Biweekly docetaxel as second-line chemotherapy of patients with advanced non-small cell lung cancer: a phase II study of the Galician Lung Cancer Group (GGCP 006-00)

This phase II trial assessed the antitumoral activity and toxicity of docetaxel 50 mg/m (1-h i.v. infusion) administered every 2 weeks as second-line treatment in 45 patients with advanced non-small cell lung cancer (NSCLC). A total of 251 infusions (median 4 per patient) were administered. The actual and relative median dose intensity values were 24.2 mg/m/week and 0.97, respectively. Thirty-seven patients were evaluable for tumor response. The overall response rate was 20% [95% confidence interval (CI) 8-32%] and included one complete response (2%) and eight partial responses (18%). Stable disease was found in seven patients (16%). With a median follow-up of 4 months, the median time to disease progression was 2.8 months (95% CI 1.9-3.7), the median overall survival was 4.0 months (95% CI 3.4-4.6) and the 1-year survival rate was 23% (95% CI 9-37). The every-2-weeks docetaxel schedule was well tolerated. Grade 3/4 non-hematological toxicities showed rates of 5% or less of patients and 2% or less of cycles. The main grade 3/4 hematological toxicity was neutropenia (16% of patients and 8% of cycles). No febrile neutropenia was found. Nevertheless, one toxic death was reported. We conclude that the biweekly docetaxel schedule showed an antitumoral activity similar to that found with the every-3-weeks or weekly docetaxel schedule in a second-line setting for advanced NSCLC. This antitumoral effect was associated with a marked reduction in hematological toxicity, therefore suggesting that this new docetaxel schedule might be useful in the design of combined second-line schedules for treating NSCLC.     

Cocaine-Induced Behavioral Sensitization Is Associated With Changes in the Expression of Endocannabinoid and Glutamatergic Signaling Systems in the Mouse Prefrontal Cortex

Background:

Endocannabinoids modulate the glutamatergic excitatory transmission by acting as retrograde messengers. A growing body of studies has reported that both signaling systems in the mesocorticolimbic neural circuitry are involved in the neurobiological mechanisms underlying drug addiction.

Methods:

We investigated whether the expression of both endocannabinoid and glutamatergic systems in the prefrontal cortex (PFC) were altered by an acute and/or repeated cocaine administration schedule that resulted in behavioral sensitization. We measured the protein and mRNA expression of the main endocannabinoid metabolic enzymes and the cannabinoid receptor type 1 (CB1). We also analyzed the mRNA expression of relevant components of the glutamate-signaling system, including glutamate-synthesizing enzymes, metabotropic receptors, and ionotropic receptors.

Results:

Although acute cocaine (10mg/kg) produced no significant changes in the endocannabinoid-related proteins, repeated cocaine administration (20mg/kg daily) induced a pronounced increase in the CB1 receptor expression. In addition, acute cocaine administration (10mg/kg) in cocaine-sensitized mice (referred to as cocaine priming) induced a selective increase in the endocannabinoid-degrading enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL). These protein changes were accompanied by an overall decrease in the ratios of endocannabinoid synthesis/degradation, especially the N-acyl phosphatidylethanolamine phospholipase D/FAAH and diacylglycerol lipase alpha/MAGL ratios.Regarding mRNA expression, while acute cocaine administration produced a decrease in CB1 receptors and N-acyl phosphatidylethanolamine phospholipase D, repeated cocaine treatment enhanced CB1 receptor expression. Cocaine-sensitized mice that were administered priming injections of cocaine mainly displayed an increased FAAH expression.These endocannabinoid changes were associated with modifications in glutamatergic transmission-related genes. An overall decrease was observed in the mRNA expression of the glutamate-synthesizing gene kidney-type glutaminase (KGA), the metabotropic glutamate receptors (mGluR3 and GluR), and subunits of NMDA ionotropic receptors (NR1, NR2A, NR2B and NR2C) after acute cocaine administration, while mice repeatedly exposed to cocaine only displayed an increase in NR2C. However, in cocaine-sensitized mice primed with cocaine, this inhibition was reversed and a strong increase was detected in the mGluR5, NR2 subunits, and both GluR1 and GluR3.

Conclusions:

These findings indicate that cocaine sensitization is associated with an endocannabinoid downregulation and a hyperglutamatergic state in the PFC that, overall, contribute to an enhanced glutamatergic input into PFC-projecting areas.     

Using time-use diaries to track changing behavior across successive stages of COVID-19 social restrictions

How did people change their behavior over the different phases of the UK COVID-19 restrictions, and how did these changes affect their risk of being exposed to infection? Time-use diary surveys are unique in providing a complete chronicle of daily behavior: 24-h continuous records of the populations’ activities, their social context, and their location. We present results from four such surveys, collected in real time from representative UK samples, both before and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of substantial changes in the UK population’s behavior relating to activities, locations, and social context. We assign different levels of risk to combinations of activities, locations, and copresence to compare risk-related behavior across successive “lockdowns.” We find evidence that during the second lockdown (November 2020), there was an increase in high-risk behaviors relative to the first (starting March 2020). This increase is shown to be associated with more paid work time in the workplace. At a time when capacity is still limited both in respect of immunization and track–trace technology, governments must continue to rely on changes in people’s daily behaviors to contain the spread of COVID-19 and similar viruses. Time-use diary information of this type, collected in real time across the course of the COVID-19 pandemic, can provide policy makers with information to assess and quantify changes in daily behaviors and the impact they are likely to have on overall behavioral-associated risks.

How did people change their behavior over the different phases of the UK COVID-19 regulations on activities and social contact, and how did these changes affect their risk of being exposed to infection? Time-use diary surveys are unique in providing a complete chronicle of daily behavior: 24-h continuous records of the populations’ activities, their social context, and their location. We present results from four such surveys, collected in real time from representative UK samples, both before and at three points over the course of the current pandemic. Comparing across the four waves, we find evidence of significant changes in the UK population’s activities, locations, and social interactions. Drawing on the epidemiological literature, we assign different levels of risk to specific combinations of activities, locations, and copresence to show how these changes affected the populations’ risk of exposure to infection over the course of the pandemic. One of our main motivations is to compare behavior across successive “lockdowns.” We find evidence that the second lockdown (November 2020) was characterized by rather more high-risk behavior than the first (starting March 2020). We discuss possible reasons for this, drawing on research that distinguishes responses to differences in regulations from responses motivated by concern about changing rates of infectious transmission. At a time when capacity is still limited in respect both of immunization and track–trace technology, governments must continue to rely on changes in people’s daily behaviors to contain the spread of COVID-19 and similar viruses. Time-use diary information of this type, collected in real time across the course of the pandemic, can provide policy makers with information to assess and quantify the changes in daily behaviors that are associated with different phases of the COVID-19 pandemic and the impact they are likely to have on overall behavioral-associated risks.Complete spatiotemporal accounts of the activities (including their location and social context) and socio-demographic characteristics of representative samples are key to understanding populations’ changing behavioral risks of infection (1). Epidemiological surveys of behavior during the pandemic have focused on measuring social contacts in order to determine risk (2–5), while social science surveys have mainly focused on asking respondents to estimate the amount of time they spent in different activities at particular times (6). Yet, neither of these sources provides a complete record of daily behavior. Time-use diaries have been used before in the context of investigating behavior related to COVID-19 (7–9) but not to report changing behavioral-related infection risks at successive periods of changing social restrictions [the UK Office of National Statistics collected pilot online time-use diaries in March to April 2020 and September to October 2020 (10) but did not take full advantage of the diary design by combining multiple diary fields of the diary to estimate behavior-related infection risks].It is clear from the epidemiological literature that infection risk involves proximity to infected individuals. From our data, we assign levels of risk associated with daily behavior to combinations of activity, location, and social context. When time-use diary–derived patterns of daily behavior are linked to infection risk in this way, it enables the identification of those changes in behavior which are most likely to contribute to subsequent changes in infection rates. In respect of our main research question, the short second (November 2020) lockdown was associated with higher levels of high-risk daily behavior than the first (starting in March 2020). We disaggregate these changes to examine potential differentials by separate activity/copresence/location combinations and by two characteristics known to be associated with the risk of infection: gender and age (11, 12).     

A Randomized Controlled Trial of Double Versus Triple Therapy with Amantadine for Genotype 1 Chronic Hepatitis C in Latino Patients

Background  

With only a third of Latinos achieving sustained virologic response (SVR), there is a need for enhanced HCV treatment. Amantadine has been proposed to improve response rates in addition to standard therapy with peginterferon α and ribavirin. Our objective is to evaluate whether triple therapy with amantadine improves SVR rates in this special population.     

A systematic review on the effectiveness of external ankle supports in the prevention of inversion ankle sprains among elite and recreational players

Epidemiological studies have shown that 10–28% of all sports injuries are ankle sprains, leading to the longest absence from athletic activity compared to other types of injuries. This study was conducted to evaluate the effectiveness of external ankle supports in the prevention of inversion ankle sprains and identify which type of ankle support was superior to the other. A search strategy was developed, using the keywords, ankle supports, ankle brace, ankle tapes, ankle sprains and athletes, to identify available literature in the databases (MEDLINE, PubMed, CINAHL, EMBASE, etc.), libraries and unpublished papers. Trials which consider adolescents and adults, elite and recreational players as participants were the study of choice. External ankle supports comprise ankle tape, brace or orthosis applied to the ankle to prevent ankle sprains. The main outcome measures were frequency of ankle sprains. Two reviewers assessed the quality of the studies included using the Joanna Briggs Institute (JBI Appraisal tool). Whenever possible, results were statistically pooled and interpreted. A total of seven trials were finally included in this study. The studies included were of moderate quality, with blinding as the hardest criteria to fulfill. The main significant finding was the reduction of ankle sprain by 69% (OR 0.31, 95% CI 0.18–0.51) with the use of ankle brace and reduction of ankle sprain by 71% (OR 0.29, 95% CI 0.14–0.57) with the use of ankle tape among previously injured athletes. No type of ankle support was found to be superior than the other.     

Alterations in the spermatic function generated by obesity in rats

In order to assess the effect of obesity on epididymal and germinal epithelia in control rats and obese rats induced by a high fat diet, we evaluated the epididymal and testicular morphologies, lipid peroxidation in the epididymis, leptin serum levels, steroid hormones, insulin, cholesterol, triglycerides, glycemia and some spermatobioscopic parameters. No significant difference was observed in the levels of insulin, glucose, cholesterol and triglycerides between the two groups. Nonetheless, in the obese rats, circulating leptin and estradiol levels showed a significant increase and there was a decline in the testosterone levels. The same group showed an increase in the lipid peroxidation of the epididymis and reduced spermatobioscopic parameters. The heads of the epididymis showed morphological differences in obese rats. No significant difference was observed between the testes of both groups. There is a clear evidence of an effect on sperm in obese rats and this seems to occur in the epididymis.