Pursestring closure of the stoma site leads to fewer wound infections: results from a multicenter randomized controlled trial.

BACKGROUND: Surgical site infection after stoma reversal is common. The optimal skin closure technique after stoma reversal has been widely debated in the literature. OBJECTIVE: We hypothesized that pursestring near-complete closure of the stoma site would lead to fewer surgical site infections compared with conventional primary closure. DESIGN: This study was a parallel prospective multicenter randomized controlled trial. SETTINGS: This study was conducted at 2 university medical centers. PATIENTS: Patients (N = 122) presenting for elective colostomy or ileostomy reversal were selected. INTERVENTIONS: Pursestring versus conventional primary closure of stoma sites were compared. MAIN OUTCOME MEASURES: Stoma site surgical site infection within 30 days of surgery, overall surgical site infection, delayed healing (open wound for >30 days), time to wound epithelialization, and patient satisfaction were the primary outcomes measured. RESULTS: The pursestring group had a significantly lower stoma site infection rate (2% vs 15%, p = 0.01). There was no difference in delayed healing or patient satisfaction between groups. Time to epithelialization was measured in only 51 patients but was significantly longer in the pursestring group (34.6 ± 20 days vs 24.1 ± 17 days, p = 0.02). LIMITATIONS: This study was limited by the variability in procedures and surgeons, the limited follow-up after 30 days, and the inability to perform blinding. CONCLUSION: Pursestring closure after stoma reversal has a lower risk of stoma site surgical site infection than conventional primary closure, although wounds may take longer to heal with the use of this approach. REGISTRATION NUMBER: NCT01713452 (www.clinicaltrials.gov).

Manual therapy followed by specific active exercises versus a placebo followed by specific active exercises on the improvement of functional disability in patients with chronic non specific low back pain: a randomized controlled trial.

BACKGROUND: Recent clinical recommendations still propose active exercises (AE) for CNSLBP. However, acceptance of exercises by patients may be limited by pain-related manifestations. Current evidences suggest that manual therapy (MT) induces an immediate analgesic effect through neurophysiologic mechanisms at peripheral, spinal and cortical levels. The aim of this pilot study was first, to assess whether MT has an immediate analgesic effect, and second, to compare the lasting effect on functional disability of MT plus AE to sham therapy (ST) plus AE. METHODS: Forty-two CNSLBP patients without co-morbidities, randomly distributed into 2 treatment groups, received either spinal manipulation/mobilization (first intervention) plus AE (MT group; n = 22), or detuned ultrasound (first intervention) plus AE (ST group; n = 20). Eight therapeutic sessions were delivered over 4 to 8 weeks. Immediate analgesic effect was obtained by measuring pain intensity (Visual Analogue Scale) before and immediately after the first intervention of each therapeutic session. Pain intensity, disability (Oswestry Disability Index), fear-avoidance beliefs (Fear-Avoidance Beliefs Questionnaire), erector spinae and abdominal muscles endurance (Sorensen and Shirado tests) were assessed before treatment, after the 8th therapeutic session, and at 3- and 6-month follow-ups. RESULTS: Thirty-seven subjects completed the study. MT intervention induced a better immediate analgesic effect that was independent from the therapeutic session (VAS mean difference between interventions: -0.8; 95% CI: -1.2 to -0.3). Independently from time after treatment, MT + AE induced lower disability (ODI mean group difference: -7.1; 95% CI: -12.8 to -1.5) and a trend to lower pain (VAS mean group difference: -1.2; 95% CI: -2.4 to -0.30). Six months after treatment, Shirado test was better for the ST group (Shirado mean group difference: -61.6; 95% CI: -117.5 to -5.7). Insufficient evidence for group differences was found in remaining outcomes. CONCLUSIONS: This study confirmed the immediate analgesic effect of MT over ST. Followed by specific active exercises, it reduces significantly functional disability and tends to induce a larger decrease in pain intensity, compared to a control group. These results confirm the clinical relevance of MT as an appropriate treatment for CNSLBP. Its neurophysiologic mechanisms at cortical level should be investigated more thoroughly. TRIAL REGISTRATION: Trial registration number: NCT01496144.

Universal screening and decolonization for control of MRSA in nursing homes : a cluster randomized controlled study

OBJECTIVE The risk of carrying methicillin-resistant Staphylococcus aureus (MRSA) is higher among nursing home (NH) residents than in the general population. However, control strategies are not clearly defined in this setting. In this study, we compared the impact of standard precautions either alone (control) or combined with screening of residents and decolonization of carriers (intervention) to control MRSA in NHs. DESIGN Cluster randomized controlled trial SETTING NHs of the state of Vaud, Switzerland PARTICIPANTS Of 157 total NHs in Vaud, 104 (67%) participated in the study. INTERVENTION Standard precautions were enforced in all participating NHs, and residents underwent MRSA screening at baseline and 12 months thereafter. All carriers identified in intervention NHs, either at study entry or among newly admitted residents, underwent topical decolonization combined with environmental disinfection, except in cases of MRSA infection, MRSA bacteriuria, or deep skin ulcers. RESULTS NHs were randomly allocated to a control group (51 NHs, 2,412 residents) or an intervention group (53 NHs, 2,338 residents). Characteristics of NHs and residents were similar in both groups. The mean screening rates were 86% (range, 27%-100%) in control NHs and 87% (20%-100%) in intervention NHs. Prevalence of MRSA carriage averaged 8.9% in both control NHs (range, 0%-43%) and intervention NHs (range, 0%-38%) at baseline, and this rate significantly declined to 6.6% in control NHs and to 5.8% in intervention NHs after 12 months. However, the decline did not differ between groups (P=.66). CONCLUSION Universal screening followed by decolonization of carriers did not significantly reduce the prevalence of the MRSA carriage rate at 1 year compared with standard precautions

Basal and stimulated lactate fluxes in primary cultures of astrocytes are differentially controlled by distinct proteins.

Lactate release by astrocytes is postulated to be of importance for neuroenergetics but its regulation is poorly understood. Basigin, a chaperone protein for specific monocarboxylate transporters (MCTs), represents a putatively important regulatory element for lactate fluxes. Indeed, basigin knockdown by RNA interference in primary cultures of astrocytes partially reduced both proton-driven lactate influx and efflux. But more strikingly, enhancement of lactate efflux induced by glutamate was prevented while the effect of sodium azide was significantly reduced by treatment of cultured astrocytes with anti-basigin small interfering RNA. Enhancement of glucose utilization was unaffected under the same conditions. Basal lactate uptake and release were significantly reduced by MCT1 knockdown, even more so than with basigin knockdown, whereas glutamate-driven or sodium azide-induced enhancement of lactate release was not inhibited by either MCT1, 2, or 4 small interfering RNAs. In conclusion, MCT1 plays a pivotal role in the control of basal proton-driven lactate flux in astrocytes while basigin is only partly involved, most likely via its interaction with MCT1. In contrast, basigin appears to critically regulate the enhancement of lactate release caused by glutamate (or sodium azide) but via an effect on another unidentified transporter at least present in astrocytes in vitro.

Survival responses in stressed organs

Apoptosis or programmed cell death is a regulated form of cell suicide executed by cysteine proteases, or "caspases", to maintain proper tissue homeostasis in multicellular organisms. Dysregulation of apoptosis leads to pathological complications including cancer, autoimmunity, neurodegenerative, and heart diseases. Beside their known function as the key executioners of apoptotic cell death, caspases were reported to mediate non-apoptotic functions. In this report we study the survival signals conveyed through caspase-3-mediated cleavage of Ras GTPase-activating proteins (RasGAP). Ubiquitously expressed, RasGAP senses caspase activity and controls the cell death/survival switch. RasGAP is cleaved once at low caspase activity and the generated N-terminal fragment (fragment N) induces a survival response by activating Ras/PI3K/Akt pathway. However, high caspase activity associated with increased stress leads to fragment Ν cleavage into fragments that do not mediate any detectable survival signals. In this thesis project we studied the role of fragment Ν in protecting stressed organs as well as in maintenance of their functionality. In response to stress in different organs, we found that mice lacking caspase-3 or unable to cleave RasGAP (Knock-In mice), and therefore unable to generate fragment N, were deficient in Akt activation and experienced increased apoptosis compared to wild-type mice. Augmented tissue damage and organ dysfunction in those mice highlight the importance of fragment Ν in activating Akt-mediated prosurvival pathway and in protection of organs during episodes of stress. In parallel we investigated the role of fragment Ν in regulating the activation of transcription factor NF-kB, a master regulator of inflammation. Sustained NF-kB activation may be detrimental by directly causing apoptosis or leading to a persistent damaging inflammation response. We found that fragment Ν is a potent inhibitor of NF-kB by favoring its nuclear export. Therefore, fragment Ν regulates NF-kB activity and contributes to a controlled response as well as maintenance of homeostasis in stressed cells. Importantly, these findings introduce new insights of how activated caspase-3 acts as a stress intensity sensor that controls cell fate by either initiating a fragment N- dependent cell resistance program or a cell suicide response. This identifies the pivotal role of fragment Ν in protection against patho-physiological damage, and encourages the development of therapies which aim to increase cell resistance to vigorous treatment. - L'apoptose, ou mort cellulaire programmée, est une forme contrôlée de suicide cellulaire exécuté par des protéines appelées caspases, dans le but de maintenir l'homéostasie des tissus sains dans les organismes multicellulaires. Un mauvais contrôle de l'apoptose peut mener à des pathologies comme le cancer, la neurodégénération et les maladies cardiaques et auto-immunes. En dehors de leur rôle connu d'exécutrices de l'apoptose, les caspases ont aussi été identifiées dans d'autres contextes non-apoptotiques. Dans ce projet, nous avons étudié les signaux de survie émis par le résultat du clivage de RasGAP par la caspase-3. Exprimée de façon ubiquitaire, RasGAP est sensible à l'activité de caspase-3 et contrôle la décision de la cellule à entreprendre la mort ou la survie cellulaire. A un taux d'activité faible, la caspase-3 clive RasGAP, ce qui mène à la génération d'un fragment N-terminal, appelé Fragment N, qui induit des signaux de survie via l'activation de la cascade Ras/PI3K/Akt. Cependant, lorsque l'activité de la caspase-3 augmente, le fragment N est clivé, ce qui a pour effet d'éliminer ces signaux de survie. Dans ce travail, nous avons étudié le rôle du Fragment N dans la protection des organes en état de stress et dans le maintien de leur fonctionnalité. En réponse à certains stress, nous avons découvert que les organes de souris n'exprimant pas la caspase-3 ou alors incapables de cliver RasGAP (souris Kl), et de ce fait n'ayant pas la possibilité de générer le Fragment N, perdaient leur faculté d'activer la protéine Akt et démontraient un taux d'apoptose plus élevé que des organes de souris sauvages. Le fait que les organes et tissus de ces souris manifestaient de graves dommages et dysfonctions met en évidence l'importance du Fragment N dans l'activation des signaux de survie via la protéine Akt et dans la neutralisation de l'apoptose induite par la caspase-3. En parallèle, nous avons investigué le rôle du Fragment N dans la régulation de l'activation de NF-kB, un facteur de transcription clé dans l'inflammation. Une activation soutenue de NF-kB peut être délétère par activation directe de l'apoptose ou peut mener à une réponse inflammatoire persistante. Nous avons découvert que le Fragment N, en favorisant l'export de NF-kB depuis le noyau, était capable de l'inhiber très efficacement. Le Fragment N régule donc l'activité de NF-kB et contribue au maintien de l'homéostasie dans des cellules stressées. Ces découvertes aident, de façon importante, à la compréhension de comment l'activation de la caspase-3 agit comme senseur de stress et décide du sort de la cellule soit en initiant une protection par le biais du fragment N, ou en induisant un suicide cellulaire. Cette étude définit le Fragment Ν comme ayant un rôle de pivot dans la protection contre des dommages patho-physiologiques, et ouvre des perspectives de développement de thérapies qui cibleraient à augmenter la résistance à divers traitements.

The Impact of CAROtid plaque Screening on Smoking (CAROSS) cessation and control of other cardiovascular risk factors: rationale and design of a randomized controlled trial

BACKGROUND: Screening tests for subclinical cardiovascular disease, such as markers of atherosclerosis, are increasingly used in clinical prevention to identify individuals at high cardiovascular risk. Being aware of these test results might also enhance patient motivation to change unhealthy behaviors but the effectiveness of such a screening strategy has been poorly studied. METHODS: The CAROtid plaque Screening trial on Smoking cessation (CAROSS) is a randomized controlled trial in 530 regular smokers aged 40-70 years to test the hypothesis that carotid plaque screening will influence smokers' behavior with an increased rate of smoking cessation (primary outcome) and an improved control of other cardiovascular risk factors (secondary outcomes) after 1-year follow-up. All smokers will receive a brief advice for smoking cessation,and will subsequently be randomly assigned to either the intervention group (with plaques screening) or the control group (without plaque screening). Carotid ultrasound will be conducted with a standard protocol. Smokers with at least one carotid plaque will receive pictures of their own plaques with a structured explanation on the general significance of plaques. To ensure equal contact conditions, smokers not undergoing ultrasound and those without plaque will receive a relevant explanation on the risks associated with tobacco smoking. Study outcomes will be compared between smokers randomized to plaque screening and smokers not submitted to plaque screening. SUMMARY: This will be the first trial to assess the impact of carotid plaque screening on 1-year smoking cessation rates and levels of control of other cardiovascular risk factors.

Influence of counselor characteristics and behaviors on the efficacy of a brief motivational intervention for heavy drinking in young men-a randomized controlled trial.

BACKGROUND: Brief motivational intervention (BMI) has shown promising results to reduce alcohol use in young adults. Knowledge on mechanisms that predict BMI efficacy could potentially improve treatment effect sizes through data that optimize clinical training and implementation. Particularly, little attention has been given to counselor influence on treatment mechanisms. METHODS: We investigated the influence of counselors on BMI efficacy in reducing alcohol use among non-treatment-seeking young men (age 20) screened as hazardous drinkers. Participants were randomly allocated to (i) a group receiving a single BMI from 1 of 18 counselors selected to maximize differences in several of their characteristics (gender, professional status, clinical experience, and motivational interviewing [MI] experience) or (ii) a control group receiving assessment only. Drinking at 3-month follow-up was first compared between the BMI and control groups to assess efficacy. Then, the influence of counselors' characteristics (i.e., gender, professional status, clinical experience, MI experience, BMI attitudes, and expectancies) and within-session behaviors (i.e., measured by the Motivational Interviewing Skill Code) on outcome was tested in regression analyses. RESULTS: There was a significant (p = 0.02) decrease in alcohol use among the BMI group compared to the control group. Counselors that were male, more experienced, that had more favorable BMI attitudes and expectancies, higher MI skills, but surprisingly less MI-consistent behaviors, had significantly better outcomes than the control group while their counterparts did not. CONCLUSIONS: The current study demonstrated BMI efficacy on alcohol use reduction within a sample of non-treatment-seeking young adult males. Moreover, BMI effect was related to interindividual differences among counselors, and results therefore provide recommendations for BMI training and implementation with similar populations.

Use of nicotine substitute prescribed at hourly plus ab libitum intake or ad libitum for heavy smokers willing to quit: a randomized controlled trial.

OBJECTIVE: To assess the impact of instructional guidance in the regular use of use nicotine nasal spray (NNS) on the true use of NNS during the first three weeks of smoking cessation for heavy smokers who are willing to quit. METHODS: This randomized, open, controlled trial included 50 patients who were heavy smokers, were willing to quit, and attending an academic outpatient clinic in Western Switzerland. Patients were randomised to instruction on NNS use as "ad libitum" (administration whenever cravings appear; control group) or to use NNS when craving appears and at least every hour when awake (intervention group). Intakes were monitored using an electronic device fixed in the spray unit (MDILog) during the first three weeks of use. Self reported abstinence from smoking at six months was confirmed by expired-air carbon monoxide. Using intention-to-treat analysis, random-effect GLS regression was used to calculate the mean difference of daily doses between groups controlling for lack of independence between measures from the same individual. RESULTS: One patient was lost to follow-up. At baseline randomization, the group receiving instruction to use NNS hourly included more women, patients with previous desires to quit, and patients with more psychiatric comorbidities and less somatic complaints compared to the group instructed to use NNS with cravings (group imbalance). Both groups self-administered more than the daily recommended dosage of 8 uses. Mean daily usage was 13.6 dose/day and 11.1 dose/day for the group instructed to use NNS hourly and with cravings, respectively. Adjusting for baseline imbalance, the increased daily doses in the intervention group (hourly use) remained nonsignificant compared to ad libitum use (-0.5 dose/day; CI 95% -6.2; 5.3, from day 1 to day 7; and 2.3 dose/day; CI 95% -5.4; 10.0, from day 8 to day 21). Instructing patients to use the NNS daily had no effect on smoking cessation at six months (RR = 0.69; CI 95% 0.34; 1.39). CONCLUSION: Heavy smokers willing to quit use NNS frequently, regardless of the instructions given. Recommending the use of NNS only when craving appears for heavy smokers willing to quit seems acceptable compared to prescribing hourly administration. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00861276.

An international, randomized, double-blind, placebo-controlled, phase III trial of pregabalin monotherapy in treatment of patients with fibromyalgia.

OBJECTIVE: To evaluate the efficacy and safety of pregabalin monotherapy versus placebo for symptomatic pain relief and improvement of patient global assessment in patients with fibromyalgia (FM) enrolled from countries outside the United States. METHODS: This international, multicenter, double-blind, placebo-controlled trial randomly assigned 747 patients with FM to placebo or 300, 450, or 600 mg/day pregabalin twice daily for 14 weeks. Primary efficacy measures were endpoint mean pain scores and Patient Global Impression of Change (PGIC). Secondary outcomes included assessments of sleep and function. RESULTS: Patients in the 450 mg/day pregabalin group showed significant improvements versus placebo in endpoint mean pain score (-0.56; p = 0.0132), PGIC (73% improved vs 56% placebo; p = 0.0017), and function [Fibromyalgia Impact Questionnaire (FIQ) total score -5.85; p = 0.0012]. PGIC was also significant for 600 mg/day pregabalin (69% improved; p = 0.0227). Results for these endpoints were nonsignificant for pregabalin at 300 mg/day and for pain and FIQ score at 600 mg/day. Early onset of pain relief was seen, with separation from placebo detected by Week 1 in all pregabalin groups. All pregabalin doses demonstrated superiority to placebo on the Medical Outcomes Study-Sleep Scale Sleep Disturbance subscale and the Sleep Quality diary. Dizziness and somnolence were the most frequently reported adverse events. CONCLUSION: Pregabalin demonstrated modest efficacy in pain, global assessment, and function in FM at 450 mg/day, and improved sleep across all dose levels, but it did not provide consistent evidence of benefit at 300 and 600 mg/day in this study. Pregabalin was generally well tolerated for the treatment of FM. (Clinical trial registry NCT00333866).

Adalimumab in Severe and Acute Sciatica (ASAS) : a multicentre, randomized, double-blind, placebo-controlled trial : 1240

Background Based on several experimental results and on a preliminary study, a trial was undertaken to assess the efficacy of adalimumab, a TNF-α inhibitor, in patients with radicular pain due to lumbar disc herniation. Methods A multicentre, double-blind, randomised controlled trial was conducted between May 2005 and December 2007 in Switzerland. Patients with acute (< 12 weeks) and severe (Oswestry Disability index > 50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomised to receive as adjuvant therapy either two subcutaneous injections of adalimumab (40 mg) at 7 days interval or matching placebo. The primary outcome was leg pain, which was recorded every day for 10 days and at 6-weeks and 6- months based on a visual analogue scale (0 to 100). Results Of the 265 patients screened, 61 were enrolled (adalimumab= 31) and 4 were lost to follow-up. Over time, the evolution of leg pain was more favourable in the adalimumab group than in the placebo group (p<0.001). However, the effect size was relatively small and at last follow-up the difference was 13.8 (CI95% -11.5 - 39.0). In the adalimumab group twice as many patients fulfilled the criteria for "responders" and for "low residual disease impact" ( p<0.05) and fewer surgical discectomies were performed (6 versus 13, p=0.04). Conclusion The addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.