Isolation, Characterization and Reactivity of Key Intermediates Relevant to Reductive (Electro)catalysis with Cp*Rh Complexes Containing Pyridyl-MIC (MIC=Mesoionic Carbene) Ligands.

In recent years, metal complexes of pyridyl-mesoionic carbene (MIC) ligands have been reported as excellent homogeneous and molecular electrocatalysts. In combination with group 9 metals, such ligands form highly active catalysts for hydrogenation/transfer hydrogenation/hydrosilylation catalysis and electrocatalysts for dihydrogen production. Despite such progress, very little is known about the structural/electrochemical/spectroscopic properties of crucial intermediates for such catalytic reactions with these ligands: solvato complexes, reduced complexes and hydridic species. We present here a comprehensive study involving the isolation, crystallographic characterization, electrochemical/spectroelectrochemical/theoretical investigations, and in-situ reactivity studies of all the aforementioned crucial intermediates involving Cp*Rh and pyridyl-MIC ligands. A detailed mechanistic study of the precatalytic activation of [RhCp*] complexes with pyridyl-MIC ligands is presented. Intriguingly, amphiphilicity of the [RhCp*]-hydride complexes was observed, displaying the substrate dependent transfer of H+ , H or H- . To the best of our knowledge, this study is the first of its kind targeting intermediates and reactive species involving metal complexes of pyridyl-MIC ligands and investigating the interconversion amongst them.

Redox-Active Triazole-Derived Mesoionic Imines with Ferrocenyl Substituents and their Metal Complexes: Directed Hydrogen-Bonding, Unusual C-H Activation and Ion-Pair Formation.

We present herein the synthesis, characterization and complexation of ferrocenyl-substituted MIIs (mesoionic imines) and their metal complexes. In the free MIIs, strong hydrogen bonding interactions are observed between the imine-N and the C-H bonds of the ferrocenyl substituents both in the solid state and in solution. The influence of this hydrogen bonding is so strong that complexation of the MIIs with [IrCp*Cl2]2 yields unique six-membered iridacycles via C-H-activation of the corresponding C-H-site at the Fc-substituent and not the Ph-substituent. This result is in contrast to previous reports in which always a preferential C-H activation at the phenyl substituent is observed in competitive reactions in the presence of ferrocenyl substituents. The corresponding Ir complexes formed after in-situ halide exchange reaction exist in either [Ir-I] contact or as [Ir]+I- solvent separated ion-pairs depending on the solvent polarity. The iodide coordinated and solvent separated ion-pairs display drastically different physical properties. The TEP (Tolman-electronic-parameter) of these ligands was determined and lines up with previously reported MII-ligands. The redox properties were investigated by a combination of electrochemical and spectroelectrochemical methods. We show here how non-covalent interactions can have a drastic influence on the physical and chemical properties of these new class of compounds.

Air-Stable Dinuclear Complexes of Four-Coordinate ZnII and NiII Ions with a Radical Bridge: A Detailed Look at Redox Activity and Antiferromagnetic Coupling.

Air-stable dinuclear complexes [(bmsab)NiII(tmsab)NiII(bmsab)]3- and [(bmsab)ZnII(tmsab)ZnII(bmsab)]3- (bmsab = bis(methanesulfoneamido)benzene, tmsab = tetra(methanesulfonamido)benzene) were prepared via a synthetic route based on heteroleptic precursor complexes. The new complexes combine a distorted tetrahedral coordination environment with an open-shell bridging ligand. The ZnII species was subjected to a detailed investigation of the (spectro-)electrochemical processes. The NiII species is a rare example of a complex that combines strong exchange coupling (J > 440 cm-1) with pronounced positive zero-field splitting (D = +72 cm-1). Combining SQUID magnetometry and (HF)EPR spectroscopy with ab initio calculations allowed for accurate quantification of the exchange interaction.

Azide-Substituted 1,2,3-Triazolium Salts as Useful Synthetic Synthons: Access to Triazenyl Radicals and Staudinger Type Reactivity.

Mesoionic carbenes (MIC) are a popular class of compound that are heavily investigated at the moment. The access to cationic MICs, and the ability of MICs to stabilize radicals are two highly attractive fields that have hardly been explored until now. Here the synthesis and characterisation of three different cationic azide-substituted 1,2,3-triazolium salts, used as building blocks for studying their reactivity towards triphenylphosphine are reported, where the reactivity is dependent on the nature of the starting triazolium salt. Furthermore, the cationic triazolium salts were used to develop a series of unsymmetrical MIC-triazene-NHC/MIC' compounds, which can be readily converted to the radical form either by electrochemical or chemical methods. These radicals, which display NIR electrochromism, were investigated using a battery of techniques such as electrochemistry, UV/Vis/NIR and EPR spectroelectrochemistry, and theoretical calculations. Interestingly, the MIC plays an important role in the stabilization of the triazenyl radical, particularly in a competitive role vis-à-vis their NHC counterparts. These results shed new light on the ability of MICs to stabilize radicals, and possibly also on their π-accepting ability.

The Best of Both Worlds: Combining the Power of MICs and WCAs To Generate Stable and Crystalline CrI -Tetracarbonyl Complexes with π-Accepting Ligands.

Invited for the cover of this issue are Biprajit Sarkar and co-workers at the University of Stuttgart and University of Freiburg. In the image, the solar flare represents the non-innocence (fluorine-specific interactions) of the counterion, and the black hole at the metal center illustrates the oxidation/electron deficiency of the Cr-center, while the electron "gets lost" in the space (oxidation agent). Read the full text of the article at 10.1002/chem.202301205.

The Best of Both Worlds: Combining the Power of MICs and WCAs To Generate Stable and Crystalline CrI -Tetracarbonyl Complexes with π-Accepting Ligands.

Here we present stable and crystalline chromium(I) tetracarbonyl complexes with pyridyl-MIC (MIC=mesoionic carbene) ligands and weakly coordinating anions (WCA=[Al(ORF )4 ]- , RF =C(CF3 )3 and BArF =[B(ArF )4 ]- , ArF =3,5-(CF3 )2 C6 H3 ). The complexes were fully characterized via crystallographic, spectroscopic and theoretical methods. The influence of counter anions on the IR and EPR spectroscopic properties of the CrI complexes was investigated, and the electronic innocence versus non-innocence of WCAs was probed. These are the first examples of stable and crystalline [Cr(CO)4 ]+ complexes with a chelating π - ${\pi -}$ accepting ligand, and the data presented here are of relevance for both the photochemical and the electrochemical properties of these classes of compounds.

Ruthenium Complexes of Polyfluorocarbon Substituted Terpyridine and Mesoionic Carbene Ligands: An Interplay in CO2 Reduction.

In recent years terpyridines (tpy) and mesoionic carbenes (MIC) have been widely used in metal complexes. With the right combination with a metal center, both of these ligands are individually known to generate excellent catalysts for CO2 reduction. In this study, we combine the potentials of PFC (PFC=polyfluorocarbon) substituted tpy and MIC ligands within the same platform to obtain a new class of complexes, which we investigated with respect to their structural, electrochemical and UV/Vis/NIR spectroelectrochemical properties. We further show that the resulting metal complexes are potent electrocatalysts for CO2 reduction in which CO is exclusively formed with a faradaic efficiency of 92 %. A preliminary mechanistic study, including the isolation and characterization of a key intermediate is also reported.

Spin State in Homoleptic Iron(II) Terpyridine Complexes Influences Mixed Valency and Electrocatalytic CO2 Reduction.

Two homoleptic Fe(II) complexes in different spin states bearing superbasic terpyridine derivatives as ligands are investigated to determine the relationship between spin state and electrochemical/spectroscopic behavior. Antiferromagnetic coupling between a ligand-centered radical and the high-spin metal center leads to an anodic shift of the first reduction potential and results in a species that shows mixed valency with a moderately intense intervalence-charge-transfer band. The differences afforded by the different spin states extend to the electrochemical reactivity of the complexes: while the low-spin species is a precatalyst for electrocatalytic CO2 reduction and leads to the preferential formation of CO with a Faradaic efficiency of 37%, the high-spin species only catalyzes proton reduction at a modest Faradaic efficiency of approximately 20%.

Financial and Clinical Impact of Virtual Care During the COVID-19 Pandemic: Difference-in-Differences Analysis.

BACKGROUND: Virtual care (VC) and remote patient monitoring programs were deployed widely during the COVID-19 pandemic. Deployments were heterogeneous and evolved as the pandemic progressed, complicating subsequent attempts to quantify their impact. The unique arrangement of the US Military Health System (MHS) enabled direct comparison between facilities that did and did not implement a standardized VC program. The VC program enrolled patients symptomatic for COVID-19 or at risk for severe disease. Patients' vital signs were continuously monitored at home with a wearable device (Current Health). A central team monitored vital signs and conducted daily or twice-daily reviews (the nurse-to-patient ratio was 1:30). OBJECTIVE: Our goal was to describe the operational model of a VC program for COVID-19, evaluate its financial impact, and detail its clinical outcomes. METHODS: This was a retrospective difference-in-differences (DiD) evaluation that compared 8 military treatment facilities (MTFs) with and 39 MTFs without a VC program. Tricare Prime beneficiaries diagnosed with COVID-19 (Medicare Severity Diagnosis Related Group 177 or International Classification of Diseases-10 codes U07.1/07.2) who were eligible for care within the MHS and aged 21 years and or older between December 2020 and December 2021 were included. Primary outcomes were length of stay and associated cost savings; secondary outcomes were escalation to physical care from home, 30-day readmissions after VC discharge, adherence to the wearable, and alarms per patient-day. RESULTS: A total of 1838 patients with COVID-19 were admitted to an MTF with a VC program of 3988 admitted to the MHS. Of these patients, 237 (13%) were enrolled in the VC program. The DiD analysis indicated that centers with the program had a 12% lower length of stay averaged across all COVID-19 patients, saving US $2047 per patient. The total cost of equipping, establishing, and staffing the VC program was estimated at US $3816 per day. Total net savings were estimated at US $2.3 million in the first year of the program across the MHS. The wearables were activated by 231 patients (97.5%) and were monitored through the Current Health platform for a total of 3474 (median 7.9, range 3.2-16.5) days. Wearable adherence was 85% (IQR 63%-94%). Patients triggered a median of 1.6 (IQR 0.7-5.2) vital sign alarms per patient per day; 203 (85.7%) were monitored at home and then directly discharged from VC; 27 (11.4%) were escalated to a physical hospital bed as part of their initial admission. There were no increases in 30-day readmissions or emergency department visits. CONCLUSIONS: Monitored patients were adherent to the wearable device and triggered a manageable number of alarms/day for the monitoring-team-to-patient ratio. Despite only enrolling 13% of COVID-19 patients at centers where it was available, the program offered substantial savings averaged across all patients in those centers without adversely affecting clinical outcomes.

Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model.

The exact mechanism of desmoplastic stromal reaction (DSR) formation is still unclear. The interaction between cancer cells and cancer-associated fibroblasts (CAFs) has an important role in tumor progression, while stromal changes are a poor prognostic factor in pleural mesothelioma (PM). We aimed to assess the impact of CAFs paracrine signaling within the tumor microenvironment and the DSR presence on survival, in a cohort of 77 PM patients. DSR formation was evaluated morphologically and by immunohistochemistry for Fibroblast activation protein alpha (FAP). Digital gene expression was analyzed using a custom-designed CodeSet (NanoString). Decision-tree-based analysis using the "conditional inference tree" (CIT) machine learning algorithm was performed on the obtained results. A significant association between FAP gene expression levels and the appearance of DSR was found (p = 0.025). DSR-high samples demonstrated a statistically significant prolonged median survival time. The elevated expression of MYT1, KDR, PIK3R1, PIK3R4, and SOS1 was associated with shortened OS, whereas the upregulation of VEGFC, FAP, and CDK4 was associated with prolonged OS. CIT revealed a three-tier system based on FAP, NF1, and RPTOR expressions. We could outline the prognostic value of CAFs-induced PI3K signaling pathway activation together with FAP-dependent CDK4 mediated cell cycle progression in PM, where prognostic and predictive biomarkers are urgently needed to introduce new therapeutic strategies.

Adjunct Use of Continuous Renal Replacement Therapy with Extracorporeal Membrane Oxygenation Achieves Negative Fluid Balance and Enhances Oxygenation Which Improves Survival in Critically Ill Patients without Kidney Failure.

INTRODUCTION: Fluid overload in extracorporeal membrane oxygenation (ECMO) patients has been associated with increased mortality. Patients receiving ECMO and continuous renal replacement therapy (CRRT) who achieve a negative fluid balance have improved survival. Limited data exist on the use of CRRT solely for fluid management in ECMO patients. METHODS: We performed a single-center retrospective review of 19 adult ECMO patients without significant renal dysfunction who received CRRT for fluid management. These patients were compared to a cohort of propensity-matched controls. RESULTS: After 72 h, the treatment group had a fluid balance of -3840 mL versus + 425 mL (p ≤ 0.05). This lower fluid balance correlated with survival to discharge (odds ratio 2.54, 95% confidence interval 1.10-5.87). Improvement in the ratio of arterial oxygen content to fraction of inspired oxygen was also significantly higher in the CRRT group (102.4 vs. 0.7, p ≤ 0.05). We did not observe any significant difference in renal outcomes. CONCLUSIONS: The use of CRRT for fluid management is effective and, when resulting in negative fluid balance, improves survival in adult ECMO patients without significant renal dysfunction.

Molecular Subtyping of Invasive Breast Cancer Using a PAM50-Based Multigene Expression Test-Comparison with Molecular-Like Subtyping by Tumor Grade/Immunohistochemistry and Influence on Oncologist's Decision on Systemic Therapy in a Real-World Setting.

In intermediate risk hormone receptor (HR) positive, HER2 negative breast cancer (BC), the decision regarding adjuvant chemotherapy might be facilitated by multigene expression tests. In all, 142 intermediate risk BCs were investigated using the PAM50-based multigene expression test Prosigna® in a prospective multicentric study. In 119/142 cases, Prosigna® molecular subtyping was compared with local and two central (C1 and C6) molecular-like subtypes relying on both immunohistochemistry (IHC; HRs, HER2, Ki-67) and IHC + tumor grade (IHC+G) subtyping. According to local IHC, 35.4% were Luminal A-like and 64.6% Luminal B-like subtypes (local IHC+G subtype: 31.9% Luminal A-like; 68.1% Luminal B-like). In contrast to local and C1 subtyping, C6 classified >2/3 of cases as Luminal A-like. Pairwise agreement between Prosigna® subtyping and molecular-like subtypes was fair to moderate depending on molecular-like subtyping method and center. The best agreement was observed between Prosigna® (53.8% Luminal A; 44.5% Luminal B) and C1 surrogate subtyping (Cohen's kappa = 0.455). Adjuvant chemotherapy was suggested to 44.2% and 88.6% of Prosigna® Luminal A and Luminal B cases, respectively. Out of all Luminal A-like cases (locally IHC/IHC+G subtyping), adjuvant chemotherapy was recommended if Prosigna® testing classified as Prosigna® Luminal A at high / intermediate risk or upgraded to Prosigna® Luminal B.

Dentogingival display through lip border movements: Report of the Committee on Research in Fixed Prosthodontics of the American Academy of Fixed Prosthodontics.

STATEMENT OF PROBLEM: Dentists strive to create natural looking teeth for their patients. However, much of the research on esthetic dentistry has used artificial and computer-generated images to establish esthetic norms. Altered images are helpful in determining personal preferences but may be misleading for natural norms. PURPOSE: The purpose of this report from the Committee on Research in Fixed Prosthodontics of the American Academy of Fixed Prosthodontics was to establish an evidence base for clinical guidelines on lip mobility and the visibility of oral tissues. MATERIAL AND METHODS: A systematic search was conducted to collect data on the lip border movements and the visibility of teeth and gingiva of human participants. RESULTS: One thousand and ninety-six articles were processed, and, based on inclusion criteria, 48 articles were reviewed. The findings determined that the upper lip lengthens with age resulting, at rest, in less display of the maxillary teeth and more of the mandibular arch. When evaluating the maxillary incisal edge position at rest, the canines are the most reproducible. Women tend to display more gingiva in a social smile than men, but this may not be so for a true smile of joy. Both the middle and lower facial thirds should be evaluated to detect a maximal smile. Care must be taken not to classify a person incorrectly as having a low smile line because they could still have a potential to show gingiva. CONCLUSIONS: Evidence-based clinical guidelines are offered to reduce the risk of esthetic failures.

Mesoionic Imines (MIIs): Strong Donors and Versatile Ligands for Transition Metals and Main Group Substrates.

We report the synthesis and the reactivity of 1,2,3-triazolin-5-imine type mesoionic imines (MIIs). The MIIs are accessible by a base-mediated cycloaddition between a substituted acetonitrile and an aromatic azide, methylation by established routes and subsequent deprotonation. C=O-stretching frequencies in MII-CO2 and -Rh(CO)2 Cl complexes were used to determine the overall donor strength. The MIIs are stronger donors than the N-heterocyclic imines (NHIs). MIIs are excellent ligands for main group elements and transition metals in which they display substituent-induced fluorine-specific interactions and undergo C-H activation. DFT calculations gave insights into the frontier orbitals of the MIIs. The calculations predict a relatively small HOMO-LUMO gap compared to other related ligands. MIIs are potentially able to act as both π-donor and π-acceptor ligands. This report highlights the potential of MIIs to display exciting properties with a huge potential for future development.

Development of weight and age-based dosing of daily primaquine for radical cure of vivax malaria.

BACKGROUND: In many endemic areas, Plasmodium vivax malaria is predominantly a disease of young adults and children. International recommendations for radical cure recommend fixed target doses of 0.25 or 0.5 mg/kg/day of primaquine for 14 days in glucose-6-phosphate dehydrogenase normal patients of all ages. However, for many anti-malarial drugs, including primaquine, there is evidence that children have lower exposures than adults for the same weight-adjusted dose. The aim of the study was to develop 14-day weight-based and age-based primaquine regimens against high-frequency relapsing tropical P. vivax. METHODS: The recommended adult target dose of 0.5 mg/kg/day (30 mg in a 60 kg patient) is highly efficacious against tropical P. vivax and was assumed to produce optimal drug exposure. Primaquine doses were calculated using allometric scaling to derive a weight-based primaquine regimen over a weight range from 5 to 100 kg. Growth curves were constructed from an anthropometric database of 53,467 individuals from the Greater Mekong Subregion (GMS) to define weight-for-age relationships. The median age associated with each weight was used to derive an age-based dosing regimen from the weight-based regimen. RESULTS: The proposed weight-based regimen has 5 dosing bands: (i) 5-7 kg, 5 mg, resulting in 0.71-1.0 mg/kg/day; (ii) 8-16 kg, 7.5 mg, 0.47-0.94 mg/kg/day; (iii) 17-40 kg, 15 mg, 0.38-0.88 mg/kg/day; (iv) 41-80 kg, 30 mg, 0.37-0.73 mg/kg/day; and (v) 81-100 kg, 45 mg, 0.45-0.56 mg/kg/day. The corresponding age-based regimen had 4 dosing bands: 6-11 months, 5 mg, 0.43-1.0 mg/kg/day; (ii) 1-5 years, 7.5 mg, 0.35-1.25 mg/kg/day; (iii) 6-14 years, 15 mg, 0.30-1.36 mg/kg/day; and (iv) ≥ 15 years, 30 mg, 0.35-1.07 mg/kg/day. CONCLUSION: The proposed weight-based regimen showed less variability around the primaquine dose within each dosing band compared to the age-based regimen and is preferred. Increased dose accuracy could be achieved by additional dosing bands for both regimens. The age-based regimen might not be applicable to regions outside the GMS, which must be based on local anthropometric data. Pharmacokinetic data in small children are needed urgently to inform the proposed regimens.

Outcomes among Patients Treated with Renal Replacement Therapy during Extracorporeal Membrane Oxygenation: A Single-Center Retrospective Study.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) are modalities used in critically ill patients suffering organ failure and metabolic derangements. Although the effects of CRRT have been extensively studied, the impact of simultaneous CRRT and ECMO is less well described. The purpose of this study is to evaluate the incidence and the impact of CRRT on outcomes of patients receiving ECMO. METHODS: A single center, retrospective chart review was conducted for patients receiving ECMO therapy over a 6-year period. Patients who underwent combined ECMO and CRRT were compared to those who underwent ECMO alone. Intergroup -statistical comparisons were performed using Wilcoxon/Kruskal-Wallis and chi-square tests. Logistic regression was performed to identify independent risk factors for mortality. RESULTS: The demographic and clinical data of 92 patients who underwent ECMO at our center were reviewed including primary diagnosis, indications for and mode of ECMO support, illness severity, oxygenation index, vasopressor requirement, and presence of acute kidney injury. In those patients that required ECMO with CRRT, we reviewed urine output prior to initiation, modality used, prescribed dose, net fluid balance after 72 h, requirement of renal replacement therapy (RRT) at discharge, and use of diuretics prior to RRT initiation. Our primary endpoint was survival to hospital discharge. During the study period, 48 patients required the combination of ECMO with CRRT. Twenty-nine of these patients survived to hospital discharge. Of the 29 survivors, 6 were dialysis dependent at hospital discharge. The mortality rate was 39.5% with combined ECMO/CRRT compared to 31.4% among those receiving ECMO alone (p = 0.074). Of those receiving combined therapy, nonsurvivors were more likely to have a significantly positive net fluid balance at 72 h (p = 0.001). A multivariate linear regression analysis showed net positive fluid balance and increased age were independently associated with mortality. CONCLUSIONS: Use of CRRT is prevalent among patients undergoing ECMO, with over 50% of our patient population receiving combination therapy. Fluid balance appears to be an important variable associated with outcomes in this cohort. Rates of renal recovery and overall survival were higher compared to previously published reports among those requiring combined ECMO/CRRT.

Environmental, climatic and host population risk factors of human cystic echinococcosis in southwest of Iran.

BACKGROUND: Cystic echinococcosis (CE), a worldwide zoonotic disease, is affected by various biological and environmental factors. We investigated dog/livestock populations, climatic and environmental factors influencing the distribution of human CE cases in Fars province, southwest Iran. METHODS: We mapped the addresses of 266 hospitalised CE patients (2004-2014) and studied the effects of different temperature models, mean annual rainfall and humidity, number of frosty days, slope, latitude, land covers, close proximity to nomads travel routes, livestock and dog densities on the occurrence of CE using geographical information systems approach. Data were analyzed by logistic regression. RESULTS: In the multivariate model predicting CE, living in an urban setting and densities of cattle and dogs were the most important CE predictors, sequentially. Dry (rained) farm, density of camel and sheep, close proximity to nomads travel routes, humidity, and slope also were considered as the determinants of CE distribution, when analyzed independently. Slope had a negative correlation with CE while temperature, frost days and latitude were not associated with CE. CONCLUSIONS: In our study, an urban setting was the most important risk factor and likely due to a combination of the high density of key life cycle hosts, dogs and livestock, a large human susceptible population and the high number of abattoirs. Farmland and humidity were highly suggestive risk factors and these conditions support the increased survival of Echinococcus granulosus eggs in the soil. These findings support the development of strategies for control of disease. More research is needed test optimal interventions.

Use of Mortality as an Endpoint in Noninferiority Trials May Lead to Ethically Problematic Conclusions.

BACKGROUND: Noninferiority trials are becoming more common. Their design often requires investigators to "trade" a secondary benefit for efficacy. Use of mortality as an outcome of interest leads to important ethical conflicts whereby researchers must establish a minimal clinically important difference for mortality, a process which has the potential to result in problematic conclusions. OBJECTIVE: We sought to investigate the frequency of the use of mortality as an outcome in noninferiority trials, as well as to determine the average pre-specified noninferiority ("delta") values. DESIGN: We searched MEDLINE for reports of parallel-group randomized controlled noninferiority trials published in five high-impact general medical journals. MAIN OUTCOME MEASURES: Data abstracted from articles including trial design parameters, results, and interpretation of results based on CONSORT recommendations. RESULTS: One hundred seventy-three manuscripts reporting 196 noninferiority comparisons were included in our analysis. Of these, over a third (67 trials) used mortality either as their sole endpoint (11 trials) or as part of a composite endpoint (56 trials). Nine trials were consort A, 21 trials consort B, 19 trials consort C, 12 were consort F, 4 consort G, and 2 were consort H. Four analyses showed statistically significant more deaths in the new treatment arm, while meeting consort criteria as "inconclusive" (consort G), (Behringer et al. in Lancet. 385(9976):1418-1427, 2015; Kaul et al. in N Engl J Med. 373(18):1709-1719, 2015; Bwakura-Dangarembizi et al. in N Engl J Med. 370(1):41-53, 2014) and thirteen trials utilizing mortality as an endpoint and had an absolute increase of > 3%, and six had an absolute increase of > 5%. CONCLUSIONS: The use of mortality as an outcome in noninferiority trials is not rare and scenarios where the new treatment is statistically worse, but a conclusion of noninferiority or inconclusive do occur. We highlight these issues and propose simple steps to reduce the risk of ethically dubious conclusions.

Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a tumour arising from pleural cavities with poor prognosis. Multimodality treatment with pemetrexed combined with cisplatin shows unsatisfying response-rates of 40%. The reasons for the rather poor efficacy of chemotherapeutic treatment are largely unknown. However, it is conceivable that DNA repair mechanisms lead to an impaired therapy response. We hypothesize a major role of homologous recombination (HR) for genome stability and survival of this tumour. Therefore, we analysed genes compiled under the term "BRCAness". An inhibition of this pathway with olaparib might abrogate this effect and induce apoptosis. METHODS: We investigated the response of three MPM cell lines and lung fibroblasts serving as a control to treatment with pemetrexed, cisplatin and olaparib. Furthermore, we aimed to find possible correlations between response and gene expression patterns associated with BRCAness phenotype. Therefore, 91 clinical MPM samples were digitally screened for gene expression patterns of HR members. RESULTS: A BRCAness-dependent increase of apoptosis and senescence during olaparib-based treatment of BRCA-associated-protein 1 (BAP1)-mutated cell lines was observed. The gene expression pattern identified could be found in approx. 10% of patient samples. Against this background, patients could be grouped according to their defects in the HR system. Gene expression levels of Aurora Kinase A (AURKA), RAD50 as well as DNA damage-binding protein 2 (DDB2) could be identified as prognostic markers in MPM. CONCLUSIONS: Defects in HR compiled under the term BRCAness are a common event in MPM. The present data can lead to a better understanding of the underlaying cellular mechanisms and leave the door wide open for new therapeutic approaches for this severe disease with infaust prognosis. Response to Poly (ADP-ribose)-Polymerase (PARP)-Inhibition could be demonstrated in the BAP1-mutated NCI-H2452 cells, especially when combined with cisplatin. Thus, this combination therapy might be effective for up to 2/3 of patients, promising to enhance patients' clinical management and outcome.

Renal replacement therapy intensity for acute kidney injury and recovery to dialysis independence: a systematic review and individual patient data meta-analysis.

Background: There is no consensus whether higher intensity dose renal replacement therapy (RRT) compared with standard intensity RRT has survival benefit and achieves better renal recovery in acute kidney injury (AKI). Methods: In an individual patient data meta-analysis, we merged individual patient data from randomized controlled trials (RCTs) comparing high with standard intensity RRT in intensive care unit patients with severe AKI. The primary outcome was all-cause mortality. The secondary outcome was renal recovery assessed as the proportion of patients who were RRT dependent at key trial endpoints and by time to the end of RRT dependence. Results: Of the eight prospective RCTs assessing different RRT intensities, seven contributed individual patient data (n = 3682) to the analysis. Mortality was similar between the two groups at 28 days [769/1884 (40.8%) and 744/1798 (41.4%), respectively; P = 0.40] after randomization. However, more participants assigned to higher intensity therapy remained RRT dependent at the most common key study point of 28 days [e.g. 292/983 (29.7%) versus 235/943 (24.9%); relative risk 1.15 (95% confidence interval 1.00-1.33); P = 0.05]. Time to cessation of RRT through 28 days was longer in patients receiving higher intensity RRT (log-rank test P = 0.02) and when continuous renal replacement therapy was used as the initial modality of RRT (log-rank test P = 0.03). Conclusions: In severe AKI patients, higher intensity RRT does not affect mortality but appears to delay renal recovery. Trial Registration: Australian New Zealand Clinical Trials Registry (ANZCTR) identifier ACTRN12615000394549 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000394549).