Disruption of ecological networks in lakes by climate change and nutrient fluctuations.

Climate change interacts with local processes to threaten biodiversity by disrupting the complex network of ecological interactions. While changes in network interactions drastically affect ecosystems, how ecological networks respond to climate change, in particular warming and nutrient supply fluctuations, is largely unknown. Here, using an equation-free modelling approach on monthly plankton community data in ten Swiss lakes, we show that the number and strength of plankton community interactions fluctuate and respond nonlinearly to water temperature and phosphorus. While lakes show system-specific responses, warming generally reduces network interactions, particularly under high phosphate levels. This network reorganization shifts trophic control of food webs, leading to consumers being controlled by resources. Small grazers and cyanobacteria emerge as sensitive indicators of changes in plankton networks. By exposing the outcomes of a complex interplay between environmental drivers, our results provide tools for studying and advancing our understanding of how climate change impacts entire ecological communities.

[High-dose Omega-3 for cardiovascular prevention, a bad idea?] / Oméga-3 fortement dosés pour la prévention cardiovasculaire : une fausse bonne idée ?

Hypertriglyceridemia is a cardiovascular risk factor independent of LDL cholesterol. Omega-3 reduce triglycerides levels, but without proven benefit to reduce cardiovascular risk. Recently, two studies on high-dose omega-3 derivatives have shown contradictory results on the risk of cardiovascular events: REDUCE-IT (4 g/day of icosapent ethyl) showed a 25 % reduction; STRENGTH (4 g/day of a mixture of eicosapentaenoic acid and docosahexaenoic acid) showed no effect. An increased risk of atrial fibrillation was observed in both studies. The European 2021 cardiovascular prevention guidelines propose to consider high-dose ethyl icosapent on a case-by-case basis in patients with hypertriglyceridemia.

L'hypertriglycéridémie est un facteur de risque cardiovasculaire indépendant du taux de LDL-cholestérol. Les oméga-3 diminuent le taux de triglycérides, mais sans effet probant sur la baisse du risque cardiovasculaire. Dernièrement, deux essais cliniques sur des oméga-3 fortement dosés sont arrivés à des résultats con tradictoires: REDUCE-IT (4 g/jour d'icosapent éthyl) a montré une diminution de 25 % des événements cardiovasculaires; STRENGTH (4 g/jour d'un mélange d'acide eicosapentaénoïque et d'acide docosahexaénoïque) n'a pas montré de bénéfice cardiovasculaire. Une augmentation du risque de fibrillation auriculaire a été observée dans les deux études. Les recommandations européennes 2021 de prévention cardiovasculaire proposent de considérer au cas par cas l'icosapent éthyl fortement dosé chez les patients avec hypertriglycéridémie.

Feasibility and acceptability of Problem Management Plus (PM+) among Syrian refugees and asylum seekers in Switzerland: a mixed-method pilot randomized controlled trial.

Background: Syrian refugees in Switzerland face several barriers in accessing mental health care. Cost-effective psychological interventions are urgently needed to meet the mental health needs of refugees. Problem Management Plus (PM+) is an evidence-based, psychological intervention delivered by trained non-specialist 'helpers'. Objective: To assess the feasibility and acceptability of PM+ among Syrian refugees in Switzerland. Methods: We conducted a single-blind pilot randomized controlled trial (RCT) with Syrian refugees impaired by psychological distress (K10 > 15 and WHODAS 2.0 > 16). Participants were randomized to PM+ or Enhanced Treatment As Usual (ETAU). Participants were assessed at baseline, and 1 week and 3 months after the intervention, and completed measures indexing mental health problems and health care usage. Semi-structured interviews were conducted with different stakeholders. Results: N = 59 individuals were randomized into PM+ (n = 31) or ETAU (n = 28). N = 18 stakeholders were interviewed about facilitators and barriers for the implementation of PM+. Retention rates in the trial (67.8%) and mean intervention attendance (M = 3.94 sessions, SD = 1.97) were high. No severe events related to the study were reported. These findings indicate that the trial procedures and PM+ were feasible, acceptable and safe. Conclusions: The findings support the conduct of a definitive RCT and show that PM+ might have the potential to be scaled-up in Switzerland. The importance, as well as the challenges, of implementing and scaling-up PM+ in high-income countries, such as Switzerland, are discussed.

Antecedentes: Los refugiados Sirios en Suiza enfrentan varias barreras para acceder a la atención en salud mental. Se necesitan con urgencia intervenciones psicológicas costo-efectivas, para satisfacer las necesidades de salud mental de los refugiados. Enfrentar Problemas Plus (PM + por sus siglas en inglés) es una intervención psicológica basada en la evidencia proporcionada por 'ayudantes' capacitados no especializados.Objetivo: Evaluar la viabilidad y aceptabilidad de PM + entre los refugiados sirios en Suiza.Métodos: Realizamos un ensayo controlado aleatorizado (ECA) piloto simple y ciego con refugiados sirios afectados por angustia psicológica (K10 > 15 y WHODAS 2.0 > 16). Los participantes fueron asignados al azar a PM + o Tratamiento usual mejorado (TUM). Los participantes fueron evaluados al inicio del estudio, 1 semana, y 3 meses después de la intervención, y completaron instrumentos que referencian problemas de salud mental y el uso de la atención médica. Se realizaron entrevistas semiestructuradas con diferentes partes relevantes.Resultados:N = 59 individuos fueron asignados al azar a PM + (n = 31) o TUM (n = 28). N = 18 partes relevantes fueron entrevistados sobre facilitadores y barreras para la implementación de PM +. Las tasas de retención en el ensayo (67,8%) y la asistencia media a la intervención (M = 3,94 sesiones, DE = 1,97) fueron altas. No se informaron eventos graves relacionados con el estudio. Estos hallazgos indican que los procedimientos del ensayo y PM + fueron factibles, aceptables y seguros.Conclusiones: Los hallazgos apoyan la realización de un ECA definitivo y muestran que PM + podría tener el potencial de ampliarse en Suiza. Se discute la importancia, así como los desafíos, de implementar y ampliar PM + en países de altos ingresos, como Suiza.

Current pathology practices in and barriers to MDS diagnosis.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell malignancies that represent a diagnostic challenge for pathologists. Accurate classification and prognostic scoring are essential to treating MDS. To understand factors that affect MDS management, a case-based survey was distributed to hematopathologists (n=53) and general pathologists (n=72) to identify perceived barriers, attitudes, and practices in MDS diagnosis. Results demonstrated confidence and practice gaps. Only 33% of general pathologists are confident in diagnosing MDS. Neither general pathologists nor hematopathologists are comfortable using the International Prognostic Scoring System to characterize risk. Thirty percent of general pathologists and 22% of hematopathologists would not include bone marrow aspirate and cytogenetics in initial testing of a neutropenic patient. Most practitioners tested appropriately for disease classification and prognosis; discrepancies were identified in testing to differentiate MDS from acute myeloid leukemia and testing in post treatment specimens. These results have implications in the management of MDS.

Adding integrative meditation with ear acupressure to outpatient treatment of cocaine addiction: a randomized controlled pilot study.

OBJECTIVES: Cocaine addiction continues to be a major public health problem in the United States. With no U.S. Food and Drug Administration-approved pharmaceutical therapy, treatment often relies on psychosocial interventions. This pilot therapy development study attempts to examine the feasibility and preliminary efficacy of adding breathing-based Integrative Meditation and Ear Acupressure (IMEA) to outpatient treatment of cocaine addiction. DESIGN: Fifty-six (56) cocaine-dependent patients were recruited from an outpatient addiction treatment facility in Baltimore, MD and randomized into either an IMEA or a treatment as usual (TAU) group for the 12 weeks of study, with weekly meetings to monitor treatment outcomes and to facilitate meditative therapy. OUTCOME MEASURES: The outcome measures consisted of treatment retention rates by week 8 and 12; abstinence rates measured by 6 continuous weeks of negative urinalysis for cocaine, and addiction-related symptoms such as anxiety, craving, depression, and withdrawal symptoms. RESULTS: With the assistance of simplified breath training and a portable MP4 device, 80% of IMEA participants self-reported practicing breathing or meditation 5+ days a week with acceptable compliance and showed strong interest in meditative techniques. Compared to TAU, IMEA participants reported significantly higher treatment completion rates by week 8 (89% versus 63%) and week 12 (81% versus 58%), higher abstinence rates (66% versus 34%), and significantly greater reduction in craving, anxiety, and other addiction-related symptoms. Some participants continued meditation after study completion. CONCLUSIONS: It is feasible to add breathing-based IMEA to outpatient treatment of cocaine addiction. Although a number of limitations exist for this pilot study, further large-scale clinical trials and therapy-development studies of IMEA for addiction are warranted.

Meditative therapies for reducing anxiety: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Anxiety disorders are among the most common psychiatric disorders and meditative therapies are frequently sought by patients with anxiety as a complementary therapy. Although multiple reviews exist on the general health benefits of meditation, no review has focused on the efficacy of meditation for anxiety specifically. METHODS: Major medical databases were searched thoroughly with keywords related to various types of meditation and anxiety. Over 1,000 abstracts were screened, and 200+ full articles were reviewed. Only randomized controlled trials (RCTs) were included. The Boutron (Boutron et al., 2005: J Clin Epidemiol 58:1233-1240) checklist to evaluate a report of a nonpharmaceutical trial (CLEAR-NPT) was used to assess study quality; 90% of the authors were contacted for additional information. Review Manager 5 was used for meta-analysis. RESULTS: A total of 36 RCTs were included in the meta-analysis (2,466 observations). Most RCTs were conducted among patients with anxiety as a secondary concern. The study quality ranged from 0.3 to 1.0 on the 0.0-1.0 scale (mean = 0.72). Standardized mean difference (SMD) was -0.52 in comparison with waiting-list control (p < .001; 25 RCTs), -0.59 in comparison with attention control (p < .001; seven RCTs), and -0.27 in comparison with alternative treatments (p < .01; 10 RCTs). Twenty-five studies reported statistically superior outcomes in the meditation group compared to control. No adverse effects were reported. CONCLUSIONS: This review demonstrates some efficacy of meditative therapies in reducing anxiety symptoms, which has important clinical implications for applying meditative techniques in treating anxiety. However, most studies measured only improvement in anxiety symptoms, but not anxiety disorders as clinically diagnosed.

Benzodiazepine use and misuse among patients in a methadone program.

BACKGROUND: Benzodiazepines (BZD) misuse is a serious public health problem, especially among opiate-dependent patients with anxiety enrolled in methadone program because it puts patients at higher risk of life-threatening multiple drug overdoses. Both elevated anxiety and BZD misuse increase the risk for ex-addicts to relapse. However, there is no recent study to assess how serious the problem is and what factors are associated with BZD misuse. This study estimates the prevalence of BZD misuse in a methadone program, and provides information on the characteristics of BZD users compared to non-users. METHODS: An anonymous survey was carried out at a methadone program in Baltimore, MD, and all patients were invited to participate through group meetings and fliers around the clinic on a voluntary basis. Of the 205 returned questionnaires, 194 were complete and entered into final data analysis. Those who completed the questionnaire were offered a $5 gift card as an appreciation. RESULTS: 47% of the respondents had a history of BZD use, and 39.8% used BZD without a prescription. Half of the BZD users (54%) started using BZD after entering the methadone program, and 61% of previous BZD users reported increased or resumed use after entering methadone program. Compared to the non-users, BZD users were more likely to be White, have prescribed medication for mental problems, have preexistent anxiety problems before opiate use, and had anxiety problems before entering methadone program. They reported more mental health problems in the past month, and had higher scores in anxiety state, depression and perceived stress (p < .05). CONCLUSIONS: Important information on epidemiology of BZD misuse among methadone-maintenance patients suggests that most methadone programs do not address co-occurring anxiety problems, and methadone treatment may trigger onset or worsening of BZD misuse. Further study is needed to explore how to curb misuse and abuse of BZD in the addiction population, and provide effective treatments targeting simultaneously addiction symptoms, anxiety disorders and BZD misuse.

Concomitant chemoradiotherapy using carboplatin, tegafur-uracil and leucovorin for stage III and IV head-and-neck cancer: results of GORTEC Phase II study.

PURPOSE: Concomitant chemoradiotherapy is the standard treatment of locally advanced, nonresectable, head-and-neck squamous cell carcinoma. However, the optimal chemotherapy regimen is still controversial. The objective of this Phase II study was to evaluate the feasibility and efficacy of a concomitant treatment using tegafur-uracil, leucovorin, carboplatin, and radiotherapy. METHODS AND MATERIALS: A total of 77 patients with head-and-neck squamous cell carcinoma Stage III and IVA were enrolled between October 2003 and July 2005. Of the 77 patients, 72 were eligible. They were treated with tegafur-uracil (300 mg/m(2)/d) and leucovorin (75 mg/d) from Days 1 to 19 and from Days 29 to 47 and carboplatin (70 mg/m(2) intravenously for 4 consecutive days), in three cycles every 21 days. Conventional radiotherapy was delivered to a total dose of 70 Gy in 35 fractions. RESULTS: With a mean follow-up of 22.8 months, the 3-year locoregional control, overall survival and disease-free survival actuarial rate was 33.1%, 41.9%, and 27.2%, respectively. The compliance of the treatment was correct. The main acute toxicity was mucositis, with 62% Grade 3-4. Three patients (4.2%) died of acute toxicity. The incidence and severity of late toxicity was acceptable, with 32% Grade 3 and no Grade 4 toxicity. CONCLUSION: The protocol of concomitant chemoradiotherapy using tegafur-uracil, leucovorin, and carboplatin for locally advanced unresectable head-and-neck squamous cell carcinoma is feasible. The compliance was correct. The incidence and severity of the acute and late toxicities were acceptable, but not improved. The efficacy of this regimen seems equivalent to the main protocols of concurrent chemoradiotherapy. It represents a possible alternative for patients without an intravenous catheter.

Alkyl-capped silicon nanocrystals lack cytotoxicity and have enhanced intracellular accumulation in malignant cells via cholesterol-dependent endocytosis.

Nanocrystals of various inorganic materials are being considered for application in the life sciences as fluorescent labels and for such therapeutic applications as drug delivery or targeted cell destruction. The potential applications of the nanoparticles are critically compromised due to the well-documented toxicity and lack of understanding about the mechanisms involved in the intracellular internalization. Here intracellular internalization and toxicity of alkyl-capped silicon nanocrystals in human neoplastic and normal primary cells is reported. The capped nanocrystals lack cytotoxicity, and there is a marked difference in the rate and extent of intracellular accumulation of the nanoparticles between human cancerous and non-cancerous primary cells, the rate and extent being higher in the malignant cells compared to normal human primary cells. The exposure of the cells to the alkyl-capped nanocrystals demonstrates no evidence of in vitro cytotoxicity when assessed by cell morphology, apoptosis, and cell viability assays. The internalization of the nanocrystals by Hela and SW1353 cells is almost completely blocked by the pinocytosis inhibitors filipin, cytochalasin B, and actinomycin D. The internalization process is not associated with any surface change in the nanoparticles, as their luminescence spectrum is unaltered upon transport into the cytosol. The observed dramatic difference in the rate and extent of internalization of the nanocrystals between malignant and non-malignant cells therefore offers potential application in the management of human neoplastic conditions.

Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL).

Tumor necrosis factor alpha (TNF-alpha) and vascular endothelial growth factor (VEGF) play an important role in the biology of chronic lymphocytic leukemia (CLL) cells. Thalidomide is a first-generation immuno-modulating agent that down-regulates TNF-alpha and VEGF. We initiated a phase 1/2 clinical trial to determine the safety and efficacy of combining thalidomide with fludarabine in patients with treatment-naïve CLL. Patients received 6 months of continuous daily thalidomide with standard monthly doses of fludarabine. Three dose levels of thalidomide (100, 200, and 300 mg) were studied. Results from the phase 1 part of this study are reported here. Thirteen patients were enrolled in the phase 1 component of the study. Dose-limiting toxicity was not reached. The most common toxicities noted were fatigue, constipation, and peripheral sensory neuropathy. Overall response rate was 100% with 55% of patients achieving complete remissions. At a median follow-up of 15+ months none of the patients have had a relapse and the median time to disease progression has not yet been reached. Responses were noted at all dose levels. Thalidomide given up to 300 mg/day concurrently with fludarabine in patients with previously untreated CLL shows encouraging clinical efficacy and acceptable toxicity. An ongoing phase 2 part of this study will help validate the clinical efficacy of this regimen.

Monomeric and dimeric bZIP transcription factor GCN4 bind at the same rate to their target DNA site.

Basic leucine zipper (bZIP) transcription factors are dimeric proteins that recognize dyadic and mostly palindromic DNA sites. Dimerization of bZIP transcription factor GCN4 is linked to the folding of its C-terminal leucine zipper domain. However, monomeric GCN4, lacking a folded leucine zipper, also recognizes the DNA site with dimerization taking place on the DNA. Here we report the kinetics of DNA recognition by unfolded monomeric and folded dimeric derivatives of GCN4 using a 19 bp double-stranded DNA containing a palindromic CRE site. The rate of DNA binding of both monomeric and dimeric GCN4 has a bimolecular rate constant of 3-5 x 10(8) M(-1) s(-1), which is near the diffusion limit. Because the rate of dimerization of GCN4 is slower (1.7 x 10(7) M(-1) s(-1)) than the rate of DNA association, the formation of the dimeric GCN4-DNA complex through consecutive binding of two monomers (monomer pathway) is faster when starting from free monomers. Thus, the results presented here support facilitated and rapid target recognition by the monomeric transcription factor. However, DNA binding of preformed folded dimeric GCN4 is as rapid as complex formation through the monomer pathway. Therefore, the monomer and dimer pathways are kinetically equivalent if monomeric and dimeric GCN4 are at equilibrium. Hence, the dimer pathway may also have a role under in vivo conditions. The lower affinity of GCN4 in which two DNA contacting residues have been mutated is due exclusively to the faster dissociation of the mutant protein-DNA complex and not to slower complex formation.

Physician compliance with outpatient oral anticoagulant guidelines in Auvergne, France.

OBJECTIVE: Oral anticoagulants (OA) are commonly used, but they can lead to severe bleeding. We studied the indications and monitoring of OA in patients treated by general practitioners. DESIGN: Retrospective cross-sectional study. SETTING: Primary care. PATIENTS: Four hundred thirty-eight randomly selected patients of a population of 2,452 patients treated with OA were studied. INTERVENTIONS: We compared the indications for OA as reported by general practitioners with indications as defined according to recent guidelines. MAIN RESULTS: Twenty-five percent of patients should not have been treated with OA. Inappropriate indications (13% of patients) were atrial fibrillation without risk factor (3.9%), prior uncomplicated myocardial infarction (2.7%), peripheral arterial disease (2.7%), superficial thrombophlebitis (2.3%), and atherothrombotic ischemic stroke (1.6%). For 12% of patients, the duration of OA was too long (venous thromboembolism without permanent risk factor in 10%). Frequency of International Normalized Ratio (INR) measurement was insufficient for 14% of patients and target INR was not achieved in 31%. CONCLUSIONS: Our study demonstrated that clinicians' adherence to recommendations regarding indications for OA and management of this treatment should be improved. Implementation of anticoagulation clinics is probably needed.

Management of primary anal canal adenocarcinoma: a large retrospective study from the Rare Cancer Network.

PURPOSE: Primary adenocarcinoma of the anus is a rare tumor. The current standard treatment consists of abdominoperineal resection (APR). The aim of this Rare Cancer Network study was to evaluate the prognostic factors and outcome after the three most commonly used treatment approaches. METHODS AND MATERIALS: This multicenter study collected data from 82 patients: 15 with T1 (18%), 34 with T2 (42%), 22 with T3 (27%), and 11 with T4 (13%) tumors according to the TNM classification (International Union Against Cancer, 1997). Patients were separated into, and analyzed according to, three treatment categories: radiotherapy/surgery (RT/S group, n = 45), combined radiochemotherapy (RT/CHT group, n = 31), and APR alone (APR group, n = 6). The main patient characteristics were evenly distributed among the three groups. RESULTS: The actuarial locoregional relapse rate at 5 years was 37%, 36%, and 20%, respectively, in the RT/S, RT/CHT, and APR groups (RT/S vs. RT/CHT, p = 0.93; RT/CH vs. APR, p = 0.78). The 3-, 5-, and 10-year overall survival rate was 47%, 29%, and 23% in the RT/S group, 75%, 58%, and 39% in the RT/CHT group, and 42%, 21%, and 21% in the APR group (RT/CHT vs. RT/S, p = 0.027), respectively. The 5- and 10-year disease-free survival rate was 25% and 18% in the RT/S group, 54% and 20% in the RT/CHT group, and 22% and 22% in the APR group (RT/CHT vs. RT/S, p = 0.038), respectively. Multivariate analysis revealed four independent prognostic factors for survival: T stage, N stage, histologic grade, and treatment modality. CONCLUSION: Primary adenocarcinoma of the anal canal requires rigorous management. Multivariate analysis showed that T and N stage, histologic grade, and treatment modality are independent prognostic factors for survival. We observed better survival rates after combined RT/CHT. We also recommend using APR only for salvage treatment.