Thoracoscopy and talc poudrage compared with intercostal drainage and talc slurry infusion to manage malignant pleural effusion: the TAPPS RCT

Background: There are around 40,000 new cases of malignant pleural effusion in the UK each year. Insertion of talc slurry via a chest tube is the current standard treatment in the UK. However, some centres prefer local anaesthetic thoracoscopy and talc poudrage. There is no consensus as to which approach is most effective. Objective: This trial tested the hypothesis that thoracoscopy and talc poudrage increases the proportion of patients with successful pleurodesis at 3 months post procedure, compared with chest drain insertion and talc slurry. Design: This was a multicentre, open-label, randomised controlled trial with embedded economic evaluation. Follow-up took place at 1, 3 and 6 months. Setting: This trial was set in 17 NHS hospitals in the UK. Participants: A total of 330 adults with a confirmed diagnosis of malignant pleural effusion needing pleurodesis and fit to undergo thoracoscopy under local anaesthetic were included. Those adults needing a tissue diagnosis or with evidence of lung entrapment were excluded. Interventions: Allocation took place following minimisation with a random component, performed by a web-based, centralised computer system. Participants in the control arm were treated with a bedside chest drain insertion and 4 g of talc slurry. In the intervention arm, participants underwent local anaesthetic thoracoscopy with 4 g of talc poudrage. Main outcome measures: The primary outcome measure was pleurodesis failure at 90 days post randomisation. Secondary outcome measures included mortality and patient-reported symptoms. A cost–utility analysis was also performed. Results: A total of 166 and 164 patients were allocated to poudrage and slurry, respectively. Participants were well matched at baseline. For the primary outcome, no significant difference in pleurodesis failure was observed between the treatment groups at 90 days, with rates of 36 out of 161 (22%) and 38 out of 159 (24%) noted in the poudrage and slurry groups, respectively (odds ratio 0.91, 95% confidence interval 0.54 to 1.55; p = 0.74). No differences (or trends towards difference) were noted in adverse events or any of the secondary outcomes at any time point, including pleurodesis failure at 180 days [poudrage 46/161 (29%), slurry 44/159 (28%), odds ratio 1.05, 95% confidence interval 0.63 to 1.73; p = 0.86], mean number of nights in hospital over 90 days [poudrage 12 nights (standard deviation 13 nights), slurry 11 nights (standard deviation 10 nights); p = 0.35] and all-cause mortality at 180 days [poudrage 66/166 (40%), slurry 68/164 (42%); p = 0.70]. At £20,000 per quality-adjusted life-year gained, poudrage would have a 0.36 probability of being cost-effective compared with slurry. Limitations: Entry criteria specified that patients must be sufficiently fit to undergo thoracoscopy, which may make the results less applicable to those patients presenting with a greater degree of frailty. Furthermore, the trial was conducted on an open-label basis, which may have influenced the results of patient-reported measures. Conclusions: The TAPPS (evaluating the efficacy of Thoracoscopy And talc Poudrage versus Pleurodesis using talc Slurry) trial has robustly demonstrated that there is no additional clinical effectiveness or cost-effectiveness benefit in performing talc poudrage at thoracoscopy over bedside chest drain and talc slurry for the management of malignant pleural effusion. Trial registration: Current Controlled Trials ISRCTN47845793. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 26. See the NIHR Journals Library website for further project information

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects

Càncer de mama; Genètica del càncer; MutacióCáncer de mama; Genética del cáncer; MutaciónBreast cancer; Cancer genetics; MutationBi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer

Assessment of the potential in vivo ecotoxicity of Double-Walled Carbon Nanotubes (DWNTs) in water, using the amphibian Ambystoma mexicanum

Because of their specific properties (mechanical, electrical, etc), carbon nanotubes (CNTs) are being assessed for inclusion in many manufactured products. Due to their massive production and number of potential applications, the impact of CNTs on the environment must be taken into consideration. The present investigation evaluates the ecotoxic potential of CNTs in the amphibian larvae (Ambystoma mexicanum). Acute toxicity and genotoxicity were analysed after 12 days of exposure in laboratory conditions. The genotoxic effects were analysed by scoring the micronucleated erythrocytes in the circulating blood of the larvae according to the French standard micronucleus assay. The results obtained in the present study demonstrated that CNTs are neither acutely toxic nor genotoxic to larvae whatever the CNTs concentration in the water, although black masses of CNTs were observed inside the gut. In the increasing economical context of CNTs, complementary studies must be undertaken, especially including mechanistic and environmental investigations

Why Muscle is an Efficient Shock Absorber

Copyright: © 2014 Ferenczi et al. Skeletal muscles power body movement by converting free energy of ATP hydrolysis into mechanical work. During the landing phase of running or jumping some activated skeletal muscles are subjected to stretch. Upon stretch they absorb body energy quickly and effectively thus protecting joints and bones from impact damage. This is achieved because during lengthening, skeletal muscle bears higher force and has higher instantaneous stiffness than during isometric contraction, and yet consumes very little ATP. We wish to understand how the actomyosin molecules change their structure and interaction to implement these physiologically useful mechanical and thermodynamical properties. We monitored changes in the low angle x-ray diffraction pattern of rabbit skeletal muscle fibers during ramp stretch compared to those during isometric contraction at physiological temperature using synchrotron radiation. The intensities of the off-meridional layer lines and fine interference structure of the meridional M3 myosin x-ray reflection were resolved. Mechanical and structural data show that upon stretch the fraction of actin-bound myosin heads is higher than during isometric contraction. On the other hand, the intensities of the actin layer lines are lower than during isometric contraction. Taken together, these results suggest that during stretch, a significant fraction of actin-bound heads is bound non-stereo-specifically, i.e. they are disordered azimuthally although stiff axially. As the strong or stereo-specific myosin binding to actin is necessary for actin activation of the myosin ATPase, this finding explains the low metabolic cost of energy absorption by muscle during the landing phase of locomotion.The work was funded by the Russian Foundation for Basic Research (RFBR) grants 11-04-00908 to A.K.T. and 11-04-00750 to S.Y.B., by the Presidium of the Russian Academy of Sciences to S.Y.B., by the Medical Research Council (UK) G0501704 to M.A.F, by an EBSA Travel Fellowship to G.V.K., and by a Royal Society Travel award to N.A.K. and A.K.T

Liver disease is a significant risk factor for cardiovascular outcomes – A UK Biobank study

Background & Aims: Chronic liver disease (CLD) is associated with increased cardiovascular disease (CVD) risk. We investigated whether early signs of liver disease (measured by iron-corrected T1-mapping [cT1]) were associated with an increased risk of major CVD events. Methods: Liver disease activity (cT1) and fat (proton density fat fraction [PDFF]) were measured using LiverMultiScan® between January 2016 and February 2020 in the UK Biobank imaging sub-study. Using multivariable Cox regression, we explored associations between liver cT1 (MRI) and primary CVD (coronary artery disease, atrial fibrillation [AF], embolism/vascular events, heart failure [HF] and stroke), and CVD hospitalisation and all-cause mortality. Liver blood biomarkers, general metabolism biomarkers, and demographics were also included. Subgroup analysis was conducted in those without metabolic syndrome (defined as at least three of: a large waist, high triglycerides, low high-density lipoprotein cholesterol, increased systolic blood pressure, or elevated haemoglobin A1c). Results: A total of 33,616 participants (mean age 65 years, mean BMI 26 kg/m2, mean haemoglobin A1c 35 mmol/mol) had complete MRI liver data with linked clinical outcomes (median time to major CVD event onset: 1.4 years [range: 0.002-5.1]; follow-up: 2.5 years [range:1.1-5.2]). Liver disease activity (cT1), but not liver fat (PDFF), was associated with higher risk of any major CVD event (hazard ratio 1.14; 95% CI 1.03–1.26; p = 0.008), AF (1.30; 1.12–1.51; p <0.001); HF (1.30; 1.09–1.56; p = 0.004); CVD hospitalisation (1.27; 1.18-1.37; p <0.001) and all-cause mortality (1.19; 1.02–1.38; p = 0.026). FIB-4 index was associated with HF (1.06; 1.01–1.10; p = 0.007). Risk of CVD hospitalisation was independently associated with cT1 in individuals without metabolic syndrome (1.26; 1.13-1.4; p <0.001). Conclusion: Liver disease activity, by cT1, was independently associated with a higher risk of incident CVD and all-cause mortality, independent of pre-existing metabolic syndrome, liver fibrosis or fat. Impact and implications: Chronic liver disease (CLD) is associated with a twofold greater incidence of cardiovascular disease. Our work shows that early liver disease on iron-corrected T1 mapping was associated with a higher risk of major cardiovascular disease (14%), cardiovascular disease hospitalisation (27%) and all-cause mortality (19%). These findings highlight the prognostic relevance of a comprehensive evaluation of liver health in populations at risk of CVD and/or CLD, even in the absence of clinical manifestations or metabolic syndrome, when there is an opportunity to modify/address risk factors and prevent disease progression. As such, they are relevant to patients, carers, clinicians, and policymakers

Minimal Proteinuria One Year after Transplant is a Risk Factor for Graft Survival in Kidney Transplantation

It is generally accepted that one-year post-transplant proteinuria over 0.5 gm per day has a negative impact on renal graft survival. In this study, the effects of minimal proteinuria less than 0.5 g/day were analyzed in 272 renal recipients who had survived for one year with a functioning graft. Recipients were classified by one-year post-transplant proteinuria: no proteinuria group (<0.2 g/day), minimal proteinuria group (0.2-0.5 g/day), and overt proteinuria group (≥0.5 g/day). Recipients were followed up for 87.1±21 months after transplantation and 38 (13.9%) lost their graft during follow-up. Fifteen percent of patients had minimal proteinuria and 7.8% had overt proteinuria. Five-year graft survival in the minimal proteinuria group was 83.0%, and that in the overt proteinuria group was 70%, in contrast to 97.1% in the no proteinuria group (p=0.01 for trend). In a multivariate analysis, the minimal proteinuria group (relative risk [RR], 4.90; 95% confidence interval [CI], 2.09-11.46) and the overt proteinuria group (RR, 8.75; 95% CI, 3.29-23.29) had higher risks of graft failure than the no proteinuria group. Even minimal proteinuria at one year after transplantation was strongly associated with poor graft outcome. Therefore, it appears logical to consider a low level of proteinuria as a risk factor for graft survival in renal recipients

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin

OPV strains circulation in HIV infected infants after National Immunisation Days in Bangui, Central African Republic

<p>Abstract</p> <p>Background</p> <p>Humans are the only host of polioviruses, thus the prospects of global polio eradication look reasonable. However, individuals with immunodeficiencies were shown to excrete vaccine derived poliovirus for long periods of time which led to reluctance to prolong the vaccination campaign for fear of this end result. Therefore, we aimed to assess the duration of excretion of poliovirus after the 2001 National Immunization Days according to Human immunodeficiency virus status.</p> <p>Findings</p> <p>Fifty three children were enrolled. Sequential stool samples were collected in between National Immunisation Days rounds and then every month during one year. Children were classified into 2 groups: no immunodepression (n = 38), immunodepression (n = 15) according to CD4+ lymphocytes cells count. Thirteen poliovirus strains were isolated from 11 children: 5 Human immunodeficiency virus positive and 6 Human immunodeficiency virus negative. None of the children excreted poliovirus for more than 4 weeks. The restriction fragment length polymorphism analysis showed that all strains were of Sabin origin including a unique Polio Sabine Vaccine types 2 and 3 (S2/S3) recombinant.</p> <p>Conclusions</p> <p>From these findings we assume that Human immunodeficiency virus positive children are not a high risk population for long term poliovirus excretion. More powerful studies are needed to confirm our findings.</p