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The lateral geniculate nucleus (LGN) is increasingly regarded as a \"smart-gating\" operator for processing visual information. Therefore, characterizing the response properties of LGN neurons will enable us to better understand how neurons encode and transfer visual signals. Efforts have been devoted to study its anatomical and functional features, and recent advances have highlighted the existence in rodents of complex features such as direction/orientation selectivity. However, unlike well-researched higher-order mammals such as primates, the full array of response characteristics vis-à-vis its morphological features have remained relatively unexplored in the mouse LGN. To address the issue, we recorded from mouse LGN neurons using multisite-electrode-arrays (MEAs) and analysed their discharge patterns in relation to their location under a series of visual stimulation paradigms. Several response properties paralleled results from earlier studies in the field and these include centre-surround organization, size of receptive field, spontaneous firing rate and linearity of spatial summation. However, our results also revealed \"high-pass\" and \"low-pass\" features in the temporal frequency tuning of some cells, and greater average contrast gain than reported by earlier studies. In addition, a small proportion of cells had direction/orientation selectivity. Both \"high-pass\" and \"low-pass\" cells, as well as direction and orientation selective cells, were found only in small numbers, supporting the notion that these properties emerge in the cortex. ON- and OFF-cells showed distinct contrast sensitivity and temporal frequency tuning properties, suggesting parallel projections from the retina. Incorporating a novel histological technique, we created a 3-D LGN volume model explicitly capturing the morphological features of mouse LGN and localising individual cells into anterior/middle/posterior LGN. Based on this categorization, we show that the ON/OFF, DS/OS and linear response properties are not regionally restricted. Our study confirms earlier findings of spatial pattern selectivity in the LGN, and builds on it to demonstrate that relatively elaborate features are computed early in the visual pathway.

Intelligent automation, including robotics, is one of the current trends in the manufacturing industry in the context of “Industry 4.0”, where cyber-physical systems control the production at automated or semi-automated factories. Robots are perfect substitutes for a skilled workforce for some repeatable, general, and strategically-important tasks. However, this transformation is not always feasible and immediate, since certain technologies do not provide the required degree of flexibility. The introduction of collaborative robots in the industry permits the combination of the advantages of manual and automated production. In some processes, it is necessary to incorporate robots from different manufacturers, thus the design of these multi-robot systems is crucial to guarantee the maximum quality and efficiency. In this context, this paper presents a novel methodology for process automation design, enhanced implementation, and real-time monitoring in operation based on creating a digital twin of the manufacturing process with an immersive virtual reality interface to be used as a virtual testbed before the physical implementation. Moreover, it can be efficiently used for operator training, real-time monitoring, and feasibility studies of future optimizations. It has been validated in a use case which provides a solution for an assembly manufacturing process.

Anal cancer remains rare (incidence of about 1·5 per 100 000 women yearly), but rates are increasing in many countries. Human papillomavirus (HPV) 16 and 18 infections cause most cases of anal cancer. We assessed efficacy of an AS04-adjuvanted HPV 16 and HPV 18 vaccine against anal infection with HPV 16, HPV 18, or both (HPV 16/18). Women from Costa Rica were registered between June 28, 2004, and Dec 21, 2005, in a randomised double-blind controlled trial that was designed to assess vaccine efficacy against persistent cervical HPV 16/18 infections and associated precancerous lesions. Eligible women were residents of Guanacaste and selected areas of Puntarenas, Costa Rica, age 18–25 years, in good general health, willing to provide informed consent, and were not pregnant or breastfeeding. Participants were randomly assigned (1:1) to receive an HPV vaccine (Cervarix, GlaxoSmithKline, Rixensart, Belgium) or a control hepatitis A vaccine (modified preparation of Havrix, GlaxoSmithKline, Rixensart, Belgium). Vaccines were administered in three 0·5 mL doses at enrolment, 1 month, and 6 months. Women, selected at the final blinded study visit 4 years after vaccination, provided anal specimens for assessment of vaccine efficacy against anal HPV 16/18 infection. Prevalence of anal HPV 16/18 infections, reported as vaccine efficacy, was the primary endpoint of the study described here. Vaccine efficacy against cervical HPV 16/18 infection in the same women at the 4-year visit was used as a comparator. Analyses were done in a restricted cohort of women who were negative for both cervical HPV 16 and HPV 18 DNA and who were HPV 16 and HPV 18 seronegative before enrolment (HPV naive), and also in the full cohort of women who provided an anal specimen. Investigators were masked to group assignment. This study is registered at ClinicalTrials.gov, number NCT00128661. All women who attended the final blinded study visit and consented to anal specimen collection were included in the analysis (4210 of 6352 eligible women). In the full cohort, vaccine efficacy against prevalent HPV 16/18 infection measured one-time, 4 years post vaccination was lower at the anus (62·0%, 95% CI 47·1–73·1) compared with the cervix (76·4%, 67·0–83·5; p for interaction by anatomical site 0·031). In the restricted cohort, vaccine efficacy against anal HPV 16/18 infection was 83·6% (66·7–92·8), which was similar to vaccine efficacy against cervical HPV 16/18 infection (87·9%, 77·4–94·0). Safety issues were not addressed in the current analysis. Additional safety data will be published later in a separate article. The AS04-adjuvanted vaccine affords strong protection against anal HPV infection, particularly among women more likely to be HPV naive at enrolment. National Cancer Institute with contributions from the National Institutes of Health Office of Research on Women's Health. Vaccine was provided by GlaxoSmithKline Biologicals.

The Costa Rica Vaccine Trial (CVT), a phase III randomized clinical trial, provided the initial data that one dose of the HPV vaccine could provide durable protection against HPV infection. Although the study design was to administer all participants three doses of HPV or control vaccine, 20% of women did not receive the three-dose regimens, mostly due to involuntary reasons unrelated to vaccination. In 2011, we reported that a single dose of the bivalent HPV vaccine could be as efficacious as three doses of the vaccine using the endpoint of persistent HPV infection accumulated over the first four years of the trial; findings independently confirmed in the GSK-sponsored PATRICIA trial. Antibody levels after one dose, although lower than levels elicited by three doses, were 9-times higher than levels elicited by natural infection. Importantly, levels remained essentially constant over at least seven years, suggesting that the observed protection provided by a single dose might be durable. Much work has been done to assure these non-randomized findings are valid. Yet, the group of recipients who received one dose of the bivalent HPV vaccine in the CVT and PATRICIA trials was small and not randomly selected nor blinded to the number of doses received. The next phase of research is to conduct a formal randomized, controlled trial to evaluate the protection afforded by a single dose of HPV vaccine. Complementary studies are in progress to bridge our findings to other populations, and to further document the long-term durability of antibody response following a single dose.

Robots are perfect substitutes for skilled workforce on some repeatable, general, and strategically important tasks, but this substitution is not always feasible. Despite the evolution of robotics, some industries have been traditionally robot-reluctant because their processes involve large or specific parts and non-serialized products; thus, standard robotic solutions are not cost-effective. This work presents a novel approach for advanced manufacturing applied to the aerospace industry, combining the power and the repeatability of the robots with the flexibility of humans. The proposed approach is based on immersive and symbiotic collaboration between human workers and robots, presenting a safe, dynamic, and cost-effective solution for this traditionally manual and robot-reluctant industry. The proposed system architecture includes control, safety, and interface components for the new collaborative manufacturing process. It has been validated in a real-life case study that provides a solution for the manufacturing of aircraft ribs. The results show that humans and robots can share the working area simultaneously without physical separation safely, providing beneficial symbiotic collaboration and reducing times, risks, and costs significantly compared with manual operations.

Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. A total of 7,466 women 18-25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661.

Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes. This was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0-10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1-12% (high-A1C exploratory cohort; n = 73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA. In the main cohort, mean A1C changes from baseline at week 24 were -0.23% with placebo and -0.58, -0.77 (P = 0.0005 vs. placebo), and -0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results. Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes.

Purpose To evaluate whether continuous barbed suturing improves postoperative pain, closure efficiency, and early functional outcomes compared to conventional interrupted suturing in primary total knee arthroplasty (TKA). Methods In this double-blinded randomised controlled trial, 143 patients undergoing primary TKA were assigned to continuous barbed ( n  = 72) or interrupted absorbable ( n  = 71) sutures for arthrotomy and subcutaneous closure. The primary endpoints were closure time and postoperative pain at 24 h; superiority testing was pre-specified only for VAS at 24 h (one-sided t-test, α = 0.025), whereas closure time was analysed two-sided (α = 0.05). Secondary outcomes included wound healing time, 6-month functional gain (Hospital for Special Surgery score), quality of life (EQ-5D), satisfaction, and complications. Results Continuous suturing significantly reduced closure times for both arthrotomy (4.2 ± 1.6 vs 6.5 ± 7.7 min; p  < 0.001) and subcutaneous layers (4.8 ± 1.9 vs 5.6 ± 1.4 min; p  < 0.001). Pain at 24 h was significantly lower in the continuous group (VAS 2.9 ± 2.1 vs 4.0 ± 2.1; p  = 0.017). The continuous group also showed faster wound healing (22.3 vs 24.8 days; p  = 0.012) and greater 6-month HSS improvement (24.5 vs 16.0 points; p  = 0.040). No significant differences were observed in complication rates, satisfaction, or quality of life. Conclusion Continuous barbed suturing improves surgical efficiency, reduces early postoperative pain, accelerates wound healing, and enhances functional recovery without increasing complication rates. This is the first randomised trial to demonstrate superior functional recovery (HSS score) with barbed continuous closure over traditional interrupted techniques, supporting its broader adoption in primary TKA. Level of evidence Level I, randomised controlled trial.

Objective: To investigate the potential determinants of Helicobacter pylori infection between adults 21–65 years old. Methods: Data are from the initial screening visit of a randomized clinical trial of three antibiotic regimens to eradicate H. pylori, conducted in seven sites (Santiago—Chile, Túquerres—Colombia, Guanacaste—Costa Rica, Copán—Honduras, Obregón and Tapachula—México, León—Nicaragua). Thousand eight hundred and fifty-nine adults from the general population were screened for H. pylori infection using an urea breath test (UBT) and were interviewed to assess socioeconomic-, demographic-, and symptom-related characteristics. Logistic regression was used to assess the relationship between these characteristics and H. pylori positivity at enrollment. Results: Among the 1,852 eligible participants for whom a conclusive UBT result was obtained, H. pylori prevalence was 79.4 %, ranging from 70.1 to 84.7 % among the seven centers. Prevalence did not differ by sex (female: 78.4, male: 80.9; p = 0.20) or age (p = 0.08). H. pylori positivity increased with increasing number of siblings (p trend <0.0001). Participants with education beyond 12 years were less likely to be UBT-positive (OR 0.4: 0.3–0.6, compared to participants with 0–6 years of schooling) as were those employed outside the home (OR 0.7: 0.6–1.0). Odds of H. pylori infection increased with the presence of certain living conditions during childhood including having lived in a household with an earth floor (OR 1.8:1.4–2.4), lack of indoor plumbing (OR 1.3: 1.0–1.8) and crowding (OR 1.4: 1.0–1.8, for having more than two persons per bedroom). Regarding current household conditions, living with more than 3 children in the household (OR 1.7: 1.2–2.5) and crowding (OR 1.8: 1.3–2.3) were associated with H. pylori infection. Conclusions: The prevalence of H. pylori in adults was high and differed significantly among the six Latin American countries studied (p < 0.001). Our findings confirm the strong link between poor socioeconomic conditions and H. pylori infection.

The production of medicinal plants under stressful environments offers an alternative to meet the requirements of sustainable agriculture. The action of mycorrhizal fungus; Funneliformis mosseae and zinc in stimulating growth and stress tolerance in medicinal plants is an intriguing area of research. The current study evaluated the combined use of nano-zinc and mycorrhizal fungus on the physiochemical responses of Dracocephalum moldavica under salinity stress. The study employed a factorial based on a completely randomized design with three replications. The treatments were different levels of salinity (0, 50, and 100 mM NaCl), two levels of mycorrhiza application (0 and 5 g kg − 1 of soil), and two levels of foliar spraying of nano zinc oxide (0 and 1000 ppm). Salinity decreased the photosynthetic pigments content, SPAD value, and chlorophyll fluorescence data ( Fm , Fv , Fv/Fm ). Plant dry weight, Na + content, and essential oil content were significantly higher at 50 mM salinity + co-application of mycorrhiza and nano zinc oxide. Electrolyte leakage increased under salt stress, while mycorrhizal inoculation compensated for the trait. The main essential oil constituents were geranyl acetate, nerol, geranial, geraniol, viridiflorol, hexadecane, humulene, and germacrene D. Energy metabolism demonstrates the effectiveness of treatment combinations in promoting the biosynthesis and accumulation of essential oil components. The overall results with more comprehensive field-based studies would be advisable for the extension section to utilize marginal salty lands for the reliable production of a valuable medicinal plant.