A Promising Approach to Effectively Reduce Cramp Susceptibility in Human Muscles: A Randomized,Controlled Clinical Trial

Background

To investigate if the cramp threshold frequency (CTF) can be altered by electrical muscle stimulation in a shortened position.

Methods

A total of 15 healthy male sport students were randomly allocated to an intervention (IG, n = 10) and a non-treatment control group (CG, n = 5). Calf muscles of both legs in the IG were stimulated equally twice a week over 6 weeks. The protocol was 3×5 s on, 10 s off, 150 µs impulse width, 30 Hz above the individual CTF, and was at 85% of the maximal tolerated stimulation energy. One leg was stimulated in a shortened position, inducing muscle cramps (CT), while the opposite leg was fixated in a neutral position at the ankle, hindering muscle cramps (nCT). CTF tests were performed prior to the first and 96 h after the 6^th (3 w) and 12^th (6 w) training session.

Results

After 3 w, the CTF had significantly (p<0.001) increased in CT calves from 23.3±5.7 Hz to 33.3±6.9 Hz, while it remained unchanged in nCT (pre: 23.6±5.7 Hz, mid: 22.3±3.5 Hz) and in both legs of the CG (pre: 21.8±3.2 Hz, mid: 22.0±2.7 Hz). Only CT saw further insignificant increases in the CTF. The applied stimulation energy (mA² • µs) positively correlated with the effect on the CTF (r = 0.92; p<0.001).

Conclusions

The present study may be useful for developing new non-pharmacological strategies to reduce cramp susceptibility.

Trial Registry

German Clinical Trials Register DRKS00005312     

A Human Lung Xenograft Mouse Model of Nipah Virus Infection

Nipah virus (NiV) is a member of the genus Henipavirus (family Paramyxoviridae) that causes severe and often lethal respiratory illness and encephalitis in humans with high mortality rates (up to 92%). NiV can cause Acute Lung Injury (ALI) in humans, and human-to-human transmission has been observed in recent outbreaks of NiV. While the exact route of transmission to humans is not known, we have previously shown that NiV can efficiently infect human respiratory epithelial cells. The molecular mechanisms of NiV-associated ALI in the human respiratory tract are unknown. Thus, there is an urgent need for models of henipavirus infection of the human respiratory tract to study the pathogenesis and understand the host responses. Here, we describe a novel human lung xenograft model in mice to study the pathogenesis of NiV. Following transplantation, human fetal lung xenografts rapidly graft and develop mature structures of adult lungs including cartilage, vascular vessels, ciliated pseudostratified columnar epithelium, and primitive “air” spaces filled with mucus and lined by cuboidal to flat epithelium. Following infection, NiV grows to high titers (10⁷ TCID₅₀/gram lung tissue) as early as 3 days post infection (pi). NiV targets both the endothelium as well as respiratory epithelium in the human lung tissues, and results in syncytia formation. NiV infection in the human lung results in the production of several cytokines and chemokines including IL-6, IP-10, eotaxin, G-CSF and GM-CSF on days 5 and 7 pi. In conclusion, this study demonstrates that NiV can replicate to high titers in a novel in vivo model of the human respiratory tract, resulting in a robust inflammatory response, which is known to be associated with ALI. This model will facilitate progress in the fundamental understanding of henipavirus pathogenesis and virus-host interactions; it will also provide biologically relevant models for other respiratory viruses.     

Mapping Risk of Nipah Virus Transmission from Bats to Humans in Thailand

Nipah virus (NiV) is a zoonotic virus that can pose a serious threat to human and livestock health. Old-world fruit bats (Pteropus spp.) are the natural reservoir hosts for NiV, and Pteropus lylei, Lyle’s flying fox, is an important host of NiV in mainland Southeast Asia. NiV can be transmitted from bats to humans directly via bat-contaminated foods (i.e., date palm sap or fruit) or indirectly via livestock or other intermediate animal hosts. Here we construct risk maps for NiV spillover and transmission by combining ecological niche models for the P. lylei bat reservoir with other spatial data related to direct or indirect NiV transmission (livestock density, foodborne sources including fruit production, and human population). We predict the current and future (2050 and 2070) distribution of P. lylei across Thailand, Cambodia, and Vietnam. Our best-fit model predicted that central and western regions of Thailand and small areas in Cambodia are currently the most suitable habitats for P. lylei. However, due to climate change, the species range is predicted to expand to include lower northern, northeastern, eastern, and upper southern Thailand and almost all of Cambodia and lower southern Vietnam. This expansion will create additional risk areas for human infection from P. lylei in Thailand. Our combined predictive risk maps showed that central Thailand, inhabited by 2.3 million people, is considered highly suitable for the zoonotic transmission of NiV from P. lylei. These current and future NiV transmission risk maps can be used to prioritize sites for active virus surveillance and developing awareness and prevention programs to reduce the risk of NiV spillover and spread in Thailand.

     

A Probabilistic Human Health Risk Assessment for Environmental Exposure to Dibutylphthalate

In the European Union, Directive 92/32/EC and EC Council Regulation (EC) 793/93 require the risk assessment of industrial chemicals. In this framework, it is agreed to characterise the level of “risk” by means of the deterministic quotient of exposure and effects parameters. Decision makers require that the uncertainty in the risk assessment be accounted for as explicitly as possible. Therefore, this paper intends to show the advantages and possibilities of a probabilistic human health risk assessment of an industrial chemical, dibutylphthalate (DBP). The risk assessment is based on non-cancer endpoints assumed to have a threshold for toxicity. This example risk assessment shows that a probabilistic risk assessment in the EU framework covering both the exposure and the effects assessment is feasible with currently available techniques. It shows the possibility of comparing the various uncertainties involved in a typical risk assessment, including the uncertainty in the exposure estimate, the uncertainty in the effect parameter, and the uncertainty in assessment factors used in the extrapolation from experimental animals to sensitive human beings. The analysis done did not confirm the reasonable worst-case character of the deterministic EU-assessment of DBP. Sensitivity analysis revealed the extrapolation procedure in the human effects assessment to be the main source of uncertainty. Since the probabilistic approach allows determination of the range of possible outcomes and their likelihood, it better informs both risk assessors and risk managers.     

A Preliminary Risk Assessment of Human Exposure to Phycotoxins in Shellfish: A Review

Over the past few decades, phycotoxins, secondary metabolites produced by toxic phytoplankton, have seen an increase in their frequency, concentrations, and geographic distribution. As shellfish accumulate phycotoxins making them unfit for human consumption, they are considered as an important food safety issue. Thus, a consumer exposure assessment on phycotoxins is necessary. Exposure assessment requires two types of information: contamination and consumption data. Shellfish contamination data on major toxins encountered by at-risk populations (Domoic Acid group, Okadaic Acid group, and Saxitoxin group) have been reviewed. Consumption data have been reviewed for both general and potential high-consumer populations. Then, we undertook acute and chronic exposure assessments, combining available French contamination data and our own consumption data. Studies including exposure assessment were then reviewed. Lastly, risk characterization was undertaken. It can be concluded that both acute and chronic exposure to phycotoxins via shellfish consumption is a matter of concern, mainly for high consumers identified in this review (specific populations and shellfish harvesters). However, the results for risk characterization must be improved. There is a need for (i) toxicological data to establish a Tolerable Daily Intake; (ii) an assessment of consumption and contamination data, undertaken at the same time, so as to assess exposure.     

Raw Sap Consumption Habits and Its Association with Knowledge of Nipah Virus in Two Endemic Districts in Bangladesh

Human Nipah virus (NiV) infection in Bangladesh is a fatal disease that can be transmitted from bats to humans who drink contaminated raw date palm sap collected overnight during the cold season. Our study aimed to understand date palm sap consumption habits of rural residents and factors associated with consumption. In November-December 2012 the field team interviewed adult respondents from randomly selected villages from Rajbari and Kushtia Districts in Bangladesh. We calculated the proportion of people who consumed raw sap and had heard about a disease from raw sap consumption. We assessed the factors associated with raw sap consumption by calculating prevalence ratios (PR) adjusted for village level clustering effects. Among the 1,777 respondents interviewed, half (50%) reported drinking raw sap during the previous sap collection season and 37% consumed raw sap at least once per month. Few respondents (5%) heard about NiV. Thirty-seven percent of respondents reported hearing about a disease transmitted through raw sap consumption, inclusive of a 10% who related it with milder illness like diarrhea, vomiting or indigestion rather than NiV. Respondents who harvested date palm trees in their household were more likely to drink sap than those who did not own date palm trees (79% vs. 65% PR 1.2, 95% CI 1.1–1.3, p<0.001). When sap was available, respondents who heard about a disease from raw sap consumption were just as likely to drink it as those who did not hear about a disease (69% vs. 67%, PR 1.0, 95% CI 0.9–1.1, p = 0.512). Respondents’ knowledge of NiV was low. They might not have properly understood the risk of NiV, and were likely to drink sap when it was available. Implementing strategies to increase awareness about the risks of NiV and protect sap from bats might reduce the risk of NiV transmission.     

Previous Exposure to Statin May Reduce the Risk of Subsequent Non-Hodgkin Lymphoma: A Nationwide Population-Based Case-Control Study

Background

The purpose of this study was to investigate the association between previous exposure to statins and the risk of non-Hodgkin lymphoma (NHL).

Methods

This nationwide population-based case–control study was conducted using the National Health Insurance Research Database of Taiwan. The NHL group consisted of the patients with a first-time diagnosis of NHL between 2005 and 2008. The cases of the control group were pair-matched to the NHL group according to sex, year of birth and date of NHL diagnosis (index date). The statin administration data from both groups were retrospectively collected from the index date to January 1, 1996. The cumulative defined daily dose (cDDD) was estimated to evaluate the statin exposure. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate logistic regression.

Results

The study population was composed of 1715 NHL patients and 16942 control subjects. The analysis revealed that previous statin administration was associated with a reduced risk of subsequent NHL with an adjusted OR of 0.52 (95% CI, 0.43–0.62). Additionally, there was a dose-response relationship between statin administration and the risk of NHL. The adjusted ORs were 0.63 (95% CI, 0.46–0.86), 0.58 (95% CI, 0.42–0.79), 0.51 (95% CI, 0.38–0.67), and 0.36 (95% CI, 0.24–0.53) for the subjects with statin administrations of fewer than 28, 28 to 90, 91 to 365, and more than 365 cDDDs, respectively, relative to the subjects without any statin administration.

Conclusions

The results of this study suggest that previous statin administration is associated with a lower risk of subsequent NHL. As statins are widely used medications, the magnitude of the risk reduction may have a substantial influence on public health. Further studies to confirm our findings are warranted.     

Efficacy of a Multi-level Intervention to Reduce Injecting and Sexual Risk Behaviors among HIV-Infected People Who Inject Drugs in Vietnam: A Four-Arm Randomized Controlled Trial

IntroductionInjecting drug use is a primary driver of HIV epidemics in many countries. People who inject drugs (PWID) and are HIV infected are often doubly stigmatized and many encounter difficulties reducing risk behaviors. Prevention interventions for HIV-infected PWID that provide enhanced support at the individual, family, and community level to facilitate risk-reduction are needed.Methods455 HIV-infected PWID and 355 of their HIV negative injecting network members living in 32 sub-districts in Thai Nguyen Province were enrolled. We conducted a two-stage randomization: First, sub-districts were randomized to either a community video screening and house-to-house visits or standard of care educational pamphlets. Second, within each sub-district, participants were randomized to receive either enhanced individual level post-test counseling and group support sessions or standard of care HIV testing and counseling. This resulted in four arms: 1) standard of care; 2) community level intervention; 3) individual level intervention; and 4) community plus individual intervention. Follow-up was conducted at 6, 12, 18, and 24 months. Primary outcomes were self-reported HIV injecting and sexual risk behaviors. Secondary outcomes included HIV incidence among HIV negative network members.ResultsFewer participants reported sharing injecting equipment and unprotected sex from baseline to 24 months in all arms (77% to 4% and 24% to 5% respectively). There were no significant differences at the 24-month visit among the 4 arms (Wald = 3.40 (3 df); p = 0.33; Wald = 6.73 (3 df); p = 0.08). There were a total of 4 HIV seroconversions over 24 months with no significant difference between intervention and control arms.DiscussionUnderstanding the mechanisms through which all arms, particularly the control arm, demonstrated both low risk behaviors and low HIV incidence has important implications for policy and prevention programming.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01689545","term_id":"NCT01689545"}}NCT01689545     

In-Car Nocturnal Blue Light Exposure Improves Motorway Driving: A Randomized Controlled Trial

Prolonged wakefulness greatly decreases nocturnal driving performance. The development of in-car countermeasures is a future challenge to prevent sleep-related accidents. The aim of this study is to determine whether continuous exposure to monochromatic light in the short wavelengths (blue light), placed on the dashboard, improves night-time driving performance. In this randomized, double-blind, placebo-controlled, cross-over study, 48 healthy male participants (aged 20–50 years) drove 400 km (250 miles) on motorway during night-time. They randomly and consecutively received either continuous blue light exposure (GOLite, Philips, 468 nm) during driving or 2*200 mg of caffeine or placebo of caffeine before and during the break. Treatments were separated by at least 1 week. The outcomes were number of inappropriate line crossings (ILC) and mean standard deviation of the lateral position (SDLP). Eight participants (17%) complained about dazzle during blue light exposure and were removed from the analysis. Results from the 40 remaining participants (mean age ± SD: 32.9±11.1) showed that countermeasures reduced the number of inappropriate line crossings (ILC) (F(2,91.11) = 6.64; p<0.05). Indeed, ILC were lower with coffee (12.51 [95% CI, 5.86 to 19.66], p = 0.001) and blue light (14.58 [CI, 8.75 to 22.58], p = 0.003) than with placebo (26.42 [CI, 19.90 to 33.71]). Similar results were found for SDLP. Treatments did not modify the quality, quantity and timing of 3 subsequent nocturnal sleep episodes. Despite a lesser tolerance, a non-inferior efficacy of continuous nocturnal blue light exposure compared with caffeine suggests that this in-car countermeasure, used occasionally, could be used to fight nocturnal sleepiness at the wheel in blue light-tolerant drivers, whatever their age. More studies are needed to determine the reproducibility of data and to verify if it can be generalized to women.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01070004","term_id":"NCT01070004"}}NCT01070004     

A Randomised Controlled Trial to Reduce Sedentary Time in Young Adults at Risk of Type 2 Diabetes Mellitus: Project STAND (Sedentary Time ANd Diabetes)

Aims

Type 2 diabetes mellitus (T2DM), a serious and prevalent chronic disease, is traditionally associated with older age. However, due to the rising rates of obesity and sedentary lifestyles, it is increasingly being diagnosed in the younger population. Sedentary (sitting) behaviour has been shown to be associated with greater risk of cardio-metabolic health outcomes, including T2DM. Little is known about effective interventions to reduce sedentary behaviour in younger adults at risk of T2DM. We aimed to investigate, through a randomised controlled trial (RCT) design, whether a group-based structured education workshop focused on sitting reduction, with self-monitoring, reduced sitting time.

Methods

Adults aged 18–40 years who were either overweight (with an additional risk factor for T2DM) or obese were recruited for the Sedentary Time ANd Diabetes (STAND) RCT. The intervention programme comprised of a 3-hour group-based structured education workshop, use of a self-monitoring tool, and follow-up motivational phone call. Data were collected at three time points: baseline, 3 and 12 months after baseline. The primary outcome measure was accelerometer-assessed sedentary behaviour after 12 months. Secondary outcomes included other objective (activPAL) and self-reported measures of sedentary behaviour and physical activity, and biochemical, anthropometric, and psycho-social variables.

Results

187 individuals (69% female; mean age 33 years; mean BMI 35 kg/m²) were randomised to intervention and control groups. 12 month data, when analysed using intention-to-treat analysis (ITT) and per-protocol analyses, showed no significant difference in the primary outcome variable, nor in the majority of the secondary outcome measures.

Conclusions

A structured education intervention designed to reduce sitting in young adults at risk of T2DM was not successful in changing behaviour at 12 months. Lack of change may be due to the brief nature of such an intervention and lack of focus on environmental change. Moreover, some participants reported a focus on physical activity rather than reductions in sitting per se. The habitual nature of sedentary behaviour means that behaviour change is challenging.

Trial Registration

Controlled-Trials.com ISRCTN08434554     

Exercise as an Intervention to Reduce Study-Related Fatigue among University Students: A Two-Arm Parallel Randomized Controlled Trial

Background

Many university students experience high levels of study-related fatigue. This high prevalence, and the negative impact of fatigue on health and academic performance, call for prevention and reduction of these symptoms. The primary aim of the current study was to investigate to what extent an exercise intervention is effective in reducing three indicators of study-related fatigue (emotional exhaustion, overall fatigue, and need for recovery). Effects of exercise on secondary outcomes (sleep quality, self-efficacy, physical fitness, and cognitive functioning) were also investigated.

Methods

Participants were students with high levels of study-related fatigue, currently not exercising or receiving other psychological or pharmacological treatments, and with no medical cause of fatigue. They were randomly assigned to either a six-week exercise intervention (low-intensity running three times a week, n = 49) or wait list (no intervention, n = 48). All participants were measured before the intervention (T0), and immediately after the intervention (T1). Exercisers were also investigated 4 weeks (T2) and 12 weeks (T3) after the intervention.

Results

Participants in the exercise condition showed a larger decrease in two of the three indicators of study-related fatigue (i.e., overall fatigue and need for recovery) as compared to controls. Additionally, sleep quality and some indicators of cognitive functioning improved more among exercisers than among controls. No effects were found for self-efficacy, and physical fitness. The initial effects of the exercise intervention lasted at follow-up (T2 and T3). At 12-week follow up (T3), 80% of participants in the exercise condition still engaged in regular exercise, and further enhancements were seen for emotional exhaustion, overall fatigue, and sleep quality.

Conclusions

These results underline the value of low-intensity exercise for university students with high levels of study-related fatigue. The follow-up effects that were found in this study imply that the intervention has the potential to promote regular exercise and accompanying beneficial effects in the longer run.

Trial Registration

Netherlands Trial Register NTR4412     

Reduction of Seizure Occurrence from Exposure to Auditory Stimulation in Individuals with Neurological Handicaps: A Randomized Controlled Trial

Background

The purpose of this work was to determine in a clinical trial the efficacy of reducing or preventing seizures in patients with neurological handicaps through sustained cortical activation evoked by passive exposure to a specific auditory stimulus (particular music). The specific type of stimulation had been determined in previous studies to evoke anti-epileptiform/anti-seizure brain activity.

Methods

The study was conducted at the Thad E. Saleeby Center in Harstville, South Carolina, which is a permanent residence for individuals with heterogeneous neurological impairments, many with epilepsy. We investigated the ability to reduce or prevent seizures in subjects through cortical stimulation from sustained passive nightly exposure to a specific auditory stimulus (music) in a three-year randomized controlled study. In year 1, baseline seizure rates were established. In year 2, subjects were randomly assigned to treatment and control groups. Treatment group subjects were exposed during sleeping hours to specific music at regular intervals. Control subjects received no music exposure and were maintained on regular anti-seizure medication. In year 3, music treatment was terminated and seizure rates followed. We found a significant treatment effect (p = 0.024) during the treatment phase persisting through the follow-up phase (p = 0.002). Subjects exposed to treatment exhibited a significant 24% decrease in seizures during the treatment phase, and a 33% decrease persisting through the follow-up phase. Twenty-four percent of treatment subjects exhibited a complete absence of seizures during treatment.

Conclusion/Significance

Exposure to specific auditory stimuli (i.e. music) can significantly reduce seizures in subjects with a range of epilepsy and seizure types, in some cases achieving a complete cessation of seizures. These results are consistent with previous work showing reductions in epileptiform activity from particular music exposure and offers potential for achieving a non-invasive, non-pharmacologic treatment of epilepsy.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01459692","term_id":"NCT01459692"}}NCT01459692     

The Ethical Conduct of Studies Involving Controlled Human Exposure to Environmental Pollutants

In recent years, the concern for human research subject protection has increased markedly in the United States. The nature of research subject participation in controlled-exposure environmental health research is such that the individual subject bears the risk of participation, while the benefits of such research accrue to society. Therefore, particular attention must be paid when designing studies to protect the health and safety of human research subject. This paper outlines principles for the appropriate selection of pollutants to which humans can be exposed, and the principles that should be used to protect the health and safety of human research subject.     

Current Status of Artemisinin-Resistant falciparum Malaria in South Asia: A Randomized Controlled Artesunate Monotherapy Trial in Bangladesh

Objective

Recent reports indicate that first cases of genuine artemisinin resistance have already emerged along the Thai-Cambodian border. The main objective of this trial was to track the potential emergence of artemisinin resistance in Bangladesh, which in terms of drug resistance forms a gateway to the Indian subcontinent.

Methods

We conducted an open-label, randomized, controlled 42-day clinical trial in Southeastern Bangladesh to investigate the potential spread of clinical artemisinin resistance from Southeast Asia. A total of 126 uncomplicated falciparum malaria patients were randomized to one of 3 treatment arms (artesunate monotherapy with 2 or 4 mg/kg/day once daily or quinine plus doxycycline TID for 7 days). Only cases fulfilling a stringent set of criteria were considered as being artemisinin-resistant.

Findings

The 28-day and 42-day cure rates in the artesunate monotherapy (2 and 4 mg/kg) and quinine/doxycyline arms were 97.8% (95% confidence interval, CI: 87.8–99.8%), 100% (95% CI: 91.1–100%), and 100% (95% CI: 83.4–100%), respectively. One case of re-infection was seen in the artesunate high dose arm, and a single case of recrudescence was observed in the low dose group on day 26. No differences in median parasite and fever clearance times were found between the 2 artesunate arms (29.8 h and 17.9 h vs. 29.5 h and 19.1 h). Not a single case fulfilled our criteria of artemisinin resistance. Parasite clearance times were considerably shorter and ex vivo results indicate significantly higher susceptibility (50% inhibitory concentration for dihydroartemisinin was 1.10 nM; 95% CI: 0.95–1.28 nM) to artemisinins as compared to SE-Asia.

Conclusion

There is currently no indication that artemisinin resistance has reached Bangladesh. However, the fact that resistance has recently been reported from nearby Myanmar indicates an urgent need for close monitoring of artemisinin resistance in the region.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00639873","term_id":"NCT00639873"}}NCT00639873.     

Solar Drinking Water Disinfection (SODIS) to Reduce Childhood Diarrhoea in Rural Bolivia: A Cluster-Randomized,Controlled Trial

Background

Solar drinking water disinfection (SODIS) is a low-cost, point-of-use water purification method that has been disseminated globally. Laboratory studies suggest that SODIS is highly efficacious in inactivating waterborne pathogens. Previous field studies provided limited evidence for its effectiveness in reducing diarrhoea.

Methods and Findings

We conducted a cluster-randomized controlled trial in 22 rural communities in Bolivia to evaluate the effect of SODIS in reducing diarrhoea among children under the age of 5 y. A local nongovernmental organisation conducted a standardised interactive SODIS-promotion campaign in 11 communities targeting households, communities, and primary schools. Mothers completed a daily child health diary for 1 y. Within the intervention arm 225 households (376 children) were trained to expose water-filled polyethyleneteraphtalate bottles to sunlight. Eleven communities (200 households, 349 children) served as a control. We recorded 166,971 person-days of observation during the trial representing 79.9% and 78.9% of the total possible person-days of child observation in intervention and control arms, respectively. Mean compliance with SODIS was 32.1%. The reported incidence rate of gastrointestinal illness in children in the intervention arm was 3.6 compared to 4.3 episodes/year at risk in the control arm. The relative rate of diarrhoea adjusted for intracluster correlation was 0.81 (95% confidence interval 0.59–1.12). The median length of diarrhoea was 3 d in both groups.

Conclusions

Despite an extensive SODIS promotion campaign we found only moderate compliance with the intervention and no strong evidence for a substantive reduction in diarrhoea among children. These results suggest that there is a need for better evidence of how the well-established laboratory efficacy of this home-based water treatment method translates into field effectiveness under various cultural settings and intervention intensities. Further global promotion of SODIS for general use should be undertaken with care until such evidence is available.

Trial Registration

www.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00731497","term_id":"NCT00731497"}}NCT00731497 Please see later in the article for Editors'' Summary