a KAP survey in a rural district in Northern Uganda (N = 1486) was examined analyzing expected behavioral patterns, agreement of partner reports, and concordance of number of sexual contacts across gender. Patterns of sexual behavior and age trends are as expected. More men (50%) than women (18.5%) reported premarital sex. The likelihood of sexual intercourse before marriage increases with age at first marriage and with education. Women marry 5 years earlier than men, and the number of marriages increases with age. Peak incidence of casual sex occurs before age 25. The male/female ratio of casual sex is 4, as compared to about 3 in other African surveys. Single men are 2.5 times more likely to engage in casual sex than married males. Agreement of partner reports was examined for 392 couples selected by chance. 86% of the couples agreed on being polygamous or monogamous. On average men reported 1.3 (SD = 0.7) wives as compared to women reporting 1.5 (SD = 0.89) wives (P < 0.001). 16.8% of women declared more, and 2.8% less cowives than their husband (r = 0.65). Self-reports on frequency of sexual intercourse in the past month were examined for 256 monogamous couples. Mean frequencies differ (5.24 +/- 5.1 for men, 4.43 +/- 4.7 for women, P < 0.001). 42.8% of couples are in agreement within +/- 1 unit (r = 0.44). The total number of extra-marital and marital sex acts, as well as the total number of partners reported by each gender are similar. There is, however, a striking gender difference in reporting of casual partners in the past year. Data were found to be accurate at the aggregate level. However, accuracy of reporting at the individual level was found to be low. The gender difference in reporting of casual partners may be due to female underreporting, to not having captured prostitutes or to a different perception of the meaning of casual partnership. All KAP surveys should include a validity analysis, so as to provide a sense of the accuracy of the surveys and allow for comparison of the quality of different KAP surveys. There is an urgent need for a standardized approach to validating the findings from AIDS-related KAP surveys. Some of the indirect methods described here could be relevant for further use.