Should we offer routine hepatitis C antibody testing in men who have sex with men?
There has been a significant rise in the number of HIV positive men who have sex with men (MSM) co-infected with hepatitis C (HCV). Most infections are thought to occur through high risk sexual practices, exacerbated by drug use. Previous data has suggested no need for routine screening in HIV negative MSM. We looked at HCV antibody testing and HCV risk assessment in all MSM clinic attenders as part of a Public Health England initiative. Routine HCV antibody testing was offered to all MSM attending a large inner city sexual health clinic from April to June 2014. Patients were asked to fill in a questionnaire assessing HCV risk. Demographic data, HIV status and STI results were collected and compared. We collected 471 HCV risk assessment questionnaires during the eight-week period. The median age was 34 (range 18-71) and 403 (85.6%) were White British. Ten (2.1%) patients were known to be HCV positive, of which 3 were on treatment and 5 (1.1%) had cleared HCV. One hundred and forty-nine (31.6%) patients were HIV negative, 254 (53.9%) were HIV positive and 68 (14.5%) had unknown HIV status at time of clinic visit. In the last three months 151 (32.1%) reported unprotected receptive anal intercourse, 58 (12.3%) reported group sex, 11 (2.3%) reported receptive fisting and 32 (6.8%) reported more than 10 partners. Eighty-seven (18.5%) patients had shared notes/straws to snort drugs and 29 (6.2%) reported injecting drugs or slamming. One hundred and forty-two (30.0%) patients reported recreational drug use in the last 12 months, with cocaine, methadrone and ketamine most popular. One hundred and fifteen (24.4%) patients reported sex under the influence of recreational drugs. There were no statistical differences between HIV positive and HIV negative patients in their risk, sexual behaviour and drug use. STI screens were performed on 269 patients with nine (3.3%) new HIV diagnoses, four (1.5%) early syphilis, and 28 (10.4%) rectal gonorrhoea infections. There were three (1.1%) new HCV diagnoses, and one (33.3%) was in an HIV negative patient. Our results show increased risk behaviour for both HIV positive and HIV negative MSM. There are a high number of patients using party drugs, participating in group sex and not using condoms, leading to high rates of new STI diagnoses. With similar rates of risk we believe HCV testing and risk assessment should be considered in all MSM regardless of HIV status.


Reactive arthritis after enteric infections in the United States: the problem of definition.
Bacterial enteric infections cause substantial morbidity in the United States both from acute illness and sequelae that follow. Reactive arthritis (ReA) is a poorly defined term that is used to describe a variety of rheumatologic phenomena that may occur after Salmonella, Shigella, Campylobacter, and Yersinia infection, as well as other types of infections (eg, Chlamydia). This review focuses on clinical and epidemiologic investigations of ReA following bacterial enteric infection in the United States. Only 2 population-based studies of ReA following enteric infection have been performed in the United States. ReA following outbreaks of Campylobacter and Yersinia infection has not been studied, and investigations following Shigella and Salmonella outbreaks have focused primarily on the more narrowly defined, but now outdated, concept of "Reiter's syndrome" rather than ReA. Additional epidemiologic studies are needed to determine the burden of illness due to ReA following enteric infection, but a clearer definition of the term is a prerequisite.


Beneficial effect of chromium supplementation on serum triglyceride levels in NIDDM.
To investigate the effect of chromium picolinate supplementation on the lipid profile of the predominantly Hispanic population of non-insulin-dependent diabetes mellitus (NIDDM) patients in San Antonio, Texas. A prospective, double-blind, placebo-controlled, crossover study was performed on 14 men and 16 women. Initially, each patient was randomly assigned to receive either chromium picolinate or placebo for 2 months. This initial treatment phase was followed by a 2-month washout period. Subjects were then crossed-over and received the alternate capsule for an additional 2 months. Fasting blood glucose, HbA1c, and serum lipids were compared at the end of each treatment phase. Twenty-eight of the originally enrolled 30 patients completed the study. There were no adverse reactions to chromium reported. There were no differences noted between the control and chromium-treated subjects in glucose control, high-density lipoprotein cholesterol levels, or low-density lipoprotein cholesterol levels. Triglyceride (TG) levels were reduced significantly (17.4%; P < 0.05) during the 2 months of chromium supplementation. Ours is the first report of a significant reduction in serum TGs in a group of NIDDM patients treated with chromium. The low cost and excellent safety profile of chromium make it an attractive lipid-lowering agent for this population. Long-term studies are needed to determine if the short-term changes in plasma lipids can be sustained.


Enhancement of antimycotic activity of amphotericin B by targeting the oxidative stress response of Candida and cryptococcus with natural dihydroxybenzaldehydes.
In addition to the fungal cellular membrane, the cellular antioxidant system can also be a viable target in the antifungal action of amphotericin B (AMB). Co-application of certain redox-potent natural compounds with AMB actually increases efficacy of the drug through chemosensitization. Some redox-potent chemosensitizers and AMB perturb common cellular targets, resulting in synergistic inhibition of fungal growth. Chemosensitizing activities of four redox-potent benzaldehydes were tested against clinical and reference strains of Candida albicans, C. krusei, C. tropicalis, and Cryptococcus neoformans in combination with AMB, based on assays outlined by the European Committee on Antimicrobial Susceptibility Testing. Two dihydroxybenzaldehydes (DHBAs), i.e., 2,3-DHBA and 2,5-DHBA, significantly enhanced activity of AMB against most strains, as measured by lower minimum inhibitory concentrations and/or minimum fungicidal concentrations (MFCs). A non-hydroxylated benzaldehyde, trans-cinnamaldehyde, showed chemosensitizing activity through lower MFCs, only. Contrastingly, a methoxylated benzaldehyde (3,5-dimethoxybenzaldehyde) had no chemosensitizing activity, as all strains were hypertolerant to this compound. Bioassays using deletion mutants of the model yeast, Saccharomyces cerevisiae, indicated DHBAs exerted their chemosensitizing activity by targeting mitochondrial superoxide dismutase. This targeting, in turn, disrupted the ability of the yeast strains to respond to AMB-induced oxidative stress. These in vitro results indicate that certain DHBAs are potent chemosensitizing agents to AMB through co-disruption of the oxidative stress response capacity of yeasts. Such redox-potent compounds show promise for enhancing AMB-based antifungal therapy for candidiasis and cryptococcosis.


Fine time course expression analysis identifies cascades of activation and repression and maps a putative regulator of mammalian sex determination.
In vertebrates, primary sex determination refers to the decision within a bipotential organ precursor to differentiate as a testis or ovary. Bifurcation of organ fate begins between embryonic day (E) 11.0-E12.0 in mice and likely involves a dynamic transcription network that is poorly understood. To elucidate the first steps of sexual fate specification, we profiled the XX and XY gonad transcriptomes at fine granularity during this period and resolved cascades of gene activation and repression. C57BL/6J (B6) XY gonads showed a consistent ~5-hour delay in the activation of most male pathway genes and repression of female pathway genes relative to 129S1/SvImJ, which likely explains the sensitivity of the B6 strain to male-to-female sex reversal. Using this fine time course data, we predicted novel regulatory genes underlying expression QTLs (eQTLs) mapped in a previous study. To test predictions, we developed an in vitro gonad primary cell assay and optimized a lentivirus-based shRNA delivery method to silence candidate genes and quantify effects on putative targets. We provide strong evidence that Lmo4 (Lim-domain only 4) is a novel regulator of sex determination upstream of SF1 (Nr5a1), Sox9, Fgf9, and Col9a3. This approach can be readily applied to identify regulatory interactions in other systems.


Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans.


Separation and enrichment of gold(III) from environmental samples prior to its flame atomic absorption spectrometric determination.
A simple and accurate method was developed for separation and enrichment of trace levels of gold in environmental samples. The method is based on the adsorption of Au(III)-diethyldithiocarbamate complex on Amberlite XAD-2000 resin prior to the analysis of gold by flame atomic absorption spectrometry after elution with 1 molL(-1) HNO3 in acetone. Some parameters including nitric acid concentration, eluent type, matrix ions, sample volume, sample flow rate and adsorption capacity were investigated on the recovery of gold(III). The recovery values for gold(III) and detection limit of gold were greater than 95% and 16.6 microgL(-1), respectively. The preconcentration factor was 200. The relative standard deviation of the method was <6%. The adsorption capacity of the resin was 12.3 mg g(-1). The validation of the presented procedure was checked by the analysis of CRM-SA-C Sandy Soil certified reference material. The presented procedure was applied to the determination of gold in some environmental samples.


Performance of Three Common Hepatitis C Virus (HCV) Genotyping Assays for Identification of HCV Genotype 2/1 Chimeras.
Besides seven major hepatitis C virus (HCV) genotypes (GT), a number of intergenotypic recombinant strains have been described. These so-called chimeras combine genetic characteristics of different HCV genotypes. However, correct genotype classification is important, as choice and duration of direct-acting antiviral (DAA) treatment is mainly based on the viral genotype. Therefore, misclassification of chimeras might lead to suboptimal treatment of patients infected with these strains. For example, 2k/1b chimeras are typically described as HCV genotype 2 strains by commercially available hybridization assays, but real-time PCR-based tests recognizing another HCV region might be more suitable for correct chimera detection. In this study, the analytic capacity of the hybridization-assay Versant HCV Genotype 2.0 (LiPA 2.0) and the real-time PCR-based-assays cobas HCV GT and Abbott RealTime HCV Genotype II were tested in a selected cohort of 230 patients infected with HCV genotype 1 (n = 53) and 2 (n = 177) and 48 patients infected with HCV 2/1 chimeric strains. While the Versant HCV Genotype 2.0 (LiPA 2.0) assay failed to identify chimeras in all of the patients (48/48, 100%), cobas HCV GT and Abbott HCV Genotype II assays identified chimeras correctly in 90% (43/48) and 65% (31/48) of the cases, respectively. In conclusion, while the hybridization-based Versant HCV Genotype 2.0 (LiPA 2.0) assay seems to be unsuitable for detection of HCV 2/1 chimeras, use of the real-time PCR-based assays cobas HCV GT and Abbott RealTime HCV Genotype II led to a higher rate of chimera detection.


Use of computed tomography to evaluate the intestinal tract of adult llamas.
In the llama, signs of colic are obscure and may be exhibited as persistent sternal recumbency and anorexia even in the presence of a surgical lesion. Diagnostic methods for evaluation of abdominal disorders are limited. As a result, surgical intervention may be prolonged and increase the risk of mortality and postoperative complications. The objective of this study was to determine the feasibility of computed tomography to evaluate the llama intestinal tract. Eighteen hours prior to the computed tomography scan, six llamas were given barium sulfate (15%) via an orogastric tube. Following induction of general anesthesia, the llamas were positioned in sternal recumbency, and 10 mm contiguous slices were obtained from the diaphragm to the tuber ischiadicum. Structures that were consistently identified included the first, second, and third compartments (C1, 2, and 3), small intestine, spiral colon, and ascending colon. C1 was easily identified in the cranial aspect of the abdomen due to its large size relative to the other compartments and characteristic saccules. C2 was located cranial, ventral, and to the right of C1, while C3 was visualized as a tubular structure to the right and ventral to C1 and C2, C3 was traced caudally until it turned dorsally and continued cranially to a dilated ampulla in the right cranial abdomen delineating the entrance to the small intestine. The spiral colon was identified consistently in the left ventral caudal abdomen. Structures that could not be conclusively identified included the cecum and mesenteric lymph nodes. Computed tomography allowed a consistent evaluation of the major intestinal structures associated with colic in the llama. Thus, computed tomography is a potentially valuable noninvasive diagnostic tool to effectively evaluate the abdominal cavity and differentiate medical from surgical lesions in the llama.


Distress and Supportive Care Needs of Ethnically Diverse Older Adults With Advanced or Recurrent Cancer.
To assess the prevalence of supportive care needs (SCNs) and distress and to describe relationships among these and patient characteristics for ethnically diverse older adults with advanced or recurrent cancer. Cross-sectional survey in five outpatient oncology clinics in an urban academic medical center involving 100 participants receiving cancer care in an economically challenged community. The supportive care framework for cancer care guided this study, and participants completed the SCN Survey Short Form 34 and the Distress Thermometer. Study variables are cancer diagnosis, gender, helping to raise children, number of comorbid diseases, race or ethnicity, treatment status, and zip code. Clinically meaningful distress was found in about a third of patients. Distress was not affected by race or ethnicity. Many ethnically diverse older patients with advanced or recurrent cancer report distress and SCNs; those with high distress are more likely to report multiple SCNs. Nursing assessment of patient SCNs and distress is integral to establishing individualized patient-centered care plans and to delivering optimal care.


The long-run poverty and gender impacts of mobile money.
Mobile money, a service that allows monetary value to be stored on a mobile phone and sent to other users via text messages, has been adopted by the vast majority of Kenyan households. We estimate that access to the Kenyan mobile money system M-PESA increased per capita consumption levels and lifted 194,000 households, or 2% of Kenyan households, out of poverty. The impacts, which are more pronounced for female-headed households, appear to be driven by changes in financial behavior-in particular, increased financial resilience and saving-and labor market outcomes, such as occupational choice, especially for women, who moved out of agriculture and into business. Mobile money has therefore increased the efficiency of the allocation of consumption over time while allowing a more efficient allocation of labor, resulting in a meaningful reduction of poverty in Kenya.


Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand?
The peroxisome proliferator-activated receptor-alpha (PPARalpha), first identified in 1990 as a member of the nuclear receptor superfamily, has a central role in the regulation of numerous target genes encoding proteins that modulate fatty acid transport and catabolism. PPARalpha is the molecular target for the widely prescribed lipid-lowering fibrate drugs and the diverse class of chemicals collectively referred to as peroxisome proliferators. The lipid-lowering function of PPARalpha occurs across a number of mammalian species, thus demonstrating the essential role of this nuclear receptor in lipid homeostasis. In contrast, prolonged administration of PPARalpha agonists causes hepatocarcinogenesis, specifically in rats and mice, indicating that PPARalpha also mediates this effect. There is no strong evidence that the low-affinity fibrate ligands are associated with cancer in humans, but it still remains a possibility that chronic activation with high-affinity ligands could be carcinogenic in humans. It is now established that the species difference between rodents and humans in response to peroxisome proliferators is due in part to PPARalpha. The cascade of molecular events leading to liver cancer in rodents involves hepatocyte proliferation and oxidative stress, but the PPARalpha target genes that mediate this response are unknown. This review focuses on the current understanding of the role of PPARalpha in hepatocarcinogenesis and identifies future research directions that should be taken to delineate the mechanisms underlying PPARalpha agonist-induced hepatocarcinogenesis.


Effect of a syphilis control programme on pregnancy outcome in Nairobi, Kenya.
To assess the impact of a syphilis control programme of pregnant women on pregnancy outcome in Kenya. Women who came to deliver to Pumwani Maternity Hospital (PMH) between April 1997 and March 1998 were tested for syphilis. Reactive rapid plasma reagin (RPR) tests were titrated and confirmed with treponema haemagglutination test (TPHA). Equal numbers of RPR and TPHA negative women were enrolled. Antenatal syphilis screening and treatment history were examined from the antenatal cards. Of 22,466 women giving birth, 12,414 (55%) were tested for syphilis. Out of these, 377 (3%) were RPR reactive of whom 296 were confirmed by TPHA. Syphilis sero-reactive women had a more risky sexual behaviour and coexistent HIV antibody positivity; 26% were HIV seropositive compared with 11% among syphilis negative mothers. The incidence of adverse obstetric outcome defined as low birth weight and stillbirth, was 9.5%. Syphilis seropositive women had a higher risk for adverse obstetric outcome (OR 4.1, 95% CI 2.4-7.2). Antenatal treatment of RPR reactive women significantly improved pregnancy outcome but the risk of adverse outcome remained 2.5-fold higher than the risk observed in uninfected mothers. These data confirm the adverse effect of syphilis on pregnancy outcome. This study also shows the efficacy of antenatal testing and prompt treatment of RPR reactive mothers on pregnancy outcome.


Scalable mode division multiplexed transmission over a 10-km ring-core fiber using high-order orbital angular momentum modes.
We propose and demonstrate a scalable mode division multiplexing scheme based on orbital angular momentum modes in ring core fibers. In this scheme, the high-order mode groups of a ring core fiber are sufficiently de-coupled by the large differential effective refractive index so that multiple-input multiple-output (MIMO) equalization is only used for crosstalk equalization within each mode group. We design and fabricate a graded-index ring core fiber that supports 5 mode groups with low inter-mode-group coupling, small intra-mode-group differential group delay, and small group velocity dispersion slope over the C-band for the high-order mode groups. We implement a two-dimensional wavelength- and mode-division multiplexed transmission experiment involving 10 wavelengths and 2 mode groups each with 4 OAM modes, transmitting 32 GBaud Nyquist QPSK signals over all 80 channels. An aggregate capacity of 5.12 Tb/s and an overall spectral efficiency of 9 bit/s/Hz over 10 km are realized, only using modular 4x4 MIMO processing with 15 taps to recover signals from the intra-mode-group mode coupling. Given the fixed number of modes in each mode group and the low inter-mode-group coupling in ring core fibres, our scheme strikes a balance in the trade-off between system capacity and digital signal processing complexity, and therefore has good potential for capacity upscaling at an expense of only modularly increasing the number of mode-groups with fixed-size (4x4) MIMO blocks.


Oxygenation of spontaneous canine tumors during fractionated radiation therapy.
Tumor oxygenation predicts treatment outcome, and reoxygenation is considered important in the efficacy of fractionated radiation therapy. Therefore, the purpose of this study was to document the changes of the oxygenation status in spontaneous canine tumors during fractionated radiation therapy using polarographic needle electrodes. Tumor oxygen partial pressure (pO(2)) measurements were performed with the Eppendorf-pO(2)-Histograph. The measurements were done under general anesthesia, and probe tracks were guided with ultrasound. pO(2) was measured before radiation therapy in all dogs. In patients treated with curative intent, measurements were done sequentially up to eight times (total dose: 45-59.5 Gy). Oxygenation status of the palliative patient group was examined before each fraction of radiation therapy up to five times (total dose: 24-30 Gy). 15/26 tumors had a pretreatment median pO(2) < or = 10 mmHg. The pO(2) values appeared to be quite variable in individual tumors during fractionated radiation therapy. The pO(2) of initially hypoxic tumors (pretreatment median pO(2) < or = 10 mmHg) remained unchanged during fractionated radiotherapy, whereas in initially normoxic tumors the pO(2) decreased. Hypoxia is common in spontaneous canine tumors, as 57.7% of the recorded values were < or = 10 mmHg. The data of this study showed that initially hypoxic tumors remained hypoxic, whereas normoxic tumors became more hypoxic.


Curcumin: from ancient medicine to current clinical trials.
Curcumin is the active ingredient in the traditional herbal remedy and dietary spice turmeric (Curcuma longa). Curcumin has a surprisingly wide range of beneficial properties, including anti-inflammatory, antioxidant, chemopreventive and chemotherapeutic activity. The pleiotropic activities of curcumin derive from its complex chemistry as well as its ability to influence multiple signaling pathways, including survival pathways such as those regulated by NF-kappaB, Akt, and growth factors; cytoprotective pathways dependent on Nrf2; and metastatic and angiogenic pathways. Curcumin is a free radical scavenger and hydrogen donor, and exhibits both pro- and antioxidant activity. It also binds metals, particularly iron and copper, and can function as an iron chelator. Curcumin is remarkably non-toxic and exhibits limited bioavailability. Curcumin exhibits great promise as a therapeutic agent, and is currently in human clinical trials for a variety of conditions, including multiple myeloma, pancreatic cancer, myelodysplastic syndromes, colon cancer, psoriasis and Alzheimer's disease.


Hydrogen sulfide: metabolism, biological and medical role.
Hydrogen sulfide (H2S) is a signaling molecule that is actively synthesized in the tissues and is involved in the regulation of vascular tone, neuromodulation, cytoprotection, inflammation and apoptosis. In recent years, new data on animal and human H2S metabolism and function under the effect of various endogenous and exogenous factors, including drugs were collected. This review is provided to introduce generalized information about the main and alternative H2S metabolism and regulation, peculiarities of transport, signaling, biological role and participation in pathogenesis. Submitted data describe H2S content and activity of H2S-synthesizing enzymes in different organs, H2S effect on blood coagulation and platelet aggregation based on our research results. The working classification of H2S metabolism modulators, which are used in biology and medicine, is proposed: 1) agents that increase H2S content in tissues (inorganic and organic H2S donors; H2S-synthesizing enzymes substrates and their derivatives, H2S-releasing drugs; agents that contain H2S-synthesizing enzymes cofactors and activators, agents that inhibit H2S utilization); 2) agents that reduce H2S content in tissues (specific and nonspecific inhibitors of H2S-synthesizing enzymes), 3) agents with uncertain impact on H2S metabolism (some medicines). It was demonstrated that vitamin-microelement and microelement complexes with H2S-synthesizing enzymes cofactors and activators represent a promising approach for H2S content correction in tissues.


Occupational airborne exposure in relation to Chronic Obstructive Pulmonary Disease (COPD) and lung function in individuals without childhood wheezing illness: A 50-year cohort study.
Evidence from longitudinal population-based studies relating occupational exposure to the full range of different forms of airborne pollutants and lung function and airway obstruction is limited. To relate self-reported COPD and lung function impairment to occupational exposure to different forms of airborne chemical pollutants in individuals who did not have childhood wheeze. A prospective cohort study was randomly selected in 1964 at age 10-15 years and followed up in 1989, 1995, 2001 and 2014 (aged 58-64) by spirometry and respiratory questionnaire. Occupational histories were recorded in 2014 and occupational exposures assigned using an airborne chemical job exposure matrix. The risk of COPD and lung function impairment was analyzed in subjects, who did not have childhood wheeze, using logistic and linear regression and linear mixed effects models. 237 subjects without childhood wheeze (mean age 60.6 years, 47% male) were analyzed. There was no association between any respiratory outcomes and exposure to gases, fibers, mists or mineral dusts and no consistent associations with exposure to fumes. Reduced FEV1 was associated with longer duration (years) of exposure to any of the six main pollutant forms - vapors, gases, dusts, fumes, fibers and mists (VGDFFiM) with evidence of a dose-response relationship (p-trend=0.004). Exposure to biological dusts was associated with self-reported COPD and FEV1<Lower Limit of Normal (LLN) (adjusted odds ratio [95%CI] 4.59 [1.15,18.32] and 3.54 [1.21,10.35] respectively), and reduced FEF25-75% (adjusted regression coefficients [95% CIs] -9.11 [-17.38, -0.84] respectively). Exposure to vapors was associated with self-reported COPD and FEV1<LLN (adjOR 6.46 [1.18,35.37] and 4.82 [1.32,17.63]). Longitudinal analysis demonstrated reduced FEV1 and FEF25-75% associated with exposure to biological dusts or vapors. People with no history of childhood wheezing who have been occupationally exposed to biological dusts or vapors or had longer duration of lifetime exposure to any VGDFFiM are at a higher risk of reduced lung function at age 58-64 years. Occupational exposure to biological dusts or vapors also increased the risk of self-reported COPD.


Recent Smell Loss Is the Best Predictor of COVID-19 Among Individuals With Recent Respiratory Symptoms.
In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean ± SD, C19+: -82.5 ± 27.2 points; C19-: -59.8 ± 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.


The medial scaffold of 3D unorganized point clouds.
We introduce the notion of the medial scaffold, a hierarchical organization of the medial axis of a 3D shape in the form of a graph constructed from special medial curves connecting special medial points. A key advantage of the scaffold is that it captures the qualitative aspects of shape in a hierarchical and tightly condensed representation. We propose an efficient and exact method for computing the medial scaffold based on a notion of propagation along the scaffold itself, starting from initial sources of the flow and constructing the scaffold during the propagation. We examine this method specifically in the context of an unorganized cloud of points in 3D, e.g., as obtained from laser range finders, which typically involve hundreds of thousands of points, but the ideas are generalizable to data arising from geometrically described surface patches. The computational bottleneck in the propagation-based scheme is in finding the initial sources of the flow. We thus present several ideas to avoid the unnecessary consideration of pairs of points which cannot possibly form a medial point source, such as the "visibility" of a point from another given a third point and the interaction of clusters of points. An application of using the medial scaffold for the representation of point samplings of real-life objects is also illustrated.


Managing patients with indolent lymphoma treated with bendamustine: a nursing perspective.
Indolent lymphoma is one of the most frequently occurring subtypes of non-Hodgkin lymphoma (NHL). Indolent NHL has a long natural history, and patients will likely receive multiple therapies during the course of their disease. Treatment options are rapidly evolving and, because oncology nurses play a major role in managing patients undergoing treatment for indolent NHL, they need to be aware of the potential adverse effects associated with new therapies that may affect patients in their care. One such agent is bendamustine, which was approved by the U. S. Food and Drug Administration in 2008 for the treatment of relapsed indolent NHL. Oncology nurses are increasingly likely to encounter bendamustine either as monotherapy or in combination with rituximab. Bendamustine is a hybrid agent with both alkylating and purine analog properties, produces a high response rate in patients with indolent NHL, and has manageable side effects that include immunosuppression, gastrointestinal toxicity, and fatigue. Oncology nurses should be familiar with the common side effects so as to provide enhanced care for the patient receiving this agent. This article reviews the safety profile of bendamustine and discusses the implications from a nursing perspective.


Cardioprotection by hormetic responses to aldehyde.
Everyone encounters various stressors (causes of stress), such as psychological pressure, mental fluctuations, and physical burdens, in their everyday life. It is well accepted that the highest levels of perceived stress correlate with early onset of cardiovascular disease. Conversely, appropriate (mild to moderate) stressors, such as physical activity, have been shown to promote health. This bidirectional dose - response relationship of treatments that are beneficial at low levels but noxious at higher levels is referred to as "hormesis". In the fields of toxicology, pharmacology, radiation biology, and medicine, the significance of the biological effects of low-level exposure to various agents has attracted considerable attention. It is very important to understand how biological systems respond to low levels of stress and their implications within society. Aldehydes, the major endproducts of lipid peroxidation, have been implicated in the pathogenesis of oxidative stress-associated diseases. In addition to the pathogenic effect associated with oxidative stress, sublethal levels of aldehydes interact with signaling systems to upregulate the expression of genes to counteract the stressor challenge and to re-establish homeostasis. The present review article discusses current discoveries regarding the hormetic response to aldehyde and its clinical significance in cardioprotection.


Structure-Based Design of Highly Selective Inhibitors of the CREB Binding Protein Bromodomain.
Chemical probes are required for preclinical target validation to interrogate novel biological targets and pathways. Selective inhibitors of the CREB binding protein (CREBBP)/EP300 bromodomains are required to facilitate the elucidation of biology associated with these important epigenetic targets. Medicinal chemistry optimization that paid particular attention to physiochemical properties delivered chemical probes with desirable potency, selectivity, and permeability attributes. An important feature of the optimization process was the successful application of rational structure-based drug design to address bromodomain selectivity issues (particularly against the structurally related BRD4 protein).


Adoption of a Portal for the Primary Care Management of Pediatric Asthma: A Mixed-Methods Implementation Study.
Patient portals may improve communication between families of children with asthma and their primary care providers and improve outcomes. However, the feasibility of using portals to collect patient-reported outcomes from families and the barriers and facilitators of portal implementation across diverse pediatric primary care settings have not been established. We evaluated the feasibility of using a patient portal for pediatric asthma in primary care, its impact on management, and barriers and facilitators of implementation success. We conducted a mixed-methods implementation study in 20 practices (11 states). Using the portal, parents of children with asthma aged 6-12 years completed monthly surveys to communicate treatment concerns, treatment goals, symptom control, medication use, and side effects. We used logistic regression to evaluate the association of portal use with child characteristics and changes to asthma management. Ten clinician focus groups and 22 semistructured parent interviews explored barriers and facilitators of use in the context of an evidence-based implementation framework. We invited 9133 families to enroll and 237 (2.59%) used the portal (range by practice, 0.6%-13.6%). Children of parents or guardians who used the portal were significantly more likely than nonusers to be aged 6-9 years (vs 10-12, P=.02), have mild or moderate/severe persistent asthma (P=.009 and P=.04), have a prescription of a controller medication (P<.001), and have private insurance (P=.002). Portal users with uncontrolled asthma had significantly more medication changes and primary care asthma visits after using the portal relative to the year earlier (increases of 14% and 16%, respectively). Qualitative results revealed the importance of practice organization (coordinated workflows) as well as family (asthma severity) and innovation (facilitated communication and ease of use) characteristics for implementation success. Although use was associated with higher treatment engagement, our results suggest that achieving widespread portal adoption is unlikely in the short term. Implementation efforts should include workflow redesign and prioritize enrollment of symptomatic children. Clinicaltrials.gov NCT01966068; https://clinicaltrials.gov/ct2/show/NCT01966068 (Archived by WebCite at http://www.webcitation.org/6i9iSQkm3).


Evaluation and analysis of polished fused silica subsurface quality by the nanoindenter technique.
We evaluate the subsurface quality of polished fused silica samples using the nanoindenter technique. Two kinds of samples, consisting of hundreds of nanometers and micrometers of subsurface damage layers, are fabricated by controlling the grinding and polishing processes, and the subsurface quality has been verified by the chemical etching method. Then several nanoindentation experiments are performed using the Berkovich tip to investigate the subsurface quality. Some differences are found by relative measurements in terms of the relationship between the total penetration and the peak load on the surfaces, the modulus calculated over the defined depths and from unload, and the indented morphology at a constant load near the surface collapse threshold. Finally, the capabilities of such a mechanical method for detecting subsurface flaws are discussed and analyzed.


Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders.
Animal models indicate that maternal infection during pregnancy can result in behavioral abnormalities and neuropathologies in offspring. We examined the association between maternal inpatient diagnosis with infection during pregnancy and risk of ASD in a Swedish nationwide register-based birth cohort born 1984-2007 with follow-up through 2011. In total, the sample consisted of 2,371,403 persons with 24,414 ASD cases. Infection during pregnancy was defined from ICD codes. In the sample, 903 mothers of ASD cases (3.7%) had an inpatient diagnosis of infection during pregnancy. Logistic regression models adjusted for a number of covariates yielded odds ratios indicating approximately a 30% increase in ASD risk associated with any inpatient diagnosis of infection. Timing of infection did not appear to influence risk in the total Swedish population, since elevated risk of ASD was associated with infection in all trimesters. In a subsample analysis, infections were associated with greater risk of ASD with intellectual disability than for ASD without intellectual disability. The present study adds to the growing body of evidence, encompassing both animal and human studies, that supports possible immune-mediated mechanisms underlying the etiology of ASD.


Observation of enhanced transmission for s-polarized light through a subwavelength slit.
Enhanced optical transmission (EOT) through a single aperture is usually achieved by exciting surface plasmon polaritons with periodic grooves. Surface plasmon polaritons are only excited by p-polarized incident light, i.e. with the electric field perpendicular to the direction of the grooves. The present study experimentally investigates EOT for s-polarized light. A subwavelength slit surrounded on each side by periodic grooves has been fabricated in a gold film and covered by a thin dielectric layer. The excitation of s-polarized dielectric waveguide modes inside the dielectric film strongly increases the s-polarized transmission. A 25 fold increase is measured as compared to the case without the dielectric film. Transmission measurements are compared with a coupled mode method and show good qualitative agreement. Adding a waveguide can improve light transmission through subwavelength apertures, as both s and p-polarization can be efficiently transmitted.


Young adults perinatally infected with HIV perform more poorly on measures of executive functioning and motor speed than ethnically matched healthy controls.
Perinatal HIV is associated with significant neurocognitive morbidities, but few studies have examined cognitive impact of early HIV infection on patients surviving to adulthood. The purpose of this study was to evaluate neurocognitive outcomes among a cohort of perinatally infected young adults. Individuals between the ages of 18 and 24 with perinatal infection were recruited for this cross-sectional study along with similarly aged healthy controls. Participants completed an MRI and brief neuropsychological assessment battery. Multivariate analysis of covariance controlling for age, gender, race/ethnicity, and education was completed to detect differences between the HIV+ and control groups. Multivariable linear regression was performed to assess HIV-associated factors potentially impacting neuropsychological findings among the HIV+ group. Twenty-nine HIV+ young adults and 13 healthy controls were included in the study. After adjusting for age and sociodemographic variables, the HIV+ group scored lower on attention/working memory (Digit Span (p = .008) and Letter-Number Sequencing (p = .038)), set-shifting (DKEFS Trail Making Test Condition 4 (p = .026) and motor speed (DKEFS Trail Making Test Condition 5 (p = .003)). For the HIV+ group, nadir CD4 was associated with better Letter-Number Sequencing score (p = .029) and use of highly active antiretroviral therapy was associated with better performance on Category Fluency (p = .040). After controlling for sociodemographic variables, executive dysfunction persists among young adults with perinatal HIV infection in comparison to controls. Future studies to further elucidate the impact of executive dysfunction on independent living and functional outcomes are indicated.


Comparison of inpatient vs. outpatient anterior cervical discectomy and fusion: a retrospective case series.
Spinal surgery is increasingly being done in the outpatient setting. We reviewed our experience with inpatient and outpatient single-level anterior cervical discectomy and fusion with plating (ACDF+P). All patients undergoing single-level anterior cervical discectomy and fusion with plating between August 2005 and May 2007 by two surgeons (RPB or JAF) were retrospectively reviewed. All patients underwent anterior cervical microdiscectomy, arthrodesis using structural allograft, and titanium plating. A planned change from doing ACDF+P on an inpatient basis to doing ACDF+P on an outpatient basis was instituted at the midpoint of the study. There were no other changes in technique, patient selection, instrumentation, facility, or other factors. All procedures were done in full-service hospitals accommodating outpatient and inpatient care. 64 patients underwent ACDF+P as inpatients, while 45 underwent ACDF+P as outpatients. When outpatient surgery was planned, 17 patients were treated as inpatients due to medical comorbidities (14), older age (1), and patient preference (2). At a mean follow-up of 62.4 days, 90 patients had an excellent outcome, 19 patients had a good outcome, and no patients had a fair or poor outcome. There was no significant difference in outcome between inpatients and outpatients. There were 4 complications, all occurring in inpatients: a hematoma one week post-operatively requiring drainage, a cerebrospinal fluid leak treated with lumbar drainage, syncope of unknown etiology, and moderate dysphagia. In this series, outpatient ACDF+P was safe and was not associated with a significant difference in outcome compared with inpatient ACDF+P.


Randomized trial of a warfarin communication protocol for nursing homes: an SBAR-based approach.
More than 1.6 million Americans currently reside in nursing homes. As many as 12% of them receive long-term anticoagulant therapy with warfarin. Prior research has demonstrated compelling evidence of safety problems with warfarin therapy in this setting, often associated with suboptimal communication between nursing home staff and prescribing physicians. We conducted a randomized trial of a warfarin management protocol using facilitated telephone communication between nurses and physicians in 26 nursing homes in Connecticut in 2007-2008. Intervention facilities received a warfarin management communication protocol using the approach "Situation, Background, Assessment, and Recommendation" (SBAR). The protocol included an SBAR template to standardize telephone communication about residents on warfarin by requiring information about the situation triggering the call, the background, the nurse's assessment, and recommendations. There were 435 residents who received warfarin therapy during the study period for 55,167 resident days in the intervention homes and 53,601 in control homes. In intervention homes, residents' international normalized ratio (INR) values were in the therapeutic range a statistically significant 4.50% more time than in control homes (95% confidence interval [CI], 0.31%-8.69%). There was no difference in obtaining a follow-up INR within 3 days after an INR value ≥4.5 (odds ratio 1.02; 95% CI, 0.44-2.4). Rates of preventable adverse warfarin-related events were lower in intervention homes, although this result was not statistically significant: the incident rate ratio for any preventable adverse warfarin-related event was .87 (95% CI, .54-1.4). Facilitated telephone communication between nurses and physicians using the SBAR approach modestly improves the quality of warfarin management for nursing home residents.


Formation of binucleated cardiac myocytes in rat heart: II. Cytoskeletal organisation.
Neonatal cardiac myocytes continue to undergo nuclear division, but lose their ability to complete cell division between 3 and 4 days of age. To examine cytoskeletal organisation of cardiac myocytes during mitosis, freshly isolated cardiac myocytes from 2-, 4-, 6- and 8-day-old rats were fixed and labeled with anti-tubulin, vinculin, desmin and sarcomeric alpha-actinin antibodies. The central, nuclear region of cardiac myocytes is expanded to form a balloon-like structure when they entered prophase. The organisation of microtubules, vinculin and desmin in mitotic myocytes from 4-, 6- and 8-day-old rats was identical to that in dividing myocytes from 2-day-old animals. Microtubules emanating from the nuclear membrane mainly ran along the longitudinal axis of cardiac myocytes in interphase. Microtubules were disassembled and reorganised into the mitotic spindle during mitosis. Desmin was disassembled, either diffusely distributed in the cytoplasm or formed spotty cytoplasmic aggregates during mitosis. Vinculin was disassembled in prometaphase, diffusely distributed in the cytoplasm and associated with cell membranes. During telophase it concentrated in the equator of mitotic spindles. Sarcomeric alpha-actinin became dispersed in the cytoplasm of mitotic myocytes from 2-day-old rats in prometaphase. It remained diffusely distributed in the cytoplasm and associated with cell membranes until the completion of cytokinesis. However, sarcomeric alpha-actinin was only partially disassembled in 4-, 6- and 8-day-old myocytes. Striations of alpha-actinin with full sarcomere length were observed in the cytoplasm as well as in the region of furrow formation. Thus, incomplete disassembly and presence of myofibrils in the equator region where cleavage furrows from may physically impede the furrowing of sarcolemma driven by the contractile ring, resulting in the formation of binucleated cardiac myocytes.


Bacteria tracking by in vivo magnetic resonance imaging.
Different non-invasive real-time imaging techniques have been developed over the last decades to study bacterial pathogenic mechanisms in mouse models by following infections over a time course. In vivo investigations of bacterial infections previously relied mostly on bioluminescence imaging (BLI), which is able to localize metabolically active bacteria, but provides no data on the status of the involved organs in the infected host organism. In this study we established an in vivo imaging platform by magnetic resonance imaging (MRI) for tracking bacteria in mouse models of infection to study infection biology of clinically relevant bacteria. We have developed a method to label Gram-positive and Gram-negative bacteria with iron oxide nano particles and detected and pursued these with MRI. The key step for successful labeling was to manipulate the bacterial surface charge by producing electro-competent cells enabling charge interactions between the iron particles and the cell wall. Different particle sizes and coatings were tested for their ability to attach to the cell wall and possible labeling mechanisms were elaborated by comparing Gram-positive and -negative bacterial characteristics. With 5-nm citrate-coated particles an iron load of 0.015 ± 0.002 pg Fe/bacterial cell was achieved for Staphylococcus aureus. In both a subcutaneous and a systemic infection model induced by iron-labeled S. aureus bacteria, high resolution MR images allowed for bacterial tracking and provided information on the morphology of organs and the inflammatory response. Labeled with iron oxide particles, in vivo detection of small S. aureus colonies in infection models is feasible by MRI and provides a versatile tool to follow bacterial infections in vivo. The established cell labeling strategy can easily be transferred to other bacterial species and thus provides a conceptual advance in the field of molecular MRI.


Inadequate Enoxaparin Dosing Predicts 90-Day Venous Thromboembolism Risk among Plastic Surgery Inpatients: An Examination of Enoxaparin Pharmacodynamics.
Evidence-based plastic surgery guidelines support the effectiveness of once-daily enoxaparin prophylaxis. Despite prophylaxis, one in 25 highest risk patients has a venous thromboembolism event. The authors examined the pharmacodynamics of standard enoxaparin doses in plastic surgery patients to examine whether patient-level factors predict enoxaparin metabolism, whether inadequate enoxaparin dose predicts downstream venous thromboembolism events, and whether a pharmacist-driven dose-adjustment protocol was effective. The authors recruited adult plastic surgery patients who received postoperative enoxaparin at 40 mg/day. Steady-state peak anti-factor Xa levels, a marker of enoxaparin effectiveness and safety, were determined. Patients with out-of-range anti-factor Xa levels had real-time dose adjustment based on a written protocol. Patients were followed for 90-day venous thromboembolism events. Ninety-four patients were recruited, and 44 percent had in-range peak anti-factor Xa levels in response to standard enoxaparin dosing. Patient-level factors including extent of surgical injury and gross weight were independent predictors of enoxaparin metabolism. Patients with low anti-factor Xa levels were significantly more likely to have 90-day venous thromboembolism (10.2 percent versus 0 percent; p = 0.041). Real-time dose adjustment allowed a significantly increased proportion of patients to have in-range levels (67.1 percent versus 44.3 percent; p = 0.002). Based on pharmacodynamic data, the majority of plastic surgery patients receive inadequate enoxaparin prophylaxis using fixed dosing. Patient-level factors can predict how patients will metabolize enoxaparin, and patients who receive inadequate enoxaparin prophylaxis are significantly more likely to have downstream venous thromboembolism events. Individualization of enoxaparin prophylaxis may minimize perioperative venous thromboembolism risk and further improve patient safety after plastic and reconstructive surgery procedures. Therapeutic, II.


A crucial RNA-binding lysine residue in the Nab3 RRM domain undergoes SET1 and SET3-responsive methylation.
The Nrd1-Nab3-Sen1 (NNS) complex integrates molecular cues to direct termination of noncoding transcription in budding yeast. NNS is positively regulated by histone methylation as well as through Nrd1 binding to the initiating form of RNA PolII. These cues collaborate with Nrd1 and Nab3 binding to target RNA sequences in nascent transcripts through their RRM RNA recognition motifs. In this study, we identify nine lysine residues distributed amongst Nrd1, Nab3 and Sen1 that are methylated, suggesting novel molecular inputs for NNS regulation. We identify mono-methylation of one these residues (Nab3-K363me1) as being partly dependent on the H3K4 methyltransferase, Set1, a known regulator of NNS function. Moreover, the accumulation of Nab3-K363me1 is essentially abolished in strains lacking SET3, a SET domain containing protein that is positively regulated by H3K4 methylation. Nab3-K363 resides within its RRM and physically contacts target RNA. Mutation of Nab3-K363 to arginine (Nab3-K363R) decreases RNA binding of the Nab3 RRM in vitro and causes transcription termination defects and slow growth. These findings identify SET3 as a potential contextual regulator of Nab3 function through its role in methylation of Nab3-K363. Consistent with this hypothesis, we report that SET3 exhibits genetic activation of NAB3 that is observed in a sensitized context.


Optimization of an off-axis three-mirror anastigmatic system with wavefront coding technology based on MTF invariance.
In this paper the invariance of modulation transfer function (MTF), which describes the insensitivity to perturbation of MTF, is defined to be the evaluating criterion of the wavefront coding system. The rapid optimization of wavefront coding system based on the MTF invariance is proposed by means of introducing the mathematical program Matlab to normal optical design process. The interface called MZDDE between Matlab and Zemax is applied to realize the fast data exchanging and merit function calculating. The genetic algorithm tool (GA) in Matlab is introduced to the optimizing process, which accelerates the converging efficiency considerably. The MTF invariance of optimized system drops to 0.0119 while that of original system is larger than 0.018. If the all the fields of view is taken into consideration, the MTF invariance of optimized system and original system is less than 0.015 and larger than 0.020 respectively. It is proven that the optimization of the unusual optical system with special property can be executed conveniently and rapidly with the help of external program and dynamic data exchange.


Coordinated patterns of cytochrome bd and lactate dehydrogenase expression in Bacillus subtilis.
A variety of pathways for electron and carbon flow in the soil bacterium Bacillus subtilis are differentially expressed depending on whether oxygen is present in the cell environment. This study characterizes the regulation of the respiratory oxidase cytochrome bd and the NADH-linked fermentative lactate dehydrogenase (LDH). Transcription of the cydABCD operon, encoding cytochrome bd, is highly regulated and only becomes activated at low oxygen availability. This induction is not dependent on the gene encoding the redox regulator Fnr or the genes encoding the ResDE two-component regulatory system. The DNA-binding protein YdiH was found to be a principal regulator that controls cydABCD expression. Transcription from the cyd promoter is stimulated 15-fold by a region located upstream of the core promoter. The upstream region may constitute a binding site for an unidentified transcription activator that is likely to influence the level of transcription but not its timing, which is negatively controlled by YdiH. This report provides evidence that YdiH also functions as a repressor of the ldh gene encoding LDH and of a gene, ywcJ, which encodes a putative formate-nitrite transporter. Based on the similarity between YdiH and the Rex protein of Streptomyces coelicolor, it is proposed that YdiH serves as a redox sensor, the activity of which is regulated by cellular differences in the free levels of NAD+ and NADH. It is suggested that ydiH be renamed as rex.


Sickling of red blood cells through rapid oxygen exchange in microfluidic drops.
We have developed a microfluidic approach to study the sickling of red blood cells associated with sickle cell anemia by rapidly varying the oxygen partial pressure within flowing microdroplets. By using the perfluorinated carrier oil as a sink or source of oxygen, the oxygen level within the water droplets quickly equilibrates through exchange with the surrounding oil. This provides control over the oxygen partial pressure within an aqueous drop ranging from 1 kPa to ambient partial pressure, i.e. 21 kPa. The dynamics of the oxygen exchange is characterized through fluorescence lifetime measurements of a ruthenium compound dissolved in the aqueous phase. The gas exchange is shown to occur primarily during and directly after droplet formation, in 0.1 to 0.5 s depending on the droplet diameter and speed. The controlled deoxygenation is used to trigger the polymerization of hemoglobin within sickle red blood cells, encapsulated in drops. This process is observed using polarization microscopy, which yields a robust criterion to detect polymerization based on transmitted light intensity through crossed polarizers.


Conveying shape with texture: experimental investigations of texture's effects on shape categorization judgments.
In this paper, we describe the results of two comprehensive controlled observer experiments intended to yield insight into the following question: If we could design the ideal texture pattern to apply to an arbitrary smoothly curving surface in order to enable its 3D shape to be most accurately and effectively perceived, what would the characteristics of that texture pattern be? We begin by reviewing the results of our initial study in this series, which were presented at the 2003 IEEE Symposium on Information Visualization, and offer an expanded analysis of those findings. We continue by presenting the results of a follow-on study in which we sought to more specifically investigate the separate and combined influences on shape perception of particular texture components, with the goal of obtaining a clearer view of their potential information carrying capacities. In each study, we investigated the observers' ability to identify the intrinsic shape category of a surface patch (elliptical, hyperbolic, cylindrical, or flat) and its extrinsic surface orientation (convex, concave, both, or neither). In our first study, we compared performance under eight different texture type conditions, plus two projection conditions (perspective or orthographic) and two viewing conditions (head-on or oblique). In this study, we found that: 1) Shape perception was better facilitated, in general, by the bidirectional "principal direction grid" pattern than by any of the seven other patterns tested; 2) shape type classification accuracy remained high under the orthographic projection condition for some texture types when the viewpoint was oblique; 3) perspective projection was required for accurate surface orientation classification; and 4) shape classification accuracy was higher when the surface patches were oriented at a (generic) oblique angle to the line of sight than when they were oriented (in a nongeneric pose) to face the viewpoint straight on. In our second study, we compared performance under eight new texture type conditions, redesigned to facilitate gathering insight into the cumulative effects of specific individual directional components in a wider variety of multidirectional texture patterns. In this follow-on study, we found that shape classification accuracy was equivalently good under a variety of test patterns that included components following either the first or first and second principal directions, in addition to other directions, suggesting that a principal direction grid texture is not the only possible "best option" for enhancing shape representation.


Immediate virological response predicts the success of short-term peg-interferon monotherapy for chronic hepatitis C.
To investigate the efficacy of short-term peg-interferon (PEG-IFN) monotherapy for chronic hepatitis C patients who achieved an immediate virological response. Defining an "immediate virological response (IVR)" as the loss of serum hepatitis C virus (HCV) RNA 7 d after the first administration of PEG-IFN alpha, we conducted a 12-wk course of PEG-IFN alpha2a monotherapy without the addition of ribavirin for 38 patients who had low pretreatment HCV RNA load and exhibited IVR. The patients included 21 men and 17 women, whose ages ranged from 22 to 77 years (mean +/- SD: 52.0 +/- 17.8 years). There were 4 patients with HCV genotype 1b, 23 patients with genotype 2a and 4 patients with genotype 2b. HCV genotype was not determined for the remaining 7 patients. Patients were categorized into a sustained virological response (SVR) group, if serum HCV RNA remained negative for 24 wk after the end of treatment, or into a relapse group. Based on the intention-to-treat analysis, 35 patients (92.1%) achieved SVR. One patient (2.6%) relapsed with serum HCV RNA 12 wk after the end of treatment. Two patients (5.3%) withdrew from the study during the 24-wk follow-up period. With regard to the HCV RNA genotype, the SVR rates were 100% (4/4) for genotype 1b, 95.7% (22/23) for genotype 2a and 100% (4/4) for genotype 2b. The SVR rate in 7 patients, whose HCV RNA genotypes were not determined, was 71.4% (5/7). Short-term PEG-IFN alpha2a monotherapy is highly effective for chronic hepatitis C patients who have low pretreatment HCV RNA load and exhibit IVR.


[Present Status of Displaying Pharmaceutical Products for Sale on Flea Market Applications for Smartphones and the Responses to Illicit Selling by Service Providers].
In Japan, a pharmacy or drug store license is required for selling pharmaceutical products. However, civilians without a pharmacy or drug store license are displaying pharmaceutical products for sale on a flea market application, which is illegal dealing. This study discussed the modality for implementing countermeasures for the illicit selling of pharmaceutical products. We extracted pharmaceutical products displayed for sale on three flea market applications (Mercari, Rakuma, Fril) on one day. One hundred and eighty-one pharmaceutical products were displayed (49 on Mercari, 86 on Rakuma, and 46 on Fril). There were 6.1% (11/181) domestically prescribed drugs, 69.1% (125/181) domestic OTC drugs, 23.8% (43/181) foreign-made prescribed drugs, and 1.1% (2/181) foreign-made OTC drugs. The seller could display the product for sale without confirming whether it is prohibited. We alerted the service providers of this illicit selling at flea markets at three different instances. The pharmaceutical product displays were deleted by the service providers at a rate of 55.1% (27/49) for Mercari and 51.2% (44/86) for Rakuma. The average number of drugs that were displayed for sale by each seller was 1.4 and the average number of total products that were displayed for sale by each seller was 100. The seller could have unintentionally displayed the pharmaceutical products for sale, without the knowledge that it is illegal. The service providers of flea market applications should create mechanisms to alert the sellers that displaying pharmaceutical products for sale is an illicit act and regulate these violations.


Utilization of Transtibial Centralization Suture Best Minimizes Extrusion and Restores Tibiofemoral Contact Mechanics for Anatomic Medial Meniscal Root Repairs in a Cadaveric Model.
Although posterior medial meniscal root (PMMR) repairs are often successful, postoperative meniscal extrusion after a root repair has been identified as a potential clinical problem. The purpose was to quantitatively evaluate the tibiofemoral contact mechanics and extent of meniscal extrusion after a PMMR repair. It was hypothesized that the addition of a centralization suture (into the posterior medial tibial plateau) would help restore normal joint load-bearing characteristics and restore the native amount of meniscal extrusion after a root tear. Furthermore, we hypothesized that the amount of meniscal extrusion would be greatest in loaded and flexed knees when measured at the posterior border of the medial collateral ligament (MCL). Controlled laboratory study. Meniscal extrusion and tibiofemoral contact mechanics were measured using 3-dimensional digitization and pressure sensors in 10 nonpaired, human cadaveric knees. The PMMR of each knee was tested under 6 states: (1) intact; (2) type 2A PMMR tear; (3) anatomic transtibial pull-out root repair; (4) anatomic transtibial pull-out repair with centralization; (5) nonanatomic transtibial pull-out repair; and (6) nonanatomic transtibial pull-out repair with centralization, with randomization of the order of conditions 3 and 4, and 5 and 6. The testing protocol loaded knees with a 1000-N axial compressive force at 4 flexion angles (0°, 30°, 60°, 90°) in each state. Meniscal extrusion was measured with a 3-dimensional coordinate digitizer at 0° and 90° in both the loaded and unloaded states and calculated from the difference from the articular margin of the tibia to the periphery of the meniscus. Peak contact pressure, contact area, and total contact pressure were also recorded for all states at all flexion angles. Statistical analysis investigated the independent effects of flexion, state, and loading using 3 distinct 2-factor models. Differences in the contact mechanics between repair techniques were most notable at higher flexion angles, demonstrating significantly higher average and peak contact pressures for nonanatomic repair states when compared with anatomic repairs with and without centralization (all P < .05). In unloaded knees at full extension, the magnitude of medial meniscal extrusion was significantly higher at the posterior border of the MCL compared with the posterior medial tibia ( P < .001) and adjacent to the root attachment on the tibia locations ( P < .001). Both anatomic repair states had no significant difference in the degree of extrusion when compared with the intact state. The anatomic transtibial pull-out root repair and the anatomic transtibial pull-out root repair with centralization techniques best restored contact mechanics of the knee and meniscal extrusion when compared with root tear and nonanatomic repair states at time zero. There were no significant differences in contact pressure or magnitude of extrusion between the anatomic repair state and the anatomic repair with centralization state. We found that extrusion is best measured in the coronal plane at the posterior border of the MCL for unloaded knees. However, the degree of extrusion increased as the knee was loaded and flexed to 90°. When there are concerns about meniscal extrusion with a medial meniscal root repair, the addition of a centralization suture may be beneficial for patients in reducing pathologic meniscal extrusion and restoring joint contact mechanics.


Dysfunction of parvalbumin neurons in the cerebellar nuclei produces an action tremor.
Essential tremor is a common brain disorder affecting millions of people, yet the neuronal mechanisms underlying this prevalent disease remain elusive. Here, we showed that conditional deletion of synaptotagmin-2, the fastest Ca2+ sensor for synaptic neurotransmitter release, from parvalbumin neurons in mice caused an action tremor syndrome resembling the core symptom of essential tremor patients. Combining brain region-specific and cell type-specific genetic manipulation methods, we found that deletion of synaptotagmin-2 from excitatory parvalbumin-positive neurons in cerebellar nuclei was sufficient to generate an action tremor. The synaptotagmin-2 deletion converted synchronous into asynchronous neurotransmitter release in projections from cerebellar nuclei neurons onto gigantocellular reticular nucleus neurons, which might produce an action tremor by causing signal oscillations during movement. The tremor was rescued by completely blocking synaptic transmission with tetanus toxin in cerebellar nuclei, which also reversed the tremor phenotype in the traditional harmaline-induced essential tremor model. Using a promising animal model for action tremor, our results thus characterized a synaptic circuit mechanism that may underlie the prevalent essential tremor disorder.


An exploratory GIS-based method to identify and characterise landscapes with an elevated epidemiological risk of Rhodesian human African trypanosomiasis.
Specific land cover types and activities have been correlated with Trypanosoma brucei rhodesiense distributions, indicating the importance of landscape for epidemiological risk. However, methods proposed to identify specific areas with elevated epidemiological risk (i.e. where transmission is more likely to occur) tend to be costly and time consuming. This paper proposes an exploratory spatial analysis using geo-referenced human African trypanosomiasis (HAT) cases and matched controls from Serere hospital, Uganda (December 1998 to November 2002) to identify areas with an elevated epidemiological risk of HAT. Buffers 3 km from each case and control were used to represent areas in which village inhabitants would carry out their daily activities. It was hypothesised that the selection of areas where several case village buffers overlapped would enable the identification of locations with increased risk of HAT transmission, as these areas were more likely to be frequented by HAT cases in several surrounding villages. The landscape within these overlap areas should more closely relate to the environment in which transmission occurs as opposed to using the full buffer areas. The analysis was carried out for each of four annual periods, for both cases and controls, using a series of threshold values (number of overlapping buffers), including a threshold of one, which represented the benchmark (e.g. use of the full buffer area as opposed to the overlap areas). A greater proportion of the overlap areas for cases consisted of seasonally flooding grassland and lake fringe swamp, than the control overlap areas, correlating well with the preferred habitat of the predominant tsetse species within the study area (Glossina fuscipes fuscipes). The use of overlap areas also resulted in a greater difference between case and control landscapes, when compared with the benchmark (using the full buffer area). These results indicate that the overlap analysis has enabled the selection of areas more likely to represent epidemiological risk zones than similar analyses using full buffer areas. The identification of potential epidemiological risk zones using this method requires fewer data than other proposed methods and further development may provide vital information for the targeting of control measures.


Representing multiple object weights: competing priors and sensorimotor memories.
When lifting an object, individuals scale lifting forces based on long-term priors relating external object properties (such as material and size) to object weight. When experiencing objects that are poorly predicted by priors, people rapidly form and update sensorimotor memories that can be used to predict an object's atypical size-weight relation in support of predictively scaling lift forces. With extensive experience in lifting such objects, long-term priors, assessed with weight judgments, are gradually updated. The aim of the present study was to understand the formation and updating of these memory processes. Participants lifted, over multiple days, a set of black cubes with a normal size-weight mapping and green cubes with an inverse size-weight mapping. Sensorimotor memory was assessed with lifting forces, and priors associated with the black and green cubes were assessed with the size-weight illusion (SWI). Interference was observed in terms of adaptation of the SWI, indicating that priors were not independently adjusted. Half of the participants rapidly learned to scale lift forces appropriately, whereas reduced learning was observed in the others, suggesting that individual differences may be affecting sensorimotor memory abilities. A follow-up experiment showed that lifting forces are not accurately scaled to objects when concurrently performing a visuomotor association task, suggesting that sensorimotor memory formation involves cognitive resources to instantiate the mapping between object identity and weight, potentially explaining the results of experiment 1 These results provide novel insight into the formation and updating of sensorimotor memories and provide support for the independent adjustment of sensorimotor memory and priors.


Detection of methylation of the promoter region of the MAL and CADM1 genes by pyrosequencing in cervical carcinoma.
Cervical cancer is the second most common cancer disease affecting the female population. A key factor in development of the disease is the human papillomavirus infection (HPV). The disease is also impacted by epigenetic changes such as DNA methylation, which causes activation or exclusion of certain genes, and simultaneously the hypermethylation of cytosines in the promoters and turn-off of previously active genes occur. In this study, we focused on the introduction of pyrosequencing for the detection of DNA methylation of the selected CADM1 and MAL genes. DNA was isolated from cytological cervical smear of patients with different types of dysplasia [L-SIL (n=14), ASC-US (n=15), H-SIL (n=1)] and four control samples from healthy women. Prepared samples were further analyzed by bisulfite conversion and subsequent pyrosequencing (Pyromark Q96 ID, Qiagen, Germany). We examined the extent of methylation of CpG islands and as control samples of this method we used a fully methylated and unmethylated DNA. Methylation level (Met level) from each sample was quantified as the mean value [sum of all methylated CpG islands in %/total number of CpG islands (MAL n=4; CADM1 n=3)]. In total, 30 clinical samples and 4 control samples from healthy women were analyzed. By means of the analysis of the CADM1promoter region, the values of the Met level were obtained [fully methylated DNA (94.83 and 88); completely unmethylated DNA (0 and 0); and control samples from healthy patients (6.825 and 0.825), L-SIL (2.107 and 2.778), ASC-US (7.313 and 3.626), H-SIL (0 and 0)]. By means of the analysis of the MAL promoter region, the values of Met level were obtained [fully methylated DNA (53.25); completely unmethylated DNA (0.875); and control samples from healthy patients (2.925), L-SIL (1.517), ASC-US (2.833), and H-SIL (4)]. We introduced a pyrosequencing method for quantification of methylation of CADM1, MAL promoter regions, and detected methylations in clinical samples and also some basal methylation in healthy women.


Caring for high-need, high-cost patients: what makes for a successful care management program?
Provider groups taking on risk for the overall costs of care in accountable care organizations are developing care management programs to improve care and thereby control costs. Many such programs target "high-need, high-cost" patients: those with multiple or complex conditions, often combined with behavioral health problems or socioeconomic challenges. In this study we compared the operational approaches of 18 successful complex care management programs in order to offer guidance to providers, payers, and policymakers on best practices for complex care management. We found that effective programs customize their approach to their local contexts and caseloads; use a combination of qualitative and quantitative methods to identify patients; consider care coordination one of their key roles; focus on building trusting relationships with patients as well as their primary care providers; match team composition and interventions to patient needs; offer specialized training for team members; and use technology to bolster their efforts.


Transcranial magnetic stimulation for auditory hallucinations in schizophrenia.
It has been suggested that low frequency transcranial magnetic stimulation (TMS) over left temporo-parietal cortex may reduce the frequency and intensity of auditory hallucinations in schizophrenia. Sixteen patients with hallucinations, treatment-resistant for at least 2 months, were randomised into a placebo-controlled crossover study of TMS at 1 Hz and 80% of motor threshold over left temporo-parietal cortex. Treatment periods lasted for 4 days, with daily duration escalating from 4 to 8, 12 and 16 min on subsequent days. Each minute of stimulation was followed by 15 s of rest to check coil position and allow the patient to move, if necessary. Both patients and symptom raters were unaware of the treatment condition. Patients' hallucination scores improved from baseline with both real and sham TMS, and there was no significant difference between real and sham treatments. There was a trend for second treatments, whether sham or real, to be more effective than first treatments. Other psychopathology scales (apart from positive symptoms) and verbal memory were not affected by real or sham TMS. Previous positive studies could not be replicated with these parameters. TMS is safe if applied within the protocol used.


Lamotrigine in breast milk and nursing infants: determination of exposure.
Although lamotrigine use during pregnancy has substantially increased over the past decade secondary to accumulated reproductive safety data, systematic data on lamotrigine during breastfeeding remains sparse. We sought to characterize the determinants of lamotrigine concentrations in breast milk and nursing-infant plasma. Women who enrolled in a prospective investigation of perinatal medication pharmacokinetics, were treated with lamotrigine, and chose to continue lamotrigine while breastfeeding were included in the analysis. Breast milk samples were collected via breast pump from foremilk to hindmilk from a single breast to determine the excretion gradient and serial samples over 24 hours to determine the time course of excretion. Paired maternal/infant plasma samples were also collected. Lamotrigine concentrations in all of the samples were determined by using high-performance liquid chromatography with ultraviolet detection. Statistical analyses of breast milk and infant plasma concentrations and their determinants were conducted. Thirty women and their nursing infants participated in the study, providing a total of 210 breast milk samples. The mean milk/plasma ratio was 41.3%. There was a nonsignificant trend for higher lamotrigine concentrations in breast milk 4 hours after the maternal dose. Infant plasma concentrations were 18.3% of maternal plasma concentrations. The theoretical infant lamotrigine dose was 0.51 mg/kg per day, and the relative infant lamotrigine dose was 9.2%. Mild thrombocytosis was present in 7 of 8 infants at the time of serum sampling. No other adverse events were observed or reported in the breastfed infants. Consistent with previous investigations of medications in breast milk, the lamotrigine milk/plasma ratio is highly variable. The rate of lamotrigine excretion into human breast milk is similar to that observed with other antiepileptic drugs. These data expand the extant literature on lamotrigine in breastfeeding and demonstrate relatively comparable nursing-infant exposure to lamotrigine compared with other antiepileptic drugs.


Function of histone deacetylase 6 as a cofactor of nuclear receptor coregulator LCoR.
Ligand-dependent corepressor LCoR was identified as a protein that interacts with the estrogen receptor alpha (ERalpha) ligand binding domain in a hormone-dependent manner. LCoR also interacts directly with histone deacetylase 3 (HDAC3) and HDAC6. Notably, HDAC6 has emerged as a marker of breast cancer prognosis. However, although HDAC3 is nuclear, HDAC6 is cytoplasmic in many cells. We found that HDAC6 is partially nuclear in estrogen-responsive MCF7 cells, colocalizes with LCoR, represses transactivation of estrogen-inducible reporter genes, and augments corepression by LCoR. In contrast, no repression was observed upon HDAC6 expression in COS7 cells, where it is exclusively cytoplasmic. LCoR binds to HDAC6 in vitro via a central domain, and repression by LCoR mutants lacking this domain was attenuated. Kinetic chromatin immunoprecipitation assays revealed hormone-dependent recruitment of LCoR to promoters of ERalpha-induced target genes in synchrony with ERalpha. HDAC6 was also recruited to these promoters, and repeat chromatin immunoprecipitation experiments confirmed the corecruitment of LCoR with ERalpha and with HDAC6. Remarkably, however, although we find evidence for corecruitment of LCoR and ERalpha on genes repressed by the receptor, LCoR and HDAC6 failed to coimmunoprecipitate, suggesting that they are part of distinct complexes on these genes. Although small interfering RNA-mediated knockdown of LCoR or HDAC6 augmented expression of an estrogen-sensitive reporter gene in MCF7 cells, unexpectedly their ablation led to reduced expression of some endogenous estrogen target genes. Taken together, these data establish that HDAC6 can function as a cofactor of LCoR but suggest that they may act in enhance expressing some target genes.


Female promiscuity promotes the evolution of faster sperm in cichlid fishes.
Sperm competition, the contest among ejaculates from rival males to fertilize ova of a female, is a common and powerful evolutionary force influencing ejaculate traits. During competitive interactions between ejaculates, longer and faster spermatozoa are expected to have an edge; however, to date, there has been mixed support for this key prediction from sperm competition theory. Here, we use the spectacular radiation of cichlid fishes from Lake Tanganyika to examine sperm characteristics in 29 closely related species. We provide phylogenetically robust evidence that species experiencing greater levels of sperm competition have faster-swimming sperm. We also show that sperm competition selects for increases in the number, size, and longevity of spermatozoa in the ejaculate of a male, and, contrary to expectations from theory, we find no evidence of trade-offs among sperm traits in an interspecific analysis. Also, sperm swimming speed is positively correlated with sperm length among, but not within, species. These different responses to sperm competition at intra- and interspecific levels provide a simple, powerful explanation for equivocal results from previous studies. Using phylogenetic analyses, we also reconstructed the probable evolutionary route of trait evolution in this taxon, and show that, in response to increases in the magnitude of sperm competition, the evolution of sperm traits in this clade began with the evolution of faster (thus, more competitive) sperm.


Stratonovich-to-Itô transition in noisy systems with multiplicative feedback.
Intrinsically noisy mechanisms drive most physical, biological and economic phenomena. Frequently, the system's state influences the driving noise intensity (multiplicative feedback). These phenomena are often modelled using stochastic differential equations, which can be interpreted according to various conventions (for example, Itô calculus and Stratonovich calculus), leading to qualitatively different solutions. Thus, a stochastic differential equation-convention pair must be determined from the available experimental data before being able to predict the system's behaviour under new conditions. Here we experimentally demonstrate that the convention for a given system may vary with the operational conditions: we show that a noisy electric circuit shifts from obeying Stratonovich calculus to obeying Itô calculus. We track such a transition to the underlying dynamics of the system and, in particular, to the ratio between the driving noise correlation time and the feedback delay time. We discuss possible implications of our conclusions, supported by numerics, for biology and economics.


Neuropsychiatric considerations in the use of electroconvulsive therapy.
ECT is an effective and rapidly acting treatment for certain major psychiatric disorders, even in patients with neurologic illness. Further, in some cases the neurologic illness itself also responds to ECT. Patients with some types of neurologic illness may be at increased risk of neurologic or cognitive side effects from ECT, but these risks can be lowered by careful pre-ECT evaluation and optimal ECT technique.


Uptake of prevention of mother-to-child-transmission using Option B+ in northern rural Malawi: a retrospective cohort study.
To identify points of dropout on the pathway from offering HIV testing to maintenance on antiretroviral therapy (ART), following the introduction of the Option B+ policy for pregnant women in Malawi (lifelong ART for HIV-positive mothers and 6 weeks nevirapine for the infants), a retrospective cohort study within a demographic surveillance system in northern Malawi. Women living in the demographic surveillance system who initiated antenatal care (ANC) between July 2011 (date of policy change) and January 2013, were eligible for inclusion. Women who consented were interviewed at home about their health facility attendance and care since pregnancy, including antenatal clinic (ANC) visits, delivery and postpartum care. Women's reports, patient-held health records and clinic health records were manually linked to ascertain service use. Among 395 women, 86% had tested for HIV before the pregnancy, 90% tested or re-tested at the ANC visit, and <1% had never tested. Among 53 mothers known to be HIV-positive before attending ANC, 15 (28%) were already on ART prior to pregnancy. Ten women tested HIV-positive for the first time during pregnancy. Of the 47 HIV-positive mothers not already on ART, 26/47 (55%) started treatment during pregnancy. All but five women who started ART were still on treatment at the time of study interview. HIV testing was almost universal and most women who initiated ART were retained in care. However, nearly half of eligible pregnant women not on ART at the start of ANC had not taken up the invitation to initiate (lifelong) ART by the time of delivery, leaving their infants potentially HIV-exposed.


Targeted and immune therapies for hepatocellular carcinoma: Predictions for 2019 and beyond.
Systemic therapy for hepatocellular carcinoma (HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However, development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1st line and 2nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed. On the other hand, clinical trials of 4 agents (regorafenib, lenvatinib, cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible (regorafenib and lenvatinib) or underway (cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization (TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib (TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early, intermediate and advanced stage, is expected to be changed drastically in the very near future.


Conversion of array-based single nucleotide polymorphic markers for use in targeted genotyping by sequencing in hexaploid wheat (Triticum aestivum).
Wheat breeders and academics alike use single nucleotide polymorphisms (SNPs) as molecular markers to characterize regions of interest within the hexaploid wheat genome. A number of SNP-based genotyping platforms are available, and their utility depends upon factors such as the available technologies, number of data points required, budgets and the technical expertise required. Unfortunately, markers can rarely be exchanged between existing and newly developed platforms, meaning that previously generated data cannot be compared, or combined, with more recently generated data sets. We predict that genotyping by sequencing will become the predominant genotyping technology within the next 5-10 years. With this in mind, to ensure that data generated from current genotyping platforms continues to be of use, we have designed and utilized SNP-based capture probes from several thousand existing and publicly available probes from Axiom® and KASP™ genotyping platforms. We have validated our capture probes in a targeted genotyping by sequencing protocol using 31 previously genotyped UK elite hexaploid wheat accessions. Data comparisons between targeted genotyping by sequencing, Axiom® array genotyping and KASP™ genotyping assays, identified a set of 3256 probes which reliably bring together targeted genotyping by sequencing data with the previously available marker data set. As such, these probes are likely to be of considerable value to the wheat community. The probe details, full probe sequences and a custom built analysis pipeline may be freely downloaded from the CerealsDB website (http://www.cerealsdb.uk.net/cerealgenomics/CerealsDB/sequence_capture.php).


Immune reactivity in early life stages of sea-cage cultured Pacific bluefin tuna naturally infected with blood flukes from genus Cardicola (Trematoda: Aporocotylidae).
Pacific bluefin tuna (PBT), Thunnus orientalis, due to its high average price on the market is an economically valuable fish species. Infections by blood flukes from the genus Cardicola (Trematoda: Aporocotylidae) represent a growing concern for the cage culture of bluefin tuna in Japan, Australia and Southern Europe. The accumulation of numerous Cardicola eggs in the fish gills causes severe pathology that has been linked to mortality in PBT juveniles up to one year old. The only effective treatment used to mitigate the infection is the oral administration of the antihelminthic drug praziquantel (PZQ) to the affected fish. However, with the need to minimise therapeutic drug use in aquaculture it is hoped that immunoprophylaxis can provide a future alternative to protect the PBT juveniles against Cardicola infection. Currently, little is known of the host immune response to these parasites and of their infection dynamics. In this study, using real-time qPCR we aimed to quantitatively detect C. orientalis and C. opisthorchis DNA within the gills and heart of cultured PBT juveniles and to investigate the host immune response at the transcriptional level in the gills. The research focused mainly during early stages of infection soon after young PBT were transferred to culture cages (from 14 to 77 days post-transfer). An increase (up to 11-fold) of immune-related genes, namely IgM, MHC-I, TCR-β and IL-1β was observed in the PBT gills infected with Cardicola spp. (28-77 days post-transfer). Furthermore, IgM (19-fold increase) and MHC-I (11.5-fold increase) transcription was strongly up-regulated in gill samples of PBT infected with C. orientalis relative to uninfected fish but not in fish infected with C. opisthorchis. Cardicola-specific DNA was first detected in the host 14 days post-transfer (DPT) to sea-cages which was 55 days earlier than the first detection of parasite eggs and adults by microscopy. Oral administration of PZQ did not have an immediate effect on parasite DNA presence in the host and the DNA presence started to reduce after 24 days only in the host heart. The results provide evidence of an immune response in early age sea-cage cultured juveniles of PBT naturally infected with C. orientalis and C. opisthorchis. This response, whilst not protective against primary infection, provides evidence that immunisation at an early age may have potential as a health strategy.


Clinicopathologic characteristics and survival outcome in patients with advanced lung adenocarcinoma and KRAS mutation.
Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are one of the most common observed genetic events in lung adenocarcinoma. The present study aimed to characterize treatment patterns and to estimate survival for patients in China with advanced lung adenocarcinoma and KRAS mutation. We identified KRAS-mutant lung adenocarcinoma between February 2013 and June 2017 in Zhejiang Cancer Hospital. Patients' characteristics and treatment outcomes were analyzed. A total of 159 lung adenocarcinoma were included, and 26 (16.4%) patients harbored KRAS mutations. Compared to KRAS-wild patients, patients with KRAS-mutant tumors were more likely to be smokers (76.9% vs. 51.9%, P = 0.029). Median tumor mutation burden (TMB) was significantly higher in the KRAS-mutant cohort than in the KRAS-wild cohort (5.4 vs. 4.2 mutations/megabases; P=0.041). Of the 93 patients receiving first-line chemotherapy, the median progression-free survival (PFS) in the KRAS-mutant group was significantly shorter than in the KRAS-wild group (1.5 vs. 7.2 months; P<0.001). The median overall survival (OS) in the KRAS-mutant group was also significantly shorter than in the KRAS-wild group (hazard ratio for progression or death for patients with KRAS mutation, 3.260; 95% CI, 1.516 to 7.013; P=0.001). In summary, our findings have several important implications for the molecular characterization and therapeutic outcome of lung adenocarcinoma initiated by oncogenic KRAS. Since the number of KRAS-mutant lung cancer is considerable, it should be taken seriously in clinical diagnosis and treatment. KRAS-mutant lung adenocarcinoma was not sensitive to chemotherapy, new and effective drugs targeting the KRAS pathway are in urgent need.


Fuzzy vector median-based surface smoothing.
This paper proposes a novel approach for smoothing surfaces represented by triangular meshes. The proposed method is a two-step procedure: surface normal smoothing through fuzzy vector median (FVM) filtering followed by integration of surface normals for vertex position update based on the least square error (LSE) criteria. Median and Order Statistic-based filters are extensively used in signal processing, especially image processing, due to their ability to reject outliers and preserve features such as edges and monotonic regions. More recently, fuzzy ordering theory has been introduced to allow averaging among similarly valued samples. Fuzzy ordering theory leads naturally to the fuzzy median, which yields improved noise smoothing over traditional crisp median filters. This paper extends the fuzzy ordering concept to vector-based data and introduces the fuzzy vector median filter. The application of FVM filters to surface normal smoothing yields improved results over previously introduced normal smoothing algorithms. The improved filtering results, coupled with LSE vertex position update, produces surface smoothing that minimizes the effects of noise while simultaneously preserving detail features. The proposed method is simple to implement and relatively fast. Simulation results are presented showing the performance of the proposed method and its advantages over commonly used surface smoothing algorithms. Additionally, optimization procedures for FVM filters are derived and evaluated.


HLA associations and HLA sharing in recurrent miscarriage: A systematic review and meta-analysis.
The aim of this meta-analysis was to evaluate whether specific maternal HLA alleles and HLA sharing of couples are associated with the occurrence of recurrent miscarriage (RM). A systematic literature search was performed for studies that evaluated the association between HLA alleles, HLA sharing and RM. RM was defined as three or more consecutive unexplained miscarriages and a control group was included of women with at least one live birth and no miscarriages in their history. Meta-analyses were performed and the pooled odds ratio (OR) was calculated. We included 41 studies. Selection bias was present in 40 studies and information bias in all studies. Meta-analyses showed an increased risk of RM in mothers carrying a HLA-DRB1*4 (OR 1.41, 95% CI 1.05-1.90), HLA-DRB1*15 (OR 1.57, 95% CI 1.15-2.14), or a HLA-E*01:01 allele (OR 1.47, 95% CI 0.20-1.81), and a decreased risk with HLA-DRB1*13 (OR 0.63, 95% CI 0.45-0.89) or HLA-DRB1*14 (OR 0.54, 95% CI 0.31-0.94). Pooling results for HLA sharing showed that HLA-B sharing (OR 1.39, 95% CI 1.11-1.75) and HLA-DR sharing (OR 1.57, 95% CI 1.10-1.25) were both associated with the occurrence of RM. Although the present systematic review and meta-analysis demonstrates that specific HLA alleles and HLA sharing are associated with RM, a high degree of bias was present and therefore observed results should be interpreted carefully.