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Concerns over the ecological impacts of urban road runoff have increased, partly due to recent research into the harmful impacts of tire particles and their chemical leachates. This study aimed to help the community of researchers, regulators and policy advisers in scoping out the priority areas for further study. To improve our understanding of these issues an interdisciplinary, international network consisting of experts (United Kingdom, Norway, United States, Australia, South Korea, Finland, Austria, China and Canada) was formed. We synthesised the current state of the knowledge and highlighted priority research areas for tire particles (in their different forms) and their leachates. Ten priority research questions with high importance were identified under four themes (environmental presence and detection; chemicals of concern; biotic impacts; mitigation and regulation). The priority research questions include the importance of increasing the understanding of the fate and transport of these contaminants; better alignment of toxicity studies; obtaining the holistic understanding of the impacts; and risks they pose across different ecosystem services. These issues have to be addressed globally for a sustainable solution. We highlight how the establishment of the intergovernmental science-policy panel on chemicals, waste, and pollution prevention could further address these issues on a global level through coordinated knowledge transfer of car tire research and regulation. We hope that the outputs from this research paper will reduce scientific uncertainty in assessing and managing environmental risks from TP and their leachates and aid any potential future policy and regulatory development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Combining antibody-drug conjugate (ADCs) with immune checkpoint inhibitors (ICIs) is emerging as a promising treatment option to increase efficacy outcomes. However, concerns arise regarding the safety of these combinations, as some toxicities may overlap. Currently, there is still limited information about the safety profiles of this strategy., Methods: A systematic review and meta-analysis was conducted to identify clinical trials investigating FDA-approved ADCs in combination with ICI drugs in the metastatic setting across all solid tumors. The primary endpoint of this study was the percentage of adverse events (AEs) of any grade and grade ≥ 3. Secondary endpoints include the percentage of patients with AEs leading to death, treatment discontinuation, proportion of complete responses (CR) and overall response rate (ORR). A parallel search was conducted to quantify the safety profile of ADCs and ICIs in monotherapy. Random effects models were used to estimate pooled outcomes., Results: Sixteen trials involving 1,133 patients treated with ADC plus ICI met the inclusion criteria with six different ADCs evaluated. Overall, 55.3 % of patients developed grade ≥ 3 AEs, 30.0 % of patients had treatment discontinuation, and 3.0 % experienced AEs leading to death. When compared to trials evaluating ADC or ICI as monotherapy, the combination results in similar rates of the most common AEs. However, it increases the risk of specific toxicities, such as ILD/pneumonitis (15.0 % with T-DXd plus ICI vs. 11.5 % with T-DXd alone). The pooled ORR was 48.8 % (95 %CI 39.4 % - 58.4 %) and the CR rate was 9.0 % (95 %CI 5.5 - 14.5). PD-L1-positive tumors showed numerically better efficacy outcomes., Conclusions: This meta-analysis shows that the safety profile of the ADC plus ICI is comparable to that of ADC monotherapy. However, it increases the risk of certain toxicities of special interest, such as ILD/pneumonitis, highlighting the need for careful monitoring., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Hydrocephalus is a clinical and neurologic condition characterized by an abnormal accumulation of cerebrospinal fluid (CSF). Currently, idiopathic Normal Pressure Hydrocephalus (iNPH) is recognized as a late-onset neurologic disorder defined by a clinical triad of gait disturbance, urinary incontinence, and dementia. Imaging studies often reveal a disproportionate increase in subarachnoid space and ventricular size relative to brain volume, with normal CSF pressure during lumbar puncture. Recent developments in neuroimaging have led to the establishment of criteria for diagnosing and managing iNPH, incorporating the concept of Disproportionately Enlarged Subarachnoid-space Hydrocephalus (DESH). Distinguishing iNPH from the natural neurological aging process and other forms of dementia, wherein brain atrophy and hydrocephalus ex vacuo can be observed, can present challenges for both neurologists and neuroradiologists. Despite DESH becoming a radiologic criterion for diagnosing iNPH in some guidelines, its recognition remains limited., Competing Interests: Declaration of competing interest There is no conflict of interest on this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Botanical supplements and herbal products are widely used by consumers for various purported health benefits, and their popularity is increasing. Some of these natural products can have adverse effects on liver function and/or interact with prescription and over-the-counter (OTC) medications. Ensuring the safety of these readily available products is a crucial public health concern; however, not all regulatory authorities require premarket safety review and/or testing. To address and discuss these and other emerging needs related to botanical safety, a symposium was held at the Society of Toxicology Annual Meeting in Salt Lake City (UT) on March 11, 2024. The symposium addressed the latest research on botanical-induced liver toxicity and botanical-drug interactions, including new approach methods to screen for toxicity, challenges in assessing the safety of botanicals, and relating human adverse events to specific products. The presentations and robust panel discussion between the speakers and audience highlighted the need for further research and collaboration to improve the safety of botanical supplements and herbal products, with the ultimate goal of protecting consumer health. Although utility of many of the modern tools presented in the symposium requires further study, the synergistic efforts of diverse experts hold promise for effective prediction and evaluation of botanical-induced hepatotoxicity and botanical-drug interaction potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The following author initials are employed by the private sector: AR., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: PCF has received consulting fees from Ninja Theory and Hooke London. All other authors declare no competing interests.

About 3 billion new tires are produced each year and about 800 million tires become waste annually. Global dependence upon tires produced from natural rubber and petroleum-based compounds represents a persistent and complex environmental problem with only partial and often-times, ineffective solutions. Tire emissions may be in the form of whole tires, tire particles, and chemical compounds, each of which is transported through various atmospheric, terrestrial, and aquatic routes in the natural and built environments. Production and use of tires generates multiple heavy metals, plastics, PAH's, and other compounds that can be toxic alone or as chemical cocktails. Used tires require storage space, are energy intensive to recycle, and generally have few post-wear uses that are not also potential sources of pollutants (e.g., crumb rubber, pavements, burning). Tire particles emitted during use are a major component of microplastics in urban runoff and a source of unique and highly potent toxic substances. Thus, tires represent a ubiquitous and complex pollutant that requires a comprehensive examination to develop effective management and remediation. We approach the issue of tire pollution holistically by examining the life cycle of tires across production, emissions, recycling, and disposal. In this paper, we synthesize recent research and data about the environmental and human health risks associated with the production, use, and disposal of tires and discuss gaps in our knowledge about fate and transport, as well as the toxicology of tire particles and chemical leachates. We examine potential management and remediation approaches for addressing exposure risks across the life cycle of tires. We consider tires as pollutants across three levels: tires in their whole state, as particulates, and as a mixture of chemical cocktails. Finally, we discuss information gaps in our understanding of tires as a pollutant and outline key questions to improve our knowledge and ability to manage and remediate tire pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Attempts to understand psychosis-the experience of profoundly altered perceptions and beliefs-raise questions about how the brain models the world. Standard predictive coding approaches suggest that it does so by minimising mismatches between incoming sensory evidence and predictions. By adjusting predictions, we converge iteratively on a best guess of the nature of the reality. Recent arguments have shown that a modified version of this framework-hybrid predictive coding-provides a better model of how healthy agents make inferences about external reality. We suggest that this more comprehensive model gives us a richer understanding of psychosis compared with standard predictive coding accounts. In this Personal View, we briefly describe the hybrid predictive coding model and show how it offers a more comprehensive account of the phenomenology of delusions, thereby providing a potentially powerful new framework for computational psychiatric approaches to psychosis. We also make suggestions for future work that could be important in formalising this novel perspective., Competing Interests: Declaration of interests PCF has received consulting fees from Ninja Theory and Hooke London. All other authors declare no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: PD1/PD-L1 immune checkpoint inhibitors (ICI) have revolutionized cancer treatment. Although there is controversy about the accuracy of surrogate endpoints in the ICI setting to predict overall survival (OS), these endpoints are commonly used in confirmatory trials. Here we aimed to explore the validity of classical and novel surrogate endpoints in randomised controlled trials (RCT) that combine ICI plus chemotherapy (CT) in the first-line setting., Material and Methods: A systematic review was conducted to identify RCT investigating anti-PD1/PD-L1 drugs plus CT versus CT alone. We performed (i) arm-level analysis to evaluate predictors of median OS (mOS) and (ii) comparison-level analysis for OS hazard ratio (HR) estimations. Linear regression models weighted by trial size were fitted and adjusted R 2 values were reported., Results: Thirty-nine RCTs involving 22,341 patients met the inclusion criteria (17 non-small cell lung, 9 gastroesophageal and 13 in other cancers) with ten different ICI under study. Overall, ICI plus CT improved OS (HR = 0.76; 95%CI: 0.73-0.80). In the arm-level analysis, the best mOS prediction was obtained with a new endpoint that combines median duration of response and ORR (mDoR-ORR) and with median PFS (R 2  = 0.5 both). In the comparison-level analysis, PFS HR showed a moderate association with OS HR (R 2  = 0.52). Early OS read-outs were highly associated with final OS outcomes (R 2  = 0.80)., Conclusions: The association between surrogate endpoints and OS in first-line RCT combining anti-PD1/PD-L1 and CT is moderate-low. Early OS read-outs showed a good association with final OS HR while the mDOR-ORR endpoint could help to better design confirmatory trials after single-arm phase II trials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background & Aims: Nitrofurantoin (NTF) is widely used for the treatment (short-term) and prevention (long-term) of urinary tract infections. We aimed to describe the clinical characteristics, outcomes, and HLA risk factors for NTF-induced liver injury (NTF-DILI) among individuals enrolled in the Drug Induced Liver Injury Network (DILIN)., Methods: Seventy-eight individuals with definite, highly likely, or probable NTF-DILI were enrolled into DILIN studies between 2004-2020. HLA alleles were compared between NTF-DILI and three control groups: population (n = 14,001), idiopathic autoimmune hepatitis (n = 231), and non-NTF DILI (n = 661)., Results: Liver injury was hepatocellular in 69% and icteric in 55%. AST > ALT was more common in the 44 long-exposure (≥1 year) NTF-DILI cases than in the 18 short (≤7 days) and 16 intermediate (>7 to <365 days) exposure cases (73% vs. 33% vs. 50%, respectively, p = 0.018), as was ANA or SMA positivity (91% vs. 44% vs. 50%, respectively, p <0.001), and corticosteroid use (61% vs. 27% vs. 44%, respectively, p = 0.06). In long-term NTF-DILI, bridging fibrosis, nodularity or cirrhosis, or clinical and imaging evidence for cirrhosis were present in 38%, with massive or sub-massive necrosis in 20%. No one in the short-term exposure group died or underwent transplantation, whereas 7 (12%) patients from the other groups died or underwent transplantation. After covariate adjustments, HLA-DRB1∗11:04 was significantly more frequent in NTF-DILI compared to population controls (odds ratio [OR] 4.29, p = 1.15 × 10 -4 ), idiopathic autoimmune hepatitis (OR 11.77, p = 7.76 × 10 -5 ), and non-NTF DILI (OR 3.34, p = 0.003)., Conclusion: NTF-DILI can result in parenchymal necrosis, bridging fibrosis, cirrhosis, and death or liver transplantation, especially with long-term exposure, and is associated with HLA-DRB1∗11:04. To mitigate against serious liver injury associated with NTF, regulators should revise the prescribing information and consider other mitigation strategies., Impact and Implications: Nitrofurantoin is a recognized cause of drug-induced liver injury (DILI). In this study consisting of a large cohort of well-phenotyped individuals with nitrofurantoin-induced liver injury, two distinct patterns of liver injury were identified: liver injury associated with short-term exposure, which is generally self-limiting, and liver injury associated with long-term exposure, which can lead to advanced fibrosis, cirrhosis and liver failure. HLA DRB1∗11:04 is a risk factor for liver injury due to long-term nitrofurantoin exposure. Our findings are important for regulators as well as physicians prescribing and pharmacists dispensing nitrofurantoin., Competing Interests: Conflict of interest Dr. Chalasani has ongoing paid consulting activities (or had in preceding 12 months) with AbbVie, Madrigal, Foresite labs, Galectin, Zydus, Boehringer-Ingelheim, Lilly and Altimmune. He has grant support from Exact Sciences and DSM. These activities are not directly or significantly related to this paper. Dr. Robert Fontana reports ongoing research support from Abbvie and Gilead but not related to current study. Dr. Herbert L Bonkovsky reports recent (in preceding 12 months) or ongoing paid consulting activities with Alnylam Pharma, Disc Medicine, Protagonist Pharma, Recordati Rare Chemicals. He serves as PI for sponsored clinical research awarded to Wake Forest Baptist Medical Center from Alnylam, Gilead Sciences, Genkyotex SA, Mitsubishi-Tanabe, NA. These activities are not directly or significantly related to this paper. Dr. Nicoletti is an employee of Sema 4. She also reports ongoing piad consulting activities with Chieso Farmaceutici S.p.A and Audentes Therapeutics, but these activities are not directly or significantly related to this paper. Drs. Barnhart, Navarro, Kleiner, Hoofnagle, Phillips, Dellinger, Gu, Tae-Hwi Schwantes-An, and Lammert have no conflicts of interests to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: Intraventricular hemorrhage (IVH) is the most common central nervous system pathology in preterm infants. No consensus has been reached over the best indication for intervention in patients with posthemorrhagic hydrocephalus (PHH). The authors present the neurological outcome of infants with IVH and an early treatment approach, defined as an intervention when ventricular dilation is less than 4-mm over the 97th-percentile of Levene's index., Methods: We performed a retrospective case-series study of 12 infants who had IVH and an early intervention, their neurological development was evaluated after 18-months of corrected age using the Bayley-III Scales. Measures of central tendency and Pearson's correlation were used for data analysis., Results: In a 15-month period, twelve patients were diagnosed with IVH and underwent an early intervention. At the time of diagnosis, 2 patients had grade II IVH, 7 grade III, and 3 grade IV. Subgaleal shunt was the first intervention. 9 (75 %) ultimately required a ventriculoperitoneal shunt. A total of 9 (75 %) patients had normal cognitive scores, 7 (58.3 %) for the language-composite, and 8 (66.7 %) for the motor-composite. 6 (50 %) patients had normal scores in all composites. The average scores reported normal results (CC:98.33 ± 22.59; LC:98.25 ± 23.93; MC:88.58 ± 21.47). There was a significant correlation between antenatal steroids and the LC-score (p = 0.044)., Conclusions: Half of the patients with PHH and early neurosurgical interventions had an average or above average neurodevelopmental score in all three areas. Current literature and undergoing clinical trials have shown promising results on the implementation of this type of intervention., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Kratom is a botanical product used as an opium substitute with abuse potential., Methods: Assessment of suspected cases of kratom-induced liver injury in a prospective US cohort., Results: Eleven cases of liver injury attributed to kratom were identified with a recent increase. The majority were male with median age 40 years. All were symptomatic and developed jaundice with a median latency of 14 days. The liver injury pattern was variable, most required hospitalization and all eventually recovered. Biochemical analysis revealed active kratom ingredients., Conclusion: Kratom can cause severe liver injury with jaundice., (Copyright © 2020. Published by Elsevier B.V.)

Attention to relevant stimulus features in a categorization task helps to optimize performance. However, the relationship between attention and categorization is not fully understood. For example, even when human adults and young children exhibit comparable categorization behavior, adults tend to attend selectively during learning, whereas young children tend to attend diffusely (Deng & Sloutsky, 2016). Here, we used a comparative approach to investigate the link between attention and categorization in two different species. Given the noteworthy categorization ability of avian species, we compared the attentional profiles of pigeons and human adults. We gave human adults (Experiment 1) and pigeons (Experiment 2) a categorization task that could be learned on the basis of either one deterministic feature (encouraging selective attention) or multiple probabilistic features (encouraging distributed attention). Both humans and pigeons relied on the deterministic feature to categorize the stimuli, albeit humans did so to a much greater degree. Furthermore, computational modeling revealed that most of the adults exhibited maximal selectivity, whereas pigeons tended to distribute their attention among several features. Our findings indicate that human adults focus their attention on deterministic information and filter less predictive information, but pigeons do not. Implications for the underlying brain mechanisms of attention and categorization are discussed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There is increasing interest in effects of radionuclides on non-human species, but methods for studying such effects are not well developed. The aims of the current study were to investigate the effects of uranium mine-affected sediments on non-biting midge Chironomus riparius and to compare sensitivity of different endpoints. The midge larvae were exposed in controlled laboratory conditions to sediments from two ponds downstream from an abandoned uranium mine and a reference pond not receiving water from the mining site. Quartz sand was used as an additional control. Developmental effects were assessed by evaluating emergence of adult midges, body mass, and fluctuating asymmetry (FA) in the length of wing upper vein. FA has been suggested to be a sensitive indicator of developmental instability, but the results of previous studies are inconsistent. In the present study, no difference in FA was observed between the treatment groups, but time to emergence was significantly delayed in the contaminated sediments. The approach used in this study (laboratory experiments with sediments from a contaminated site) avoids confounding due to uncontrolled environmental variables and adaptation to long-term contamination, which may mask effects on natural populations. Using this approach, we found no effects on FA of wing length. Time to emergence, in contrast, was found to be a more sensitive endpoint., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background & Aims: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients., Methods: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina., Results: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10 -8 ). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI., Conclusion: HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI., Lay Summary: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward., (Copyright © 2017. Published by Elsevier B.V.)

Background: Patients with end-stage liver disease have a predictable and progressive decline in their quality of life because of physical symptoms and psychological distress. Early palliative care intervention (EPCI) correlates with better symptom control and mood. We aimed to improve symptomatology and mood in liver transplant candidates by implementing a longitudinal multidisciplinary EPCI., Measures: Depression level and symptom burden were assessed with Center for Epidemiological Studies Depression Scale and a modified liver-specific Edmonton Symptom Assessment System scale., Intervention: All patients referred for liver transplant evaluation between July 2013 and May 2014 were scheduled for EPCI., Outcomes: After EPCI, 50% of moderate-to-severe symptoms improved (P < 0.05), and 43% of patients showed improvement in clinically significant depressive symptoms (P = 0.003). Notably, patients with more symptoms showed a greater improvement in Center for Epidemiological Studies Depression Scale scores (P = 0.001)., Conclusions/lessons Learned: Implementation of EPCI improved symptom burden and mood in end-stage liver disease patients awaiting transplant., (Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess long-term efficacy of the gasket seal, a method for watertight closure of the cranial base using autologous fascia lata held in place by a rigid buttress, in a large case series., Methods: A prospectively acquired database of all endonasal endoscopic surgeries performed over a 5-year period at Weill Cornell Medical College starting in September 2005 was reviewed., Results: The gasket seal was used in 46 consecutive patients. Mean age was 53 years (range 7-83 years). All patients had extensive intracranial disease with a significant intraoperative cerebrospinal fluid (CSF) leak. Pathology included craniopharyngioma (39.1%), meningioma (23.9%), and pituitary adenoma (17.4%). After a mean follow-up of 28 months (range 3-63 months), two (4.3%) patients had a postoperative CSF leak. Excluding the patients with adenomas, the CSF leak rate was 5.2% (2 of 38 patients). One leak was controlled with reoperation, and the other was stopped with a lumbar drain (LD). The significance of pathology, type of approach, exposure of the ventricular system, use of fat graft, use of nasoseptal (NS) flap, and use of lumbar drain (LD) was examined, and none of these were significant predictors of postoperative CSF leak., Conclusions: Gasket seal closure is a reliable long-term effective method for achieving watertight closure of the cranial base. It can be used in association with an intracranial fat graft, NS flap, LD, and tissue sealants. In this series, none of these other factors were significant predictors of postoperative CSF leak., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Introduction: The addition of cetuximab to weekly paclitaxel has demonstrated high efficacy in the first-line treatment of patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, this combination has been widely extended to patients who present resistance to first line chemotherapy (CT) or those who are not candidates for platinum-based CT., Material and Methods: We have retrospectively analyzed the efficacy and safety of cetuximab in combination with weekly paclitaxel in patients with R/M-SCCHN who present disease progression after platinum schedules or those who were not candidates for platinum-based CT. Patients received weekly paclitaxel 80mg/m(2) and cetuximab 250mg/m(2) (initial dose of 400mg/m(2)) until progression or unacceptable toxicity., Results: Twenty-two patients were included. Median age was 58 (43-68), ECOG PS (0/1/2): 6/10/4, 19 patients had received prior platinum-based treatment (nine patients were platinum-sensitive and nine were platinum-refractory). With a median follow-up of 6.18months (range 1.3-29.7), overall response rate (ORR) was 55% (95% CI 31-76%):1 (5%) complete response and 9 (50%) partial responses. Median duration of response was 10.23months. Median progression free survival (PFS) and overall survival (OS) were 5.4 and 9.1months, respectively. There were no differences in response rate according to platinum sensitivity (66% sensitive vs 44% refractory; P=0.61). The main toxicity consisted of rash in 70% of patients (5% grade 3), with an association between rash severity and ORR (grade 0-1: 33% vs grade 2-3: 64%; P=0.03) and a trend for better PFS and OS., Conclusion: Weekly paclitaxel in combination with cetuximab is a well tolerated and highly active second-line treatment in patients with R/MSCCHN who experience disease progression after platinum-based CT, including those who present resistant disease. Our results suggest that the efficacy of this combination is apparently superior than the published data on single agent cetuximab in this setting., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: The identification of effective continuation and maintenance strategies for elderly patients with psychotic depression is a critical issue that has not been fully explored. The aim of this study was to assess the tolerability and efficacy of continuation/maintenance electroconvulsive therapy (ECT) in elderly patients with psychotic depression after acute ECT remission., Methods: The authors used a longitudinal, randomized, single-blind design to compare by survival analysis the 2-year outcome of two subgroups of elderly patients with psychotic unipolar depression who were ECT (plus nortriptyline) remitters. One group was treated with a continuation/maintenance nortriptyline regimen (N = 17) and the other with combined continuation/maintenance ECT plus nortriptyline (N = 16)., Results: Over 2 years of treatment in elderly, psychotic, unipolar depressed ECT (plus nortriptyline) remitters, the mean survival time was significantly longer in the combined ECT plus nortriptyline subgroup than in the nortriptyline subgroup. No differences were observed between treatments with regard to tolerability., Conclusions: This study supports the judicious use of combined continuation/maintenance ECT and antidepressant treatment in elderly patients with psychotic unipolar depression who are ECT remitters.

Chagas' heart disease, caused by protozoan Trypanosoma cruzi, is a common cause of cardiomyopathy in the Americas. Transmission of T. cruzi occurs through Reduviids, the kissing bugs. Less common ways of transmission are blood transfusion, congenital transmission, organ transplantation, laboratory accident, breastfeeding, and oral contamination. Infestation results in cardiac dysautonomia, myocardial apoptosis, and myocardial fibrosis. In acute phase, death is mostly caused by myocarditis and in chronic phase, it is mostly by irreversible cardiomyopathy. A majority of the patients with Chagas' disease remain in the latent phase of disease for 10 to 30 years or even for life. Specific anti-Chagas' therapy with trypanocide drugs is useful in acute phase but the management of chronic Chagas' heart disease is mostly empirical. The mortality during the acute phase of cardiac Chagas is around 5%. Five-year mortality of chronic Chagas' disease with cardiac dysfunction is above 50%. The clinical aspects of the Chagas' heart disease are concisely reviewed.

Objective: To examine the etiology and clinical significance of elevated serum cardiac troponin I (cTnI) in patients with rhabdomyolysis., Methods: Data on 91 (63 men) consecutive patients with rhabdomyolysis were examined., Results: The mean age was 57.8+/-19.6 years (range 24-97 years). Patients were divided into two groups: cTnI-positive with serum cTnI >0.6 ng/ml (n=19) and cTnI-negative with serum cTnI <0.6 ng/ml (n=72). Prevalence of cardiovascular risk factors was equal in both groups. Illicit substance use was more common in the cTnI-positive group (31% vs. 14%, P=0.04). Peak creatine kinase (CK) was higher in cTnI-positive group (34,811+/-38,309 vs. 15,070+/-21,655 U/l, P=0.04) but there was no difference in the MB isoenzyme (CK-MB) (118+/-132 vs. 89+/-451 ng/ml, P=0.63). In cTnI-positive group, there was a strong correlation between peak CK and CK-MB (r(2)=0.606, P=0.00008) but not between peak cTnI and peak CK (r(2)=0.164 and P=0.08) or CK-MB (r(2)=0.134 and P=0.12) levels. Serum creatinine was higher in cTnI-positive group (3.58+/-2.73 vs. 1.83+/-2.01 mg/dl, P=0.02) but there was no correlation between serum creatinine and cTnI (r(2)=0.121, P=0.158). None of the cTnI-positive patient had segmental wall motion abnormalities. Seventeen (89%) patients in cTnI-positive and 19 (26%) in cTnI-negative group required admission to intensive care unit (P=0.0001). Hypotension (37% vs. 6%, P=0.0002) and sepsis (47% vs. 11%, P=0.0003) were more common in cTnI-positive group. Duration of hospitalization was longer in cTnI-positive group (17.7+/-11.7 vs. 8.9+/-13 days, P=0.007) but there was no significant difference in mortality., Conclusion: In rhabdomyolysis, serum cTnI may be elevated unrelated to the degree of muscle damage, renal failure and cardiovascular risk factors, and is likely related to the etiology of rhabdomyolysis, as is evidenced by significantly higher serum cTnI with illicit substance use, hypotension, and sepsis. Elevated serum cTnI is associated with a higher morbidity.

Background: Daily dialysis has shown excellent clinical results because a higher frequency of dialysis is more physiologic. On-line hemodiafiltration (OL-HDF) is a HDF technique that combines diffusion with high convection in which the dialysis fluid itself is used as a reinfusion solution. The aim of this study was to demonstrate the beneficial effect of the more effective dialysis schedule (daily dialysis) with the dialysis modality that offers the highest uremic toxin removal (on-line HDF)., Methods: Eight patients, six males and two females, on standard 4 to 5 hours three times a week OL-HDF (S-OL-HDF) were switched to daily OL-HDF (D-OL-HDF) 2 to 21/2 hours six times per week. Dialysis parameters were identical during both periods and only frequency and dialysis time of each session were changed. Tolerance, uremic toxin removal, urea kinetics, biochemical and anemia profiles, blood pressure, and left ventricular hypertrophy were evaluated., Results: D-OL-HDF was well accepted and tolerated. The disappearance of postdialysis fatigue was rapidly reported by patients. Patients mantained the same [time average concentration (TAC) and weekly single-pool Kt/V (spKt/V)] throughout the study. However, equivalent renal urea clearance (EKR), standard Kt/V and weekly urea reduction ratio (URR) were increased during D-OL-HDF. Weekly urea, creatinine, osteocalcin, beta2-microglobulin, myoglobin, and prolactin reduction ratios were improved with D-OL-HDF. There was a significant decrease in predialysis plasma levels of urea, creatinine, acid uric, beta2-microglobulin and homocysteine over 6 months. Phosphate binders were reduced and antihypertensive drugs were stopped. A 30% regression of left ventricular mass was observed., Conclusion: The change from S-OL-HDF to D-OL-HDF was well tolerated. Disappearance of postdialysis fatigue, better dialysis adequacy, a higher removal of middle and large molecules, a reduction of phosphate binders, improvement of status nutritional, and an important reduction of cardiovascular risk factors were observed.