Considering the importance of sleep

Considering the importance of sleep health, many studies have examined sleep quality as a marker of general health [28]. Sleep quality, which is a self evaluation of sleep, is considered more important than sleep quantity in the assessment of general health [29,30]. Poor sleep quality is associated with fatigue and impaired mental and occupational functions [31]. This index is affected by many sleep-wake carboxypeptidase a disorders and studies have shown that stimulants affect sleep quality as well [32]. As there are not enough studies assessing sleep quality in methamphetamine dependent patients during prolonged abstinence, especially after prolonged use [33]; the present study aims to evaluate subjective changes in sleep quality of methamphetamine dependent patients during early remission period.


In this study, a total of 90 patients with methamphetamine dependence disorder were examined in terms of quality of sleep and symptoms of depression and anxiety through three consecutive measurements. Table 1 summarizes the patients\’ demographic variables. As shown in Table 1 most of the participants were males, who were married and employed. Preferred route of using was smoking methamphetamine with pipe in all participants. The improper quality of sleep, which is shown with PSQI>5, was very common within the first days of withdrawal from methamphetamine (97.8% of participants in the first assessment), while its frequency was reduced considerably four weeks after being abstinent (52.2% of participants in the third assessment) (Table 1).
Figs. 1–3 are the scatter diagrams that show the sleep quality results obtained through three assessments in the participants. According to the diagrams, distribution pattern of sleep quality index of the participants shows minimal changes between the first and second evaluations (Figs. 1 and 2), but it appears that the last assessment which was done one month after quitting the substance has different pattern of distribution (Fig. 3). Given the results of the Table 2, mean sleep quality scores of the participants has reduced significantly in the third assessment in comparison to the previous assessments (P=0).
Table 3 shows the mean changes of the sleep quality, depression and anxiety of the participants through the three consecutive measurements. The data indicates that the index of sleep quality of participants has considerable reduction four weeks after the complete abstinence from methamphetamine, yet the scores of BDI-II and BAI decreased in repeated assessments too. Considering the fact that the alteration in depression and anxiety symptoms can influence the patients\’ quality of sleep, the multivariate regression model was used to measure the impact of the decreased scores of patients\’ depression and anxiety on the decreased index of sleep quality. Table 3 shows the respective results. Although the variations of depression and anxiety levels within four weeks after stopping amphetamine use was significantly effective in prediction of patients\’ variation of sleep quality, the measured impact was low (adjusted R2<0.5). Furthermore, the impact of these two intervening variables on patients\' quality of sleep was dwindled over time after quitting amphetamine use (Table 4).
Results showed that the improper quality of sleep during the early days of treatment was reported very high (97.8%). Since the quality of sleep, which is measured by PSQI, is the outcome of several parameters including the general description of the subject on his/her own sleeping, the sleep latency, sleep duration, sleep sufficiency, sleep maintenance and morning performance, any change in the mentioned factors may decrease sleep quality [41]. There are reports about the reduced sleep duration, the prolonged delay in falling sleep, decreased sleep duration and more frequent spontaneous awakenings from sleep within 3–5 days after using amphetamines [13]. On the other hand, it has been suggested that quitting methamphetamine use may increase the daytime drowsiness [28]. Therefore, the low quality of sleep due to using methamphetamines is expected. However, the high prevalence of disturbed sleep inthe early days of study demonstrates that methamphetamines broadly affect the brain centers which are tasked with regulating the sleep-wake cycle. In fact, 88 out of 90 participants reported the low-quality sleep at the beginning of the study; while analysis of low-quality sleep prevalence in other chronic diseases using similar tool (PSQI) showed lower values. For instance, studies have shown that sleep quality is usually low in 75% of patients with end-stage renal disease who are being treated with dialysis [46], 56% of patients suffering systemic lupus erythematosus [47], 47% of patients with Parkinson disease [48] and 71% of patients with type 2 diabetes mellitus [49]. Thus, the very high prevalence of low-quality sleep in methamphetamines users emphasizes the importance of sleep problems issues in treatment protocols. On the other hand, although the drug tolerance is common after long-term use of most stimulants, the high rate of sleep disturbance at the beginning of this study indicated that tolerance to the disturbing effects of methamphetamine on sleep-wake cycle is not observed in methamphetamines abusers, even in severe cases such as methamphetamine dependence disorder patients.

br Discussion br Conclusion br Conflict



Conflict of interest

There are limited statistics available in South Africa regarding poisoning as the cause of death. In 2007, the 9th Annual Report of the National Injury Mortality Surveillance System (NIMSS) attributed 4% of deaths to poisoning, with a peak in the 30–34 year age group.
Poison Information Centre (PIC) statistics in the United States of America show that, during 2008, more than 2.4 million human exposures were logged by 61 PICs, of which 1315 were fatalities i.e. 8.2 exposures per thousand carboxypeptidase a with a fatality rate of 0.05%. Since 1999 the National Poison Information Service (NPIS) in the United Kingdom has provided both a national telephone service as well as free access to an internet database service (TOXBASE) for all professionals registered with the National Health Service. The implementation of the TOXBASE system almost halved the call load to the National Poison Information Service. South Africa does not have a single national poison information service or a facility for access to an online database.

Approach to the management of the poisoned patient

Management of the poisoned patient
Staff should be aware of the necessity of taking universal measures to prevent cross contamination during the initial evaluation, depending on the nature of the poison (e.g. organophosphates, cyanide). An ABC-approach should be followed ensuring a protected airway, adequate ventilation and hemodynamic stability. Supportive and symptomatic care remains the cornerstone of treatment. The poisoned patient should be kept under close observation with frequent re-evaluation of vital signs and level of consciousness.
A stepwise approach to decrease the bioavailability of a toxin is illustrated in Box 4.

Patients with intentional self poisoning should undergo a risk assessment for further self harm before discharge. High risk factors (Box 6) should prompt the involvement of the psychiatric team for a full psychiatric evaluation. These patients should always be discharged in the care of a responsible adult. Social support must also be offered to substance abuse patients. This includes assistance with rehabilitation.


Ujuzi is intended to be a regular feature for colleagues to share practical interventions, innovations and novelties that have proved useful in the management of patients in the prehospital environment or Emergency Centre. You can let Ujuzi know about your practical ideas by emailing .
Intramuscular ketamine for sedation of patients in danger and/or endangering others
Safety can be improved in these cases by the judicious use of intramuscular ketamine. This dose provides profound dissociative sedation within 5min. Ketamine is best administered into the deltoid muscle or anterior thigh. The highest concentration of ketamine available (100mg/ml) is most appropriate and will allow administration of the required dose in less than 5ml.
The patient should be left alone as far as possible after injection until sedation ensues.

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Executive summary
Vision: To create an International Model Curriculum for Emergency Medicine Specialist Training on behalf of the International Federation of Emergency Medicine (IFEM). This consensus based curriculum model will provide educators and institutions with the minimum basic requirements for the development of graduate level training for emergency medicine specialists.
Rationale: There is critical, overwhelming, and growing need for emergency physicians and other emergency medicine resources worldwide. Currently, there exist a small number of national curricula for emergency medicine, and no standard, carboxypeptidase a recognized international curricula for the training of emergency medicine specialists.

Based on these controlled and prospective results

Based on these controlled and prospective results, the authors reach the important conclusion that cold ischemia provides greater protection of renal function than does warm ischemia. Other authors have stressed correctly that baseline renal function and the amount of renal parenchymal preservation are the most important factors in the final renal function. The results of the present study are in complete agreement with those points. The need or benefit of cold ischemia is a “relative” one dependent on the overall health of the patient and the renal substrate, the degree of difficulty (ie, duration) of tumor removal, and renal reconstruction. All can agree that the duration of any ischemia should be kept to the minimum that is possible. However, the experience from organ procurement, preservation, and transplantation clearly shows that cold ischemia is preferable to warm ischemia. It seems very illogical to suggest that these pathophysiological facts do not apply to renal surgery for partial nephrectomy for RCC. One must keep in mind that the findings in the present study apply to open surgery. The findings cannot address whether or not minimally invasive surgery for small tumors, with brief warm ischemic times, in patients with excellent baseline renal function, result in any statistically decreased renal function compared with that obtained with cold ischemia and open surgery. Much of the controversy would disappear if one developed a feasible technique for provision of cold ischemia during minimally invasive surgery. I congratulate the authors on the important findings from this well-performed study.

It is estimated that 74,690 individuals will be diagnosed with carboxypeptidase a cancer in the United States in 2014, of which 20%-30% will have muscle-invasive bladder cancer (MIBC). If MIBC is left untreated, the survival rate at 5 years approaches zero. The current gold standard therapy for MIBC is radical cystectomy (RC), which provides a 5-year overall survival (OS) of approximately 53%-57%. However, the morbidity associated with this surgery is not insignificant, with reported 90-day complication rates as high as 64%. The high morbidity associated with surgery has likely contributed to the underuse of this curative therapy.
Trimodality bladder preservation therapy (BPT) has gained popularity as an alternative therapy to RC as it offers avoidance of surgical morbidity and preservation of the native bladder. Ideal candidates for BPT include those with an organ-confined solitary tumor, no associated carcinoma in situ (CIS), no hydronephrosis, and the ability to tolerate chemotherapy. Several series have reported long-term survival results with BPT that are similar to modern RC series. However, these are nonrandomized trials, and patients receiving BPT are often highly selected. Unfortunately, no published randomized controlled trials (RCTs) exist comparing BPT to RC. Previous attempts to compare the 2 therapies were stifled by poor accrual, which suggests future RCTs are very unlikely.

Urothelial carcinoma of the bladder is estimated to account for 74,690 cases and 15,580 deaths in the United States for 2014. Three quarters of new cases present with non–muscle-invasive disease and can be effectively managed with transurethral resection and intravesical therapy. A third of patients will progress to muscle-invasive disease, and for these patients, as well as for the 25% who present initially with muscle-invasive disease, the standard of care is radical cystectomy, pelvic lymphadenectomy, and neoadjuvant chemotherapy. Regionalization of complex cancer care has led to the majority of radical cystectomy being performed at (mostly urban) tertiary cancer centers, resulting in increased travel burden for many patients. Although there are undoubtedly benefits to regionalization of complex surgical procedures to high-volume centers, a consequence of such regionalization is difficulty of access, particularly for patients living in rural or underserved areas who have longer distances to travel to reach a cancer center. Greater distance to a treatment facility has been associated with reduced health care utilization, advanced stage at diagnosis, and worse oncologic outcomes in many cancer types. Given that radical cystectomy is associated with >50% morbidity, close liaison between patients and the urologic surgeon is imperative throughout the perioperative period. Patients with long travel distance may be less likely to seek care for postoperative complications or may opt to have their postsurgical care at local medical centers. Thus, the distance traveled to treatment facility could potentially influence the quality of care received and outcomes of patients after radical cystectomy. In this study, we examined the effect of distance to treatment facility on quality measures including time to surgery, utilization of neoadjuvant chemotherapy, and short- and long-term survival outcomes of bladder cancer patients treated with radical cystectomy.

br Results br Discussion In the six on farm FECRTs


In the six on-farm FECRTs (phase 1), treatment with abamectin alone was variably effective against Cooperia spp. but generally effective against Ostertagia spp. This is consistent with previous studies which have shown that ML-resistance is common in C. oncophora in New Zealand but relatively rare in O. ostertagi (Waghorn et al., 2006; Leathwick and Miller, 2013). It was noteworthy that in this study ML-resistance in Ostertagia spp. was indicated on one farm as this is still an unusual occurrence. In contrast, levamisole was consistently effective against Cooperia, but it’s efficacy against Ostertagia spp. was highly variable and sometimes poor (range 13%–99%, Table 3), a result similar to other studies in New Zealand (Mason and McKay, 2006) and overseas (Anderson and Lord, 1979; Williams et al., 1991; Williams and Broussard, 1995; Rendell, 2010). It would appear that levamisole has never shown consistent high efficacy against this parasite and so a definition of resistance in this case is problematic. However, as was also found in these other studies, in the current evaluation levamisole remained effective against other important nematodes (e.g. Cooperia spp.), and so it remains an important carboxypeptidase a for its ability to control these species.
Given the generally high efficacy of abamectin against Ostertagia, apart from the one exception, and of levamisole against Cooperia then it would be expected that a combination product containing both actives would be effective against both worm genera. This was indeed the case with the combination oral which achieved ≥97% efficacy against both genera in all tests. However, while the combination pour‐ons were sometimes highly effective, each failed to achieve 95% efficacy at least once against both Cooperia and Ostertagia spp. In particular, Aba+Lev pour‐on 2 failed to achieve 95% efficacy in 45% (5/11) evaluations; 4/6 tests against Cooperia and 1/5 tests against Ostertagia. This failure of the pour‐ons to achieve 95% efficacy occurred despite there being no indication of levamisole resistance in Cooperia and only one farm where there was an indication of ML-resistance in Ostertagia spp., based on the efficacy of the single actives administered as orals. What is more, in a number of tests the abamectin + levamisole combination pour‐ons were less effective than one or both actives used alone as oral formulations. For example, on both of Farms 1 and 2, abamectin and levamisole used alone as orals were each 100% effective against Cooperia spp. and yet pour‐on 2, which contained both these actives, was only 88% and 93% effective, respectively against this parasite. Similarly, on Farm 2 abamectin oral was 100% effective against Ostertagia and yet both the combination pour‐ons had poor efficacy against this species (74% and 32% efficacy for pour‐ons 1 and 2, respectively). Such results were unexpected given that combinations of two independent actives can be expected to result in an additive anthelmintic effect (Bartram et al., 2012) and such an effect has been demonstrated numerous times with oral combinations (Anderson et al., 1988; McKenna, 1990b; Anderson et al., 1991; Le Jambre et al., 2010). Also, an earlier study in New Zealand found that when ivermectin and levamisole were administered as two separate pour‐on products to the same animals, the efficacy against both Ostertagia and Cooperia spp. was consistently high, at least for the first two weeks after treatment (Mason and McKay, 2006).
That the combination pour‐ons were less effective in some of the phase 1, on-farm FECRT studies than their constituent actives used alone, indicates that the components of the pour-ons (i.e. abamectin and levamisole) were each achieving lower efficacies than indicated by the efficacy of the single actives administered as orals. In each of the FECRT all the pour-on treated animals were run together after treatment, and given that one of the pour-on products tended to outperform the other, it therefore seems unlikely that the reduced efficacy was a result of erratic delivery of actives due to animals licking themselves or each other. Given that each test was conducted against the same worm population on the same day it can only be assumed that this difference in efficacy reflects lower levels of drug reaching the target worms following pour‐on administration. The concentration of drug reaching the target worms is the ultimate determinant of efficacy and it has been shown that this can vary enormously between routes of administration (Bogan and McKellar, 1988; Gokbulut et al., 2010; Lloberas et al., 2012). In particular, oral administration involves two pathways for active to reach worms in the gut, with a portion of the administered dose remaining in the intestinal fluids and passing directly to the abomasum and intestine while the remainder is absorbed and travels systemically via plasma. In contrast, active administered topically or by injection can only reach target worms in the gut systemically. This difference can result in much higher concentrations of active in the gut tissue, and in the worms themselves, following oral administration than after topical administration or injection (Bogan and McKellar, 1988; Gokbulut et al., 2010; Lloberas et al., 2012; Leathwick and Miller, 2013).

br Materials and methods br Results br Discussion As

Materials and methods


As with many other plus-strand RNA viruses, arterivirus genomes are 5′-capped (Snijder et al., 2013), and thus, a cap-dependent translation is essential for viral protein production. In the present study, we have described that PRRSV blocks the nuclear export of host mRNAs to the cytoplasm and accumulates them in the nucleus (Fig. 1). This is a novel finding for viruses in the order of Nidovirales. The virus-mediated nuclear imprisonment of host mRNAs makes them difficult to access the cytoplasm for translation, while the viral genomic RNA and subgenomic mRNAs can effectively recruit ribosomes for efficient translation with less competitions with host mRNAs. A small amount of viral RNA is detected by oligo(dT) probe, and this is probably due to the binding of viral RNA with nsp1β protein (Xue et al., 2010), resulting in the nuclear transport of viral RNA by piggyback riding on the nsp1β. The host mRNA nuclear retention is observed for both genotypes (types I and II) of PRRSV, and LDV and SHFV, suggesting that this strategy is extensively utilized by PRRSV and by other member viruses in the family Arteriviridae with an exception of EAV. Host mRNA nuclear accumulation is not observed carboxypeptidase a by EAV nsp1, despite EAV nsp1 being a nuclear protein, which suggests a different mechanism for EAV nsp1 to mediate IFN suppression.
The nuclear localization of PRRSV N protein relies on the specific nuclear localization signal (NLS), and the NLS of N has been shown to be a virulence factor of PRRSV (Pei et al., 2008). The nsp1α in the nucleus participates in the CREB-binding protein degradation (Han et al., 2013). It has been noted that nsp1β protein is distributed exclusively in the nucleus in gene-transfected carboxypeptidase a but is distributed both in the nucleus and cytoplasm in virus-infected cells. The reason for such a difference is unclear, but may be due to the interaction of nsp1β with nsp1 to mediate nsp2TF frameshifting during virus infection, whereas in gene-transfected cells, such an interaction with nsp2 is absent. We have shown that the host mRNA nuclear accumulation is associated with the nuclear distribution of nsp1β. In PRRSV-infected cells, host mRNA nuclear accumulation is significantly in concert with the nsp1β nuclear staining (Fig. 1D). According to the kinetic studies, host mRNA accumulation is detectable as early as 8h of infection, which is consistent with the first appearance of nsp1β in the nucleus (Fig. 1D).
All subunits of nsp1 of arteriviruses are able to suppress IFN production. As one of the suppression mechanisms, PRRSV-nsp1α, LDV-nsp1α, and SHFV-nsp1γ degrade the CREB-binding protein in the nucleus (Han et al., 2014), and for SHFV-nsp1αβ, the domain responsible for IFN suppression has been mapped to the nsp1β portion (Han and Yoo, 2014). PRRSV-nsp1β is a multifunctional protein inhibiting various signaling pathways including the IFN production, IFN signaling, and TNF-α production (Beura et al., 2010; Patel et al., 2010; Song et al., 2010). It is tempting to assume that such inhibitions by nsp1β may be due to the inhibition of nsp1β-mediated host mRNA nuclear export.
A SAP motif is found in some of host cell nuclear proteins besides PRRSV nsp1β, including the scaffold attachment factors A and B (SAF-A and -B), PIAS, and myocardia (Aravind and Koonin, 2000; Okubo et al., 2004). The SAP motif is essential for binding to AT-rich DNA sequences present in scaffold-attachment region/matrix-attachment region (SAR/MAR) (Aravind and Koonin, 2000). The signature motif of LxxLL in the N-terminal region of SAP domain of PIAS leads to the inhibition of STAT1-dependent transcription, whereas a SAP mutant of PIAS does not inhibit type I IFN transcription (Kubota et al., 2011; Liu et al., 2001). A SAP domain is also found in Lpro of foot-and-mouse disease virus (FMDV), and mutations introduced in the conserved SAP motif prevent the nuclear localization of Lpro and degradation of NF-κB (de los Santos et al., 2009). Remarkably, a SAP-mutant FMDV was attenuated and did not cause clinical signs, and the cattle immunized with the SAP-mutant FMDV developed a strong neutralizing antibody response (Segundo et al., 2012). The composition of SAP sequence identified in PRRSV nsp1β meets the SAP consensus motif identified in the cellular proteins, and three hydrophobic residues of L126, L130, and L135 are highly maintained in PRRSV nsp1β.

br Following the bivariate analysis described above separate models were

Following the bivariate analysis described above, separate models were built for benefit ratings and risk ratings. Benefit ratings were regressed on the BFI personality traits identified from the bivariate analysis along with the GRA categories, sex, and therapeutic area. A forward and backwards stepwise regression selection method was used to determine the final model with the best model fit [37]. Variables with nonstatistically significant estimates (>0.05) were removed at each iteration. The evaluation of the benefit ratings and the PRA categories, sex, and therapeutic area followed the same model-building approach as above. This process was replicated for building the models for the risk ratings. All parameter estimates with statistically significant results at the less than 0.05 level are reported along with data for model fit. The authors are aware that the use of stepwise regression methods has several limitations and that there are alternatives to this carboxypeptidase a approach (e.g., testing the final model in an independent sample), but given the peculiarity of the study sample, that is, the limited availability of European medical assessors, the uniqueness of the sample population, and the number of variables included for testing (DOSPERT, Big Five taxonomy), the chosen approach appeared to be the most pragmatic. All statistical analyses were conducted using SPSS 18.


Demographic Characteristics

Of the 80 assessors enrolled in the study, 75 (94%) responded in phase 1, while 59 (73%) assessors completed phases 2 and 3. No difference was found for age, sex, role in the agency, regulatory experience, or therapeutic area expertise between dropouts from phase 1 and those who continued on to phases 2 and 3.

As presented in Table 1, the group was equally balanced by sex; 31% were between 20 and 39 years old. Many assessors had multiple educational degrees; 51% of the assessors were medically qualified, followed by PhD (29%) and pharmacists (13%). Assessors within the NCAs generally focus on single area of expertise. In our sample, most of the assessors were experts in assessing clinical efficacy (63.8%). Assessors with less than 5 years of experience comprised most of the group (55%).

Table 1.
Demographic characteristics.VariableCharacteristicFrequencySexMale38Female37Age (y)Between 20 and 291Between 30 and 3922Between 40 and 4930Between 50 and 5918>603Professional qualificationsMD27MD/PhD11PhD19PhD/Pharm3Pharmacist10Other5Role in NCACHMP member6Internal assessor57External assessor9Other3Years of regulatory experience by country<5 y5+ yFrance28Spain43The Netherlands83United Kingdom46Germany37Austria91Italy100Ireland03Portugal13CHMP, Committee for Medicinal Purposes for Human Use; NCA, National Competent Authority.Full-size tableTable optionsView in workspaceDownload as CSV

Risk Attitudes among Assessors

The mean scores for the DOSPERT scales (risk taking and risk perceptions) for the five domains (social, financial, health/safety, recreational, and ethical) are trichocysts given in Table 2. When the domain subscale scores for both risk taking and risk perception scales were categorized by domain, assessors were predominantly risk neutral/tolerant, with the remaining assessors evenly distributed among the other categories (Table 3). When the risk taking scale was evaluated across the domains as presented in Table 4, 2.5% of the assessors were risk seeking for all domains, no assessor was risk averse for all domains, and 15% of the assessors were neutral/tolerant in their GRA. Similarly, for the risk perception scale, 2.5% of the assessors were categorized as being “perceived risk seeking” for all domains and 2.5% were “perceived risk averse” for all domains, while 17.5% of the assessors were perceived risk neutral/tolerant.

Table 4.
DOSPERT scale—Risk attitudes across all domains.Risk attitude categoriesGeneral risk attitude (from the Risk Taking subscale)Perceived risk attitude (from the Risk Perception subscale)N = 75%N = 75%Seeking22.522.5Seeking neutral2632.52835.0Neutral1215.01417.5Neutral averse2430.02531.2Averse0022.5Mixed1113.845.0DOSPERT, Domain Specific Risk Taking.Full-size tableTable optionsView in workspaceDownload as CSV