Patient-reported extremity symptoms after robot-assisted laparoscopic cystectomy.

AIMS AND OBJECTIVES: To describe patient-reported extremity symptoms after robot-assisted laparoscopic cystectomy in patients with bladder cancer. BACKGROUND: Preventive activities for remaining patient safety due to correct positioning play an important part in perioperative nursing care.Extremity injuries are well-known after prolonged surgery, especially in robot-assisted urologic surgery in the steep Trendelenburg position. The risk of injury increases due to patient-related and operative risk factors. METHODS: A quantitative prospective observational study was conducted. Patients were followed up with the QuickDASH (Disabilities in the Arm, Shoulder and Hand), Lower Extremity Functional Scale (LEFS) and a study-specific questionnaire 7-10 days and monthly, up to six months after surgery in patients with extremity symptoms. The study adheres to STROBE (strengthening the reporting of observational studies in epidemiology) guidelines, see Supporting information File S1. RESULTS: Out of the 94 included participants, 46.8% (n = 44) experienced extremity symptoms 7-10 days after surgery. Pain, numbness and weakness were the most frequent symptoms. There was a discrepancy between the patients reported symptoms and the documentation in the patient records. Only 13.6% (n = 3) of the reported pain was documented, respectively 27.5% (n = 11) of other symptoms. CONCLUSION: A large proportion of the patients report postoperative extremity symptoms after robot-assisted laparoscopic cystectomy. Prevention of complications in the perioperative setting, are together with follow-ups, important nursing activities for maintaining patient safety and may both prevent and detect postoperative extremity symptoms and injuries. RELEVANCE TO CLINICAL PRACTICE: This study reveals the need of accurate documentation regarding extremity symptoms in digital patient records, as well as continuous follow-ups during the hospital stay and after hospital discharge to enable detection of treatable extremity injuries. The result of this study also indicates the importance of nursing activities such as evidence-based positioning guidelines in the operating theatre for optimal positioning.

Prophylaxis and treatment of HIV-1 infection in pregnancy - Swedish Recommendations 2017.

Prophylaxis and treatment with antiretroviral drugs have resulted in a very low rate of mother-to-child transmission (MTCT) of HIV during recent years. Registration of new antiretroviral drugs, modification of clinical praxis, updated general treatment guidelines and increasing knowledge about MTCT have necessitated regular revisions of the recommendations for 'Prophylaxis and treatment of HIV-1 infection in pregnancy'. The Swedish Reference Group for Antiviral Therapy (RAV) has updated the recommendations from 2013 at an expert meeting 19 September 2017. In the new text, current treatment guidelines for non-pregnant are considered. The most important revisions are that: (1) Caesarean section and infant prophylaxis with three drugs are recommended when maternal HIV RNA >150 copies/mL (previously >50 copies/mL). The treatment target of undetectable HIV RNA remains unchanged <50 copies/mL; (2) Obstetric management and mode of delivery at premature rupture of the membranes and rupture of the membranes at full term follow the same procedures as in HIV negative women; (3) Vaginal delivery is recommended to a well-treated woman with HIV RNA <150 copies/mL regardless of gestational age, if no obstetric contraindications are present; (4) Treatment during pregnancy should begin as soon as possible and should continue after delivery; (5) Ongoing well-functioning HIV treatment at pregnancy start should usually be retained; (6) Recommended drugs and drug combinations have been updated.

Locked Out.

Brain-computer interfaces (BCIs) can enable communication for persons in severe paralysis including locked-in syndrome (LIS); that is, being unable to move or speak while aware. In cases of complete loss of muscle control, termed "complete locked-in syndrome," a BCI may be the only viable solution to restore communication. However, a widespread ignorance regarding quality of life in LIS, current BCIs, and their potential as an assistive technology for persons in LIS, needlessly causes a harmful situation for this cohort. In addition to their medical condition, these persons also face social barriers often perceived as more impairing than their physical condition. Through social exclusion, stigmatization, and frequently being underestimated in their abilities, these persons are being locked out in addition to being locked-in. In this article, we (1) show how persons in LIS are being locked out, including how key issues addressed in the existing literature on ethics, LIS, and BCIs for communication, such as autonomy, quality of life, and advance directives, may reinforce these confinements; (2) show how these practices violate the United Nations Convention on the Rights of Persons with Disabilities, and suggest that we have a moral responsibility to prevent and stop this exclusion; and (3) discuss the role of BCIs for communication as one means to this end and suggest that a novel approach to BCI research is necessary to acknowledge the moral responsibility toward the end users and avoid violating the human rights of persons in LIS.

Six-week follow-up after HIV-1 exposure: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

In 2014 the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy (RAV) conducted a review and analysis of the state of knowledge on the duration of follow-up after exposure to human immunodeficiency virus (HIV). Up until then a follow-up of 12 weeks after exposure had been recommended, but improved tests and new information on early diagnosis motivated a re-evaluation of the national recommendations by experts representing infectious diseases and microbiology, county medical officers, the RAV, the Public Health Agency, and other national authorities. Based on the current state of knowledge the Public Health Agency of Sweden and the RAV recommend, starting in April 2015, a follow-up period of 6 weeks after possible HIV-1 exposure, if HIV testing is performed using laboratory-based combination tests detecting both HIV antibody and antigen. If point-of-care rapid HIV tests are used, a follow-up period of 8 weeks is recommended, because currently available rapid tests have insufficient sensitivity for detection of HIV-1 antigen. A follow-up period of 12 weeks is recommended after a possible exposure for HIV-2, since presently used assays do not include HIV-2 antigens and only limited information is available on the development of HIV antibodies during early HIV-2 infection. If pre- or post-exposure prophylaxis is administered, the follow-up period is recommended to begin after completion of prophylaxis. Even if infection cannot be reliably excluded before the end of the recommended follow-up period, HIV testing should be performed at first contact for persons who seek such testing.

Diagnoses and treatment proposals in periodontal treatment. A comparison between dentists, dental hygienists and undergraduate students.

The aim of this study is to find out how professionals in Swedish dental care perform diagnostic procedures in general. Is there a common ground between dentists and dental hygienists concerning sharing different job assignments in an effective way? Are the methods of treatment used in accordance with degree of severity of the disease and to what extent is proposed treatment in accordance with the National Guidelines? A questionnaire consisting of three different patient cases with periodontal disease was sent to 804 private practitioners, 809 dentists in Dental Public Service, 802 dental hygienists and 40 dental students on their final semester at the Dental School in Malmö. The questionnaire was completed by 1,103 respondents (47%). A majority of all practitioner groups (94%) found that a relatively healthy patient had disease, the risk for developing further disease was deemed none too low by 97%, but 91% wanted to give preventive care. A vast majority suggested more dental care to healthy patients as compared to patients with severe periodontal disease. In Conclusion the two groups, i.e. dentists and dental hygienists, did not to a sufficiently high degree share views on diagnosis and treatment, in order to optimize the resources in dentistry. The delivery of dental care was not in line with the severity of disease and too much attention was paid to the needs of relatively healthy persons. To change this pattern, the incentives in and structure of the national assurance system could be adapted. Furthermore, the knowledge basis for periodontal diagnosis and treatment needs, with special reference to the National Guidelines, should to a higher degree be shared by all caregivers.

Psychometric evaluation of the HIV stigma scale in a Swedish context.

BACKGROUND: HIV-related stigma has negative consequences for infected people's lives and is a barrier to HIV prevention. Therefore valid and reliable instruments to measure stigma are needed to enable mapping of HIV stigma. This study aimed to evaluate the psychometric properties of the HIV stigma scale in a Swedish context with regard to construct validity, data quality, and reliability. METHODS: The HIV stigma scale, developed by Berger, Ferrans, and Lashley (2001), was distributed to a cross-sectional sample of people living with HIV in Sweden (n = 194). The psychometric evaluation included exploratory factor analysis together with an analysis of the distribution of scores, convergent validity by correlations between the HIV stigma scale and measures of emotional well-being, and an analysis of missing items and floor and ceiling effects. Reliability was assessed using Cronbach's α. RESULTS: The exploratory factor analysis suggested a four-factor solution, similar to the original scale, with the dimensions personalised stigma, disclosure concerns, negative self-image, and concerns with public attitudes. One item had unacceptably low loadings and was excluded. Correlations between stigma dimensions and emotional well-being were all in the expected direction and ranged between -0.494 and -0.210. The instrument generated data of acceptable quality except for participants who had not disclosed their HIV status to anybody. In line with the original scale, all subscales demonstrated acceptable internal consistency with Cronbach's α 0.87-0.96. CONCLUSION: A 39-item version of the HIV stigma scale used in a Swedish context showed satisfactory construct validity and reliability. Response alternatives are suggested to be slightly revised for items assuming the disclosure of diagnosis to another person. We recommend that people that have not disclosed should skip all questions belonging to the dimension personalised stigma. Our analysis confirmed construct validity of the instrument even without this dimension.

Risk of HIV transmission from patients on antiretroviral therapy: a position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy.

The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.

Prophylaxis and treatment of HIV-1 infection in pregnancy: Swedish recommendations 2013.

Prophylaxis and treatment with antiretroviral drugs and elective caesarean section delivery have resulted in very low mother-to-child transmission of HIV during recent years. Updated general treatment guidelines and increasing knowledge about mother-to-child transmission have necessitated regular revisions of the recommendations for the prophylaxis and treatment of HIV-1 infection in pregnancy. The Swedish Reference Group for Antiviral Therapy (RAV) updated the recommendations from 2010 at an expert meeting on 11 September 2013. The most important revisions are the following: (1) ongoing efficient treatment at confirmed pregnancy may, with a few exceptions, be continued; (2) if treatment is initiated during pregnancy, the recommended first-line therapy is essentially the same as for non-pregnant women; (3) raltegravir may be added to achieve rapid reduction in HIV RNA; (4) vaginal delivery is recommended if at > 34 gestational weeks and HIV RNA is < 50 copies/ml and no obstetric contraindications exist; (5) if HIV RNA is < 50 copies/ml and delivery is at > 34 gestational weeks, intravenous zidovudine is not recommended regardless of the delivery mode; (6) if HIV RNA is > 50 copies/ml close to delivery, it is recommended that the mother should undergo a planned caesarean section, intravenous zidovudine, and oral nevirapine, and the infant should receive single-dose nevirapine at 48-72 h of age and post-exposure prophylaxis with 2 drugs; (7) if delivery is preterm at < 34 gestational weeks, a caesarean section delivery should if possible be performed, with intravenous zidovudine and oral nevirapine given to the mother, and single-dose nevirapine given to the infant at 48-72 h of age, as well as post-exposure prophylaxis with 2 additional drugs.

Thinking Ahead on Deep Brain Stimulation: An Analysis of the Ethical Implications of a Developing Technology.

Deep brain stimulation (DBS) is a developing technology. New generations of DBS technology are already in the pipeline, yet this particular fact has been largely ignored among ethicists interested in DBS. Focusing only on ethical concerns raised by the current DBS technology is, albeit necessary, not sufficient. Since current bioethical concerns raised by a specific technology could be quite different from the concerns it will raise a couple of years ahead, an ethical analysis should be sensitive to such alterations, or it could end up with results that soon become dated. The goal of this analysis is to address these changing bioethical concerns, to think ahead on upcoming and future DBS concerns both in terms of a changing technology and changing moral attitudes. By employing the distinction between inherent and noninherent bioethical concerns we identify and make explicit the particular limits and potentials for change within each category, respectively, including how present and upcoming bioethical concerns regarding DBS emerge and become obsolete. Many of the currently identified ethical problems with DBS, such as stimulation-induced mania, are a result of suboptimal technology. These challenges could be addressed by technical advances, while for instance perceptions of an altered body image caused by the mere awareness of having an implant may not. Other concerns will not emerge until the technology has become sophisticated enough for new uses to be realized, such as concerns on DBS for enhancement purposes. As a part of the present analysis, concerns regarding authenticity are used as an example.

A multivariable analysis of patient dental satisfaction and oral health-related quality-of-life. A cross-sectional study based on DVSS and OHIP-14.

OBJECTIVE: The aim of this paper was to study the association between dental satisfaction and oral health-related quality-of-life (OHRQoL) when controlling for individual, clinical and psychological factors. MATERIALS: Secondary analysis was conducted using data from a large study carried out in the Swedish region of Värmland in 2004. The questionnaire included demographic variables, clinical assessment and the following instruments: the Dental Visit Satisfaction Scale (DVSS), the short version of Oral Health Impact Profile (OHIP-14) and a modified version of the revised helping alliance questionnaire. Internal consistency analysis was undertaken on the instruments to assess reliability; bivariate comparisons were assessed to compare DVSS scores with individual factors (age, gender and education). In addition, a three step hierarchical multiple regression analysis was performed with DVSS as a dependent variable. RESULTS: Data were completed for 485 randomly selected patients. The mean age of participants was 43.5 years, 54.6% were women,and 41.2% had high education. The median DVSS score was 48 (range 10-50) and the median OHIP was 3.0 (range 0-56). All the instruments showed good reliability. Bivariate analysis showed that females were more satisfied than males (p ≤ 0.01) and patients of 50 years or older were more satisfied than the younger ones (p ≤ 0.05). Finally, the following variables explained 31% of the variance of being very satisfied with dental visit: a good OHRQoL and patients' positive perceptions of the relationship with their care provider. CONCLUSION: This study showed positive associations between dental satisfaction and OHRQoL when controlling for related factors. The result suggests that care providers should take into account the various dimensions of OHRQoL rather than use only clinical measurements when they evaluate patient satisfaction.

Impact of periodontal disease experience on oral health-related quality of life.

BACKGROUND: Periodontal research has traditionally focused on the site level, regarding etiology, pathogenesis, and treatment outcome. Recently, some studies have indicated that the presence of periodontal disease is associated with reduced quality of life. The aim of this study is to investigate the impact of periodontal disease experience on the quality of life. METHODS: This cross-sectional study includes 443 individuals. Clinical and radiographic examinations were performed; in conjunction, the oral health-related quality of life of all participants was assessed using the Swedish short-form version of the Oral Health Impact Profile (OHIP-14). Based on marginal bone loss, measured on radiographs, three different groups were identified: participants with loss of supporting bone tissue of less than one third of the root length (BL-), loss of supporting bone tissue of one third or more of the root length in <30% of teeth (BL), or loss of supporting bone tissue of one third or more of the root length in ≥ 30% of teeth (BL+). RESULTS: The effect of periodontal disease experience on quality of life was considerable. For the BL- group, the mean OHIP-14 score was 3.91 (SD: 5.39). The corresponding mean values were 3.81 (SD: 5.29) for the BL group and 8.47 (SD: 10.38) for the BL+ group. The difference among all groups was statistically significant (P ≤ 0.001). A comparison among the mean OHIP-14 scores in the different groups (BL-, BL, and BL+) revealed significant differences in six of seven conceptual domains. CONCLUSIONS: The BL+ individuals experienced reduced quality of life, expressed as the OHIP-14 score, compared with the BL and BL- participants.

Long-term gender-based outcomes for atazanavir/ritonavir (ATV/r)- containing regimens in treatment-experienced patients with HIV.

Clinical data on antiretroviral effectiveness in women are limited, especially long-term data, because women are usually underrepresented in clinical trials. This sub-analysis of a large European non-comparative, retrospective, observational cohort study evaluated gender differences in long-term outcomes in antiretroviral-experienced adult patients with HIV-1 infection switched to an ATV/r-based regimen between October 2004 and March 2007. Data were extracted from 3 European HIV databases every 6 months (maximum follow-up 5 years). Time to virological failure (VF), defined as two consecutive HIV-1 RNA≥50 c/mL or one HIV-1 RNA≥50 c/mL followed by treatment discontinuation (TD), and time to TD were analyzed using the Kaplan-Meier method. Associations of gender with VF and TD were analyzed using multivariate Cox proportional models. Safety and tolerability were evaluated. In total, 1294 patients (336 women, 958 men) were analyzed. No gender differences in time to VF were observed; at 3 years, the probability of not having VF was 0.59 (95%CI: 0.52, 0.65) and 0.63 (95%CI: 0.59, 0.67) for women and men, respectively. In multivariate analyses, women had a higher risk of TD than men (hazard ratio [HR], 1.54; 95%CI: 1.28, 1.85) but no increased risk of VF (HR, 1.06; 95%CI: 0.85, 1.33). Safety and tolerability were comparable between genders. In a clinical setting, long-term efficacy and safety outcomes of ATV/r-based regimens were similar by gender. Women had a higher risk of TD but no increased risk of VF. ATV/r is an effective and well-tolerated therapeutic option for treatment-experienced men and women with HIV-1 infection.

Novel anti-apoptotic effect of the retinoblastoma protein: implications for polyamine analogue toxicity.

The retinoblastoma protein (pRb) pathway is frequently altered in breast cancer cells. pRb is involved in the regulation of cell proliferation and cell death. The breast cancer cell line L56Br-C1 does not express pRb and is extremely sensitive to treatment with the polyamine analogue N(1),N(11)-diethylnorspermine (DENSPM) which causes apoptosis. Polyamines are essential for the regulation of cell proliferation, cell differentiation and cell death. DENSPM depletes cells of polyamines, e.g., by inducing the activity of the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT). In this study, L56Br-C1 cells were transfected with human pRb-cDNA. Overexpression of pRb inhibited DENSPM-induced cell death and DENSPM-induced SSAT activity. This suggests that the pRb protein level is a promising marker for polyamine depletion sensitivity and that there is a connection between pRb and the regulation of SSAT activity. We also show that SSAT protein levels and SSAT activity do not always correlate, suggesting that there is an unknown regulation of SSAT.

Multivariate analyses of patient financial systems and oral health-related quality of life.

OBJECTIVES: Since 1999, the public dental health service (PDHS) in the county of Värmland, Sweden, has two co-existing patient financial systems, i.e. ways for the patient to pay for dental care services. Alongside the traditional system of fee-for-service payment, i.e. paying afterwards for provided services, a new system of contract care is offered. In this system, dental care is covered by a contractual agreement, for which the patient pays an annual fee and receives care covered by the contract without additional costs. The aim of this article was to study whether patient financial system was associated with oral health-related quality of life (OHRQoL). METHODS: A questionnaire was answered by 1324 randomly selected patients, 52% from contract care and 48% from fee-for-service. The questionnaire contained questions about how much one was prepared to pay for dental care, how much one paid for dental care the previous year, OHIP-14 (measured OHRQoL), dental anxiety, humanism of caregiver, SF-36 (measured general health), multidimensional health locus of control, sense of coherence (SOC), self-esteem and demographics. Data on patient financial system, gender and age were obtained from the sampling frame. The material was analysed with a hierarchical block method of multiple regression analysis. RESULTS: When controlling for all other variables, patient financial system was one of the strongest associations with OHRQoL: patients in fee-for-service had worse OHRQoL than those in contract care. OHRQoL was also associated with general health, SOC and to some extent also with psychological and economic factors. Of the social variables, only being foreign born was significant: it was associated with worse OHRQoL. CONCLUSIONS: Patient financial system was associated with OHRQoL when controlling for confounding factors: patients in contract care had better OHRQoL than those in fee-for-service care.

Effect of polyamine deficiency on proteins involved in Okazaki fragment maturation.

Polyamine depletion causes S phase prolongation, and earlier studies indicate that the elongation step of DNA replication is affected. This led us to investigate the effects of polyamine depletion on enzymes crucial for Okazaki fragment maturation in the two breast cancer cell lines MCF-7 and L56Br-C1. In MCF-7 cells, treatment with N(1),N(11)-diethylnorspermine (DENSPM) causes S phase prolongation. In L56Br-C1 cells the prolongation is followed by massive apoptosis. In the present study we show that L56Br-C1 cells have substantially lower basal expressions of two Okazaki fragment maturation key proteins, DNA ligase I and FEN1, than MCF-7 cells. Thus, these two proteins might be promising markers for prediction of polyamine depletion sensitivity, something that can be useful for cancer treatment with polyamine analogues. DENSPM treatment affects the cellular distribution of FEN1 in L56Br-C1 cells, but not in MCF-7 cells, implying that FEN1 is affected by or involved in DENSPM-induced apoptosis.

Polyamine depletion with two different polyamine analogues causes DNA damage in human breast cancer cell lines.

It is well known that the positively charged polyamines have a DNA-stabilizing function and that polyamine depletion alters chromatin function. We have previously shown that polyamine depletion causes an S phase prolongation, and others have shown that there is an accumulation of Okazaki-like fragments in polyamine-depleted cells. In the present study, we have used the comet assay to investigate polyamine depletion-induced DNA strand breaks. Three breast cancer cell lines and one normal-like breast cell line were treated with the polyamine analogue N(1),N(11)-diethylnorspermine or with the polyamine biosynthesis inhibitor 4-amidinoindan-1-one 2'-amidinohydrazone (CGP 48664). The comet assay showed that polyamine depletion resulted in DNA strand breaks. We also show that these DNA strand breaks occurred in cells where there was no expression of gamma-H2AX, which is a marker of DNA double-strand breaks. Thus, our conclusion is that polyamine depletion causes DNA single-strand breaks, which may be the cause for the observed delay in S phase progression.

Novel anti-apoptotic effect of Bcl-2: prevention of polyamine depletion-induced cell death.

The spermine analogue N(1),N(11)-diethylnorspermine (DENSPM) efficiently depletes the polyamine pools in the breast cancer cell line L56Br-C1 and induces apoptotic cell death via the mitochondrial pathway. In this study, we have over-expressed the anti-apoptotic protein Bcl-2 in L56Br-C1 cells and investigated the effect of DENSPM treatment. DENSPM-induced cell death was significantly reduced in Bcl-2 over-expressing cells. Bcl-2 over-expression reduced DENSPM-induced release of the pro-apoptotic proteins AIF, cytochrome c, and Smac/DIABLO from the mitochondria. Bcl-2 over-expression reduced the DENSPM-induced activation of caspase-3. Bcl-2 over-expression also prevented DENSPM-induced Bax cleavage and reduction of Bcl-X(L) and survivin levels. The DENSPM-induced activation of the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase was reduced by Bcl-2 over-expression, partly preventing polyamine depletion. Thus, Bcl-2 over-expression prevented a number of DENSPM-induced apoptotic effects.

Antiretroviral treatment of HIV infection: Swedish recommendations 2007.

On 3 previous occasions, in 2002, 2003 and 2005, the Swedish Medical Products Agency (Läkemedelsverket) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly published recommendations for the treatment of HIV infection. An expert group, under the guidance of RAV, has now revised the text again. Since the publication of the previous treatment recommendations, 1 new drug for the treatment of HIV has been approved - the protease inhibitor (PI) darunavir (Prezista). Furthermore, 3 new drugs have become available: the integrase inhibitor raltegravir (MK-0518), the CCR5-inhibitor maraviroc (Celsentri), both of which have novel mechanisms of action, and the non-nucleoside reverse transcriptase inhibitor (NNRTI) etravirine (TMC-125). The new guidelines differ from the previous ones in several respects. The most important of these are that abacavir is now preferred to tenofovir and zidovudine, as a first line drug in treatment-naïve patients, and that initiation of antiretroviral treatment is now recommended before the CD4 cell count falls below 250/microl, rather than 200/microl. Furthermore, recommendations on the treatment of HIV infection in children have been added to the document. As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels).