Field-resolved infrared spectroscopy of biological systems.

The proper functioning of living systems and physiological phenotypes depends on molecular composition. Yet simultaneous quantitative detection of a wide variety of molecules remains a challenge1-8. Here we show how broadband optical coherence opens up opportunities for fingerprinting complex molecular ensembles in their natural environment. Vibrationally excited molecules emit a coherent electric field following few-cycle infrared laser excitation9-12, and this field is specific to the sample's molecular composition. Employing electro-optic sampling10,12-15, we directly measure this global molecular fingerprint down to field strengths 107 times weaker than that of the excitation. This enables transillumination of intact living systems with thicknesses of the order of 0.1 millimetres, permitting broadband infrared spectroscopic probing of human cells and plant leaves. In a proof-of-concept analysis of human blood serum, temporal isolation of the infrared electric-field fingerprint from its excitation along with its sampling with attosecond timing precision results in detection sensitivity of submicrograms per millilitre of blood serum and a detectable dynamic range of molecular concentration exceeding 105. This technique promises improved molecular sensitivity and molecular coverage for probing complex, real-world biological and medical settings.

Low-Dose Lipopolysaccharide Protects from Lethal Paramyxovirus Infection in a Macrophage- and TLR4-Dependent Process.

Respiratory diseases are a major public health burden and a leading cause of death and disability in the world. Understanding antiviral immune responses is crucial to alleviate morbidity and mortality associated with these respiratory viral infections. Previous data from human and animal studies suggested that pre-existing atopy may provide some protection against severe disease from a respiratory viral infection. However, the mechanism(s) of protection is not understood. Low-dose LPS has been shown to drive an atopic phenotype in mice. In addition, LPS has been shown in vitro to have an antiviral effect. We examined the effect of LPS treatment on mortality to the murine parainfluenza virus Sendai virus. Low-dose LPS treatment 24 h before inoculation with a normally lethal dose of Sendai virus greatly reduced death. This protection was associated with a reduced viral titer and reduced inflammatory cytokine production in the airways. The administration of LPS was associated with a marked increase in lung neutrophils and macrophages. Depletion of neutrophils failed to reverse the protective effect of LPS; however, depletion of macrophages reversed the protective effect of LPS. Further, we demonstrate that the protective effect of LPS depends on type I IFN and TLR4-MyD88 signaling. Together, these studies demonstrate pretreatment with low-dose LPS provides a survival advantage against a severe respiratory viral infection through a macrophage-, TLR4-, and MyD88-dependent pathway.

Systemic anticancer therapy for urothelial carcinoma: UK oncologists' perspective.

Urothelial carcinoma (UC) is a common cancer associated with a poor prognosis in patients with advanced disease. Platinum-based chemotherapy has remained the cornerstone of systemic anticancer treatment for many years, and recent developments in the treatment landscape have improved outcomes. In this review, we provide an overview of systemic treatment for UC, including clinical data supporting the current standard of care at each point in the treatment pathway and author interpretations from a UK perspective. Neoadjuvant cisplatin-based chemotherapy is recommended for eligible patients with muscle-invasive bladder cancer and is preferable to adjuvant treatment. For first-line treatment of advanced UC, platinum-eligible patients should receive cisplatin- or carboplatin-based chemotherapy, followed by avelumab maintenance in those without disease progression. Among patients unable to receive platinum-based chemotherapy, immune checkpoint inhibitor (ICI) treatment is an option for those with programmed death ligand 1 (PD-L1)-positive tumours. Second-line or later treatment options depend on prior treatment, and enfortumab vedotin is preferred after prior ICI and chemotherapy, although availability varies between countries. Additional options include rechallenge with platinum-based chemotherapy, an ICI, or non-platinum-based chemotherapy. Areas of uncertainty include the optimal number of first-line chemotherapy cycles for advanced UC and the value of PD-L1 testing for UC.

High prevalence of hepatitis B virus among MSM living with HIV in India.

People living with HIV (PWH) have been shown to bear a higher burden of hepatitis B virus (HBV) due to shared routes and risk factors for transmission. Populations such as men who have sex with men (MSM) are at an increased risk of both being infected with HBV and HIV, that places them at higher risk of hepatocellular carcinoma. Using weighted and adjusted multilevel logistic regression, we characterized the prevalence and correlates of hepatitis B surface antigen (HBsAg) among MSM living with HIV across 12 Indian cities from 2012 to 2013. Overall, the prevalence of HBsAg was 8% (range across cities: 0.5%-19%). Being between the ages of 25-34, and 35-44 increased the odds of having chronic HBV infection compared to MSM 24 years or younger. Daily or seasonal employment and being unemployed increased the odds of HBsAg prevalence compared to those with monthly or weekly wages. Sexual risk behaviours such as having had sex with both men and women in the prior 6 months and history of sex work increased the odds of having HBV. Ever having insertive sex with a man or hijra (assigned male at birth, currently identifies as female/nonbinary) was negatively associated with HBV. Despite the existence of efficacious vaccines, HBV continues to have high prevalence among PWHs. Programmes to increase early screening, vaccinations and HBV literacy are urgently needed. Integrating HBV and HIV programmes for MSM populations could be critical in addressing this dual burden and improving outcomes for both infections.

Accurate photosynthetic parameter estimation at low stomatal conductance: effects of cuticular conductance and instrumental noise.

Accurate estimation of photosynthetic parameters is essential for understanding plant physiological limitations and responses to environmental factors from the leaf to the global scale. Gas exchange is a useful tool to measure responses of net CO2 assimilation (A) to internal CO2 concentration (Ci), a necessary step in estimating photosynthetic parameters including the maximum rate of carboxylation (Vcmax) and the electron transport rate (Jmax). However, species and environmental conditions of low stomatal conductance (gsw) reduce the signal-to-noise ratio of gas exchange, challenging estimations of Ci. Previous works showed that not considering cuticular conductance to water (gcw) can lead to significant errors in estimating Ci, because it has a different effect on total conductance to CO2 (gtc) than does gsw. Here we present a systematic assessment of the need for incorporating gcw into Ci estimates. In this study we modeled the effect of gcw and of instrumental noise and quantified these effects on photosynthetic parameters in the cases of four species with varying gsw and gcw, measured using steady-state and constant ramping techniques, like the rapid A/Ci response method. We show that not accounting for gcw quantitatively influences Ci and the resulting Vcmax and Jmax, particularly when gcw exceeds 7% of the total conductance to water. The influence of gcw was not limited to low gsw species, highlighting the importance of species-specific knowledge before assessing A/Ci curves. Furthermore, at low gsw instrumental noise can affect Ci estimation, but the effect of instrumental noise can be minimized using constant-ramping rather than steady-state techniques. By incorporating these considerations, more precise measurements and interpretations of photosynthetic parameters can be obtained in a broader range of species and environmental conditions.

Response of carbon fixation, allocation, and growth to source-sink manipulation by defoliation in vegetative citrus trees.

Source-sink balance in plants determines carbon distribution, and altering it can impact carbon fixation, transport, and allocation. We aimed to investigate the effect of altered source-sink ratios on carbon fixation, transport, and distribution in 'Valencia' sweet orange (Citrus x sinensis) by various defoliation treatments (0%, 33%, 66%, and 83% leaf removal). Gas exchange parameters were measured on 0 and 10 days after defoliation using A/Ci response curves, and leaf export was measured two days after defoliation using radioisotope tracer techniques. Greater defoliation increased the maximum rate of carboxylation (Vcmax), electron transport rate (J1200), and triose-phosphate utilization rate (TPU). Leaf export was unaffected by defoliation but increased in leaves closer to the shoot apex. Basipetal translocation velocity in the trunk remained unaltered, indicating that more photosynthates remained in the shoot rather than being transported directly to the root sink. Defoliated plants initiated more new flush shoots but accumulated less shoot biomass per plant after 8 weeks. Carbon allocation to fine roots was smaller in defoliated plants, suggesting defoliation led to retention of carbohydrates in aboveground organs such as the trunk and other shoots from previous growing cycles. In conclusion, the low source-sink ratio increased carbon fixation without impacting individual leaf export in citrus. The results suggest that intermediate sinks such as the aboveground perennial organs play a role in mediating the translocation velocity. Further research is necessary to better understand the dynamics of source-sink regulation in citrus trees.

Healthy lifestyles and better periodontal health: Results from two large population-based surveys.

AIM: To ascertain whether healthy lifestyles are associated with periodontal diseases in two large-scale surveys in the US (National Health and Nutrition Examination Survey - NHANES) and the UK Biobank. METHODS: 9854 US adults and 111 679 UK adults were included in the analyses. A healthy lifestyle score (HLS), ranging between 0 and 5, was calculated based on the reported number of healthy behaviours, including never smoking, no heavy alcohol consumption, top third of leisure-time physical activity, higher dietary quality, and ideal sleep duration. The prevalence of periodontal diseases was the primary outcome in both surveys. In the NHANES, periodontal status was assessed through a full-mouth periodontal examination, while in the UKB, only self-reported periodontal status was available. RESULTS: Multiple regression analyses confirmed that the presence of at least 2-3 healthy behaviours (vs. 0-1) was associated with lower odds of overall and severe periodontitis (ORs 0.5, 0.4-0.6; p < .001 and 0.5, 0.3-0.8; p = .003, respectively) in the NHANES, and of bleeding gums (OR = 0.9, 0.8-1.0; p = .092) and loose teeth (OR = 0.6, 0.5-0.7; p < .001) in UKB. This association increased when considering prevalence of 4-5 healthy behaviours (vs. 0-1) in both the NHANES (periodontitis: OR = 0.3, 0.2-0.4; p < .001; severe periodontitis: OR = 0.1, 0.01-0.2; p < .001) and the UKB (bleeding gums: OR = 0.8, 0.7-0.9; p < .001; loose teeth: OR = 0.5, 0.4-0.6; p < .001). Mediation analyses revealed how these protective associations could be partially mediated (1-14%) by differences in biomarkers of systemic inflammation (white blood cells and neutrophils count as well as C-reactive protein). CONCLUSIONS: Adoption of healthy lifestyle behaviours is associated with a lower prevalence of periodontal diseases within two large population-based samples. This relationship exhibits a dose-response pattern, implying that greater adherence to healthy habits leads to a more significant protective effect against the odds of periodontal diseases. Additionally, our findings suggest that this protective effect is, in part, mediated by reductions in systemic inflammation.

Genetic diversity, spatial connectivity, and population structure of Asian silurid catfish Wallago attu (Bloch and Schneider, 1801) in the Ganga River System: insights from mitochondrial DNA analysis.

BACKGROUND: The Ganga River System (GRS) is a biodiversity hotspot, its ecological richness is shaped by a complex geological history. In this study, we examined the genetic diversity, spatial connectivity, and population structure of the Asian Silurid catfish, Wallago attu, across seven tributaries of the GRS. METHODS AND RESULTS: We employed three mitochondrial DNA (mtDNA) regions: cytochrome c oxidase subunit I (COXI), cytochrome b (Cyt b), and control region (CR). Our comprehensive dataset encompassed 2420 bp of mtDNA, derived from 176 W. attu individuals across 19 sampling sites within the seven rivers of GRS. Our findings revealed high gene diversity (Hd:0.99) within W. attu populations. Analysis of Molecular Variance (AMOVA) highlighted that maximum genetic variations were attributed within the populations, and the observed genetic differentiation among the seven populations of W. attu ranged from low to moderate. Network analysis uncovered the presence of three distinct genetic clades, showing no specific association with seven studied rivers. Bayesian skyline plots provided insights into the demographic history of W. attu, suggesting a recent population expansion estimated to have occurred approximately 0.04 million years ago (mya) during the Pleistocene epoch. CONCLUSIONS: These results significantly enhance our understanding of the genetic diversity and spatial connectivity of W. attu, serving as a vital foundation for developing informed conservation strategies and the sustainable management of this economically valuable resource within the Ganga River System.

Outcome of pediatric living donor liver transplant: Experience from Pakistan; a resource limited setting.

INTRODUCTION: Liver transplantation (LT) has emerged as a lifesaving modality for many liver diseases in children. Pediatric LT is an established treatment in the Western world but is relatively a new procedure in resource-limited countries like Pakistan. The study aims to highlight the outcomes and survival of pediatric recipients from the first pediatric liver transplant center in Pakistan. METHOD: A retrospective analysis of pediatric LT was done from 2012 to 2019. The study was conducted in the Hepatobiliary and liver transplant department of Shifa International Hospital (SIH), Islamabad. A detailed analysis for indications for pediatric LT, survival, and complications was done. RESULTS: Forty-five patients under 18 years of age underwent Living donor liver transplant (LDLT) in SIH. Median age was 9 years and M:F of 2:1. Cryptogenic liver disease followed by Wilson disease were the two most common indications of LT. The majority of patients had chronic liver disease 34 (75%) while 11 (24%) had acute liver failure. The right lobe graft was the most common type of graft 19 (42.2%). Thirty days, 1-year, 3-year, and 5-year survival was 77.8%, 75.6%, 73.3%, and 60.6% respectively. Mortality was highest in patients with biliary atresia 4 (33%). Causes of death included pulmonary embolism, sepsis, surgical complications, and acute kidney injury. Mean survival was 88.850 months (±7.899) (CI 73.369-104.331). CONCLUSION: Pediatric LDLT has offered disease-free survival for patients. Survival can improve further with nutritional rehabilitation and anticipation and management of post-operative complications.

Toxicological assessment of dietary exposure of polyethylene microplastics on growth, nutrient digestibility, carcass and gut histology of Nile Tilapia (Oreochromis niloticus) fingerlings.

This study was conducted to ascertain the negative effects of dietary low-density polyethylene microplastics (LDPE-MPs) exposure on growth, nutrient digestibility, body composition and gut histology of Nile tilapia (Oreochromis niloticus). Six sunflower meal-based diets (protein 30.95%; fat 8.04%) were prepared; one was the control (0%) and five were incorporated with LDPE-MPs at levels of 2, 4, 6, 8 and 10% in sunflower meal-based diets. A total of eighteen experimental tanks, each with 15 fingerlings, were used in triplicates. Fish were fed at the rate of 5% biomass twice a day for 60 days. Results revealed that best values of growth, nutrient digestibility, body composition and gut histology were observed by control diet, while 10% exposure to LDPE-MPs significantly (P < 0.05) reduced weight gain (WG%, 85.04%), specific growth rate (SGR%, 0.68%), and increased FCR (3.92%). The findings showed that higher level of LDPE-MPs (10%) exposure in the diet of O. niloticus negatively affects nutrient digestibility. Furthermore, the results revealed that the higher concentration of LDPE-MPs (10%) had a detrimental impact on crude protein (11.92%) and crude fat (8.04%). A high number of histological lesions were seen in gut of fingerlings exposed to LDPE-MPs. Hence, LDPE-MPs potentially harm the aquatic health.

X-ray photoelectron spectroscopy and tunable photoluminescence study of gold nanoparticles embedded in PVA films.

This article reports the systematic photoluminescence study of the various contents of gold nanocomposites in polyvinyl alcohol (PVA) films. The variations in the gold content in PVA film were 0.2, 0.5, 1.0, and 1.5 wt%. All the samples were excited at two selected wavelengths; those are at 400 nm and 532 nm. On exciting the gold-PVA nanocomposite films at 400 nm the photoluminescence was observed in the region of 430-500 nm in comparison to pure PVA films that show an emission at 400 nm. However, on exciting the gold-PVA nanocomposites at 532 nm, the emission was observed at 560-650 nm with a long tail till 700 nm that is unlike the pure PVA films that do not show any emission peak in this region. This suggests that emission between 430 and 500 nm regions is due to the coordination of PVA with gold nanoparticles because PVA has an emission at 400 nm. However, the emission peak between 560 and 650 nm is entirely due to the gold nanocomposite particle. The peak also shows a smaller red-shift that is usually with the increasing nanoparticles size with the increasing content in the PVA films. The formation of gold nanoparticles was justified by X-ray diffraction (XRD) analysis which is further supported by X-ray photoelectron spectroscopy (XPS) analysis.

Investigating the relationship between heat load and shade seeking behaviour in dairy buffaloes.

The study presented in this Research Communication aimed to investigate the relationship between physiological responses, body surface temperature and shade-seeking behaviour in Nili Ravi dairy buffaloes during summer months. We enrolled 60 buffaloes, and each animal was observed for three consecutive days starting before sunrise until they moved towards the shade structures. A repeated measures ANOVA was employed to assess the changes in physiological parameters and body surface temperature between the early morning and the occurrence of shade-seeking behaviour. The average temperature humidity index and heat load index during the behavioural monitoring period (0400 to 1200 h) were 81.3 ± 6.5 and 92.9 ± 17, respectively (mean ± sd). There was no significant difference in core body temperature between sunrise and the time of shade-seeking event. However, the buffaloes had a slightly higher respiration rate at the time of shade-seeking (19.2 vs. 22.4 breaths/min). In addition, body surface temperature, measured at the flank region, shoulder, base of the ear and forehead was significantly higher at the occurrence of shade-seeking behaviour compared to the early morning. On average, the buffaloes sought shade when the surface temperature was 2°C higher than the temperature recorded before sunrise. Overall, the current findings suggest that body surface temperature, rather than core body temperature was strongly associated with shade-seeking behaviour in dairy buffaloes. These findings could be useful in developing strategies to mitigate the effects of heat stress in dairy buffalo herds and thereby improve animal welfare.

Management of Velopharyngeal Dysfunction (VPD) Following Cleft Palate Repair: A Comprehensive Decision-Making Process Based on Severity and Structural Deficiencies.

OBJECTIVE: To describe a comprehensive decision-making process for surgical correction of structural Velopharyngeal Dysfunction (VPD) following cleft palate repair and evaluate its efficacy. DESIGN: Retrospective study. SETTING: Tertiary care hospital. PATIENTS: 300 consecutive patients with unilateral or bilateral cleft lip and palate (CLP) or isolated cleft palate (CP) diagnosed with clinical VPD following cleft palate repair between 2009 and 2014. Of these 206 patients had structural VPD and underwent surgical correction. INTERVENTIONS: Surgical corrections were carried out according to the comprehensive two stage decision making process developed by the investigators. Step 1 of decision-making involved visualisation of the VP sphincter function by nasoendoscopy. This was followed by step 2 which involved per-operative identification of scarring, tissue loss, hypoplasia and other structural deficiencies in the soft palate and septal mucoperiosteum. The choice of operation was then made from a repertoire of interrelated and escalating surgical procedures consisting of palate revision and pharyngoplasties ranging from most anatomical to the least. MAIN OUTCOME MEASURES: Evidence of postoperative restoration of VP function on nasoendoscopy, evaluation of speech for hypernasality, understandability, acceptability and symptoms of obstructive sleep apnea. RESULTS: Complete VP closure was demonstrated in 94% of patients treated using this algorithm. There was significant improvement in all speech parameters (p < 0.00001). CONCLUSION: Our comprehensive decision-making process is designed to effectively correct structural VPD according to the severity of structural and functional deficiencies in the soft palate and avoid over treatment.

Evaluation of growth, nutrient absorption, body composition and blood indices under dietary exposure of iron oxide nanoparticles in Common carp (Cyprinus carpio).

The bioavailability, small size and direct absorption in the blood, make nanoparticles (NPs) a remarkable feed additive in the aquaculture industry. Therefore, dietary iron oxide nanoparticles (Fe2 O3 -NPs) were used to examine their effects on growth, nutrient absorption, body composition and blood indices in Cyprinus carpio (Common carp) fingerlings. Healthy C. carpio fingerlings (n = 270) were fed with six canola meal based experimental diets (D1-control, D2, D3, D4, D5, D6) supplemented with 0, 10, 20, 30, 40 and 50 mg/kg Fe2 O3 -NPs respectively. A total of 15 fingerlings (average initial weight 5.51 ± 0.04 g/fish) were kept in triplicates for 70 days. The results indicated that maximum growth performance, apparent digestibility coefficient, body composition and haematological parameters were observed in 40 mg/kg Fe2 O3 -NPs supplementation. All the experimental diets were significantly improved (p < 0.05) in all the above parameters than control diet. In the present research, the recommended dosage of Fe2 O3 -NPs as dietary supplement is 40 mg/kg for improving the growth, nutrient absorption, body composition and haematological indices in C. carpio fingerlings. Hence, this study demonstrates the potential of NPs to improve the health of fish.

Impact of feeding biochar sources in rohu (Labeo rohita): Evaluating the growth, nutrient absorption, carcass composition, haematology and mineral status.

Biochar, an organic carbonaceous matter, is a unique feed additive that is now being used in aquaculture industry to formulate a cost-effective and eco-friendly diet. This experiment (in door) was conducted over course of 90 days to determine the most effective form of biochar, produced from various sources, for supplementation in Moringa oleifera seed meal-based diet. These sources were: farmyard manure biochar, parthenium biochar (PB), vegetable waste biochar, poultry waste biochar (PWB) and corncob waste biochar, added at 2 g/kg concentration to determine the effect of supplementation on the growth indices, nutrient absorption, carcass composition, haematology and mineral status of Labeo rohita (rohu) fingerlings. The research design consisted of six test diets with three replications (6 × 3) of each. Total of 270 fingerlings (6.30 ± 0.020 g) were fed at 5% body weight and 15 of them were kept in separate steel tanks. The results indicated that PWB was most effective in improving weight gain (285.58 ± 4.54%) and feed conversion ratio (1.060 ± 0.040) compared to control diet and other test diets. The same type of biochar (PWB) produced the best results for nutrient digestibility, that is, crude protein, crude fat and gross energy and carcass composition. In terms of haematology and mineral status, PWB showed the best results. In conclusion, it was found that PWB significantly enhanced (p < 0.05) L. rohita fingerling's growth, carcass composition, nutrient digestibility, haematological parameters (red blood cells, white blood cells, platelets and haemoglobin) and mineral composition (Ca, Na, P, Mg, Fe, Mn, Zn, K and Cu) whereas PB negatively affected all parameters. It is anticipated that the potential use of biochar will increase in aquaculture industry, as research on its incorporation in fish feeds is still limited.

Development of topical silver nano gel formulation of Bixin: Characterization, and evaluation of anticancer activity.

Objective: Skin cancer refers to the pathological condition characterized by the proliferation of atypical skin cells in an uncontrolled manner. Plant-based products such as bixin although show promising anticancer properties, but maintaining their stability in a formulation is a difficult task. The objective of the research is to formulate a silver nanoparticle gel preparation of bixin and evaluate its anticancer properties. Methods: The extract from Bixa orellana seed was prepared by hot extraction technique to isolate the active ingredient, bixin. A green synthesis approach was utilized for preparing the silver nanoparticle gel of bixin (BOAgNPs). Characterization of silver nanoparticles was done using FTIR, scanning electron microscopy, compatibility study, homogeneity testing, pH evaluation, and drug content determination. The in-vitro anticancer activity was performed using cell lines (B16F10) and in-vivo by chemical carcinogen (7,12-dimethylbenz (a) anthracene) in mice. Results: The BOAgNPs-loaded topical gel was found to be homogeneous (clear orange color) and pH-compatible (pH ≈ 6.66) with the skin. The characterization studies indicated the presence of all functional groups in the formulation. An optimized batch of bixin-nano gel showed about 60% inhibitory effects on B16F10 cell lines (in-vitro activity) when equated with a reference drug, 5-fluorouracil. The in-vivo anticancer study suggested suppression of tumorigenesis and promotion of the healing process with bixin-nano gel application on the skin. Conclusion: The results suggested the promising anticancer property of bixin when formulated in silver nanoparticle gel. The preparation of silver particles nano gel with bixin might provide an effective alternative option for treating skin cancers, provided more research complements the findings of the present study.

A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer.

BACKGROUND: This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC). METHODS: The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone. RESULTS: In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated. CONCLUSIONS: Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC. CLINICAL TRIAL REGISTRATION: EudraCT number 2013-004011-41.

Diagnosis, treatment and survival from bladder, upper urinary tract, and urethral cancers: real-world findings from NHS England between 2013 and 2019.

OBJECTIVE: We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. MATERIALS AND METHODS: Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. RESULTS: Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7-42.0%]) were referred outside the 2-week-wait pathway and 15 340 (mean [range] 12.2% [11.7-12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97-0.97) at 2 years in contrast to other cancers. CONCLUSION: The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete.

Atopic Neutrophils Prevent Postviral Airway Disease.

Respiratory syncytial virus (RSV) infection in infancy is associated with increased risk of asthma, except in those with allergic disease at the time of infection. Using house dust mite allergen, we examined the effect of pre-existing atopy on postviral airway disease using Sendai virus in mice, which models RSV infection in humans. Sendai virus drives postviral airway disease in nonatopic mice; however, pre-existing atopy protected against the development of airway disease. This protection depended upon neutrophils, as depletion of neutrophils at the time of infection restored the susceptibility of atopic mice to postviral airway disease. Associated with development of atopy was an increase in polymorphonuclear neutrophil-dendritic cell hybrid cells that develop in Th2 conditions and demonstrated increased viral uptake. Systemic inhibition of IL-4 reversed atopic protection against postviral airway disease, suggesting that increased virus uptake by neutrophils was IL-4 dependent. Finally, human neutrophils from atopic donors were able to reduce RSV infection of human airway epithelial cells in vitro, suggesting these findings could apply to the human. Collectively our data support the idea that pre-existing atopy derives a protective neutrophil response via potential interaction with IL-4, preventing development of postviral airway disease.

Optimization of wear behavior of heat-treated Ti-6Al-7Nb biomedical alloy by response surface methodology.

Titanium-based metals are used most often in biomedical implant studies because they have good qualities like being biocompatible, not being poisonous, Osseo-integration, high specific properties, wear resistance, etc. The main goal of this work is to improve the wear resistance of Ti-6Al-7Nb biomedical metal by using a mix of Taguchi, ANOVA, and Grey Relational Analysis. The effect of changeable control process factors like applied load, spinning speed, and time on wear reaction measures like wear rate (WR), coefficient of friction (COF), and frictional force. The optimal combinations of wear rate, COF, and frictional force minimise wear characteristics. The L9 Taguchi orthogonal array was used to plan the experiments, which were done on a pin-on-disc set-up according to ASTM G99. To find the best set of control factors, Taguchi, ANOVA, and Grey relationship analysis were used. The results show that a load of 30 N, a speed of 700 rpm, and a time of 10 min are the best control settings.