Colorectal cancer is one of the most common malignancies in Sweden, with more than 5000 new cases annually. Median age at time of diagnosis is approximately 75 years. Owing to the ageing population, the incidence of colorectal cancer is increasing. The improvement in surgical technique and the introduction of adjuvant radio- and chemotherapy increased the 5-year survival rate from approximately 30-40% in the early 1960s to almost 60% in the late 1990s. The cost of public health care has risen considerably, and case-costing systems are increasingly demanded. Linked to clinical guidelines and quality registers, such control systems form a proper basis for quality assurance projects and improvement. The aim of this thesis is to describe the efficiency and cost effectiveness of colorectal cancer treatment in a defined Swedish population. Emergency surgery for colon cancer, constituting 25% of the cases, increased both mortality and cost. Among emergency cases there was not only an increase in postoperative mortality but also a stage specific decrease in long-term survival rate. Correct staging is decisive for further treatment of patients after colon cancer surgery and influences long-term survival. The number of lymph nodes examined varied between different pathology departments and could be used as a quality measurement. The proportion of tumour stage III increased the more nodes examined. A prognostic estimation of stage III cases that is less sensitive to the number of nodes examined is proposed. A case-control study aimed at identifying risk factors for anastomotic leakage after rectal cancer surgery confirmed previously known risk factors but failed to identify further steps during the perioperative course that were amenable to improvement. This research has confirmed that population-based quality and case-costing registers, linked to clinical guidelines, constitute a proper source for projects of quality improvement and decisions about distribution of resources in health care.

Background: The relevance of conducting this thesis is evident by the fact that bus and coach casualties have been “stubbornly stable” in Europe recent years and a need for investigating if a similar trend could be found in Sweden is therefore obvious. It was also important to add new knowledge to the bus and coach research in Sweden, since many areas were scarcely addressed. Aims: To describe bus and coach occupants’ injuries, crash and injury mechanisms generated in a traffic environment based on data from the medical sector. Additional aims were to investigate the injury reducing effect of a 3-point belt, the effect of cross-winds, and crucial factors in the emergency- and rescue response. Material and methods: Injury data analyses were based on a complete ten-year medical data set from a catchment-area with about 130,000 inhabitants. A number of crash studies with the scope in different crash phases were conducted by applying and elaborating the Haddon matrix as a framework. An additional framework, Protocol for Major Incidents was used in order to investi-gate the emergency- and rescue response to a severe coach crash. Results: Between the first and second five-year period, the incidence of injured in non-crash in-cidents was increased by 24%. In non-crash incidents, 54% were injured; 2/3 while alighting from a bus or coach. The pre-crash factor cross-wind, in addition to vehicle design, vehicle speed and road friction, was investigated in ten crashes. It was confirmed that cross-wind, in relation to vehicle speed and slippery road conditions, needs more attention. The importance of goods load-ing and passengers’ position in the bus, was indicated by the fact that a displacement of the cen-tre of mass rearwards with 10% increased the necessary coefficient of friction with, on average 45%, which in many cases corresponded to dry road conditions. Three Swedish rollover crashes were analysed with regard to the injury outcome, mechanisms and the possible injury reduction for occupants using a safety belt. A considerable increase in safety for occupants belted with 3-point belts was shown through limiting interior contacts, occupant interaction and the possibility of ejection. Crucial post-crash factors in the emergency- and rescue response showed that ordi-nary ways of working and equipment are not always useful and proper equipment for lifting a coach body is essential in the case of a rollover. Finally, the communication between the hospitals is important, and the telephone systems may be overloaded by calls from worried relatives and media. Conclusions: In non-crash events: Non-crash events constitute a majority of all bus and coach casualties with a high proportion of elderly female occupants among the MAIS 2+ injury cases. Boarding and, especially alighting causes many injuries to the lower extremities. In the pre-crash phase: Cross-winds do affect the safety of buses and coaches and requires more at-tention. Seat belt usage among bus and coach occupants has to be increased. In the crash phase: Rollover and ejection are the major causes behind serious and fatal injuries to bus and coach occupants, consequently, retentive glazing, pillars or rails need more attention. An upgrade from 2-point seat belts to 3-point seat belts yields an increase in the estimated injury re-duction from approximately 50% up to 80% for the MAIS 2+ casualties in a rollover crash. In the post-crash phase: In order to be able to lift a coach body proper equipment originated from experience and development is essential in a rescue operation of a crashed bus or coach. Fur-thermore, to improve the emergency response inside crashed coaches proper methods originated from experience need to be developed. Euro NBAP: Based on the results and conclusions generated in this thesis, a European New Bus and Coach Assessment Programme is suggested, which would provide bus and coach occupants with a assessment programme similar to the Euro NCAP.

<p>Human physiology is dependent on an accurate phosphate (Pi) homeostasis. Defective Pi regulation causes hyper- or hypophosphatemia, which are associated with ectopic calcification or impaired bone mineralization, and a shortened life span. Current endocrine models of Pi homeostasis are incomplete. However, studies of acquired and hereditary disorders of Pi homeostasis have revealed new potential Pi regulating hormones, Phosphatonin(s). One of these is fibroblast growth factor-23 (FGF23). FGF23 is produced in bone and is secreted into the circulation. Mutations in FGF23 causes disturbed Pi regulation, without the appropriate counter-regulatory actions of parathyroid hormone or vitamin D. By the generation of FGF23 transgenic mice, which display phenotypic similarities to patients with hypophosphatemic disorders, we show that FGF23 exerts endocrine actions in the kidney and causes osteomalacia. Renal FGF23 actions severely decrease Pi reabsorption and expression of Klotho, a suggested age suppressor gene, known to be crucial in FGF23 receptor binding and activation. In bone, our transgenic model displays impaired osteoclast polarization, which should be detrimental to osteoclastic bone resorption in osteomalacia. However, in our model osteoclasts efficiently participate in bone matrix degradation. Furthermore, we investigated a large population-based cohort in order to elucidate the role of FGF23 in normal physiology. Importantly, we were able to demonstrate an association of FGF23 to parathyroid hormone, renal function and bone mineral density and we found a correlation of FGF23 to weight and body fat mass. The studies on which this thesis is based, demonstrate that FGF23 has phosphatonin-like properties and that the skeleton functions as an endocrine organ. In addition, the results indicate that FGF23 has a role in bone mineral and lipid metabolism, and that FGF23 is a possible diagnostic marker and therapeutic target for the future.</p>

Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data. Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome. Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases. Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.

Image guidance and visualization play an important role in modern surgery to help surgeons perform their surgical procedures. Here, the focus is on neurosurgery applications, in particular brain tumor surgery where a craniotomy (opening of the skull) is performed to access directly the brain region to be treated. In this type of surgery, once the skull is opened the brain can change its shape, and this deformation is known as brain shift. Moreover, the boundaries of many types of tumors are difficult to identify by the naked eye from healthy tissue. The main goal of this work was to study and develop image guidance and visualization methods for tumor surgery in order to overcome the problems faced in this type of surgery. Due to brain shift the magnetic resonance dataset acquired before the operation (preoperatively) no longer corresponds to the anatomy of the patient during the operation (intraoperatively). For this reason, in this work methods were studied and developed to compensate for this deformation. To guide the deformation methods, information of the superficial vessel centerlines of the brain was used. A method for accurate (approximately 1 mm) reconstruction of the vessel centerlines using a multiview camera system was developed. It uses geometrical constraints, relaxation labeling, thin plate spline filtering and finally mean shift to find the correct correspondences between the camera images. A complete non-rigid deformation pipeline was initially proposed and evaluated with an animal model. From these experiments it was observed that although the traditional non-rigid registration methods (in our case coherent point drift) were able to produce satisfactory vessel correspondences between preoperative and intraoperative vessels, in some specific areas the results were suboptimal. For this reason a new method was proposed that combined the coherent point drift and thin plate spline semilandmarks. This combination resulted in an accurate (below 1 mm) non-rigid registration method, evaluated with simulated data where artificial deformations were performed. Besides the non-rigid registration methods, a new rigid registration method to obtain the rigid transformation between the magnetic resonance dataset and the neuronavigation coordinate systems was also developed. Once the rigid transformation and the vessel correspondences are known, the thin plate spline can be used to perform the brain shift deformation. To do so, we have used two approaches: a direct and an indirect. With the direct approach, an image is created that represents the deformed data, and with the indirect approach, a new volume is first constructed and only after that can the deformed image be created. A comparison of these two approaches, implemented for the graphics processing units, in terms of performance and image quality, was performed. The indirect method was superior in terms of performance if the sampling along the ray is high, in comparison to the voxel grid, while the direct was superior otherwise. The image quality analysis seemed to indicate that the direct method is superior. Furthermore, visualization studies were performed to understand how different rendering methods and parameters influence the perception of the spatial position of enclosed objects (typical situation of a tumor enclosed in the brain). To test these methods a new single-monitor-mirror stereoscopic display was constructed. Using this display, stereo images simulating a tumor inside the brain were presented to the users with two rendering methods (illustrative rendering and simple alpha blending) and different levels of opacity. For the simple alpha blending method an optimal opacity level was found, while for the illustrative rendering method all the opacity levels used seemed to perform similarly. In conclusion, this work developed and evaluated 3D reconstruction, registration (rigid and non-rigid) and deformation methods with the purpose of minimizing the brain shift problem. Stereoscopic perception of the spatial position of enclosed objects was also studied using different rendering methods and parameter values.

Rectal cancer is one of the three most common malignancies in Sweden with an annual incidence of about 2000 cases. Current treatment consists of surgical resection of the rectum including the loco-regional lymph nodes in the mesorectum. In advanced cases, neoadjuvant chemo-radiotherapy (CRT) prior to the operative treatment reduces local recurrences and enables surgery. The neoadjuvant treatment can also eradicate the tumour completely, i.e. complete response. This research project was designed to investigate the effects of preoperative radiotherapy/ CRT and analyze methods to predict response to CRT. Study I investigated the expression of the FXYD-3 protein with immunohistochemistry in rectal cancer, with or without preoperative radiotherapy. The results from the total cohort showed that, strong FXYD-3 expression was correlated to infiltrative tumour growth (p = 0.02). In the radiotherapy group, strong FXYD-3 expression was related to an unfavourable prognosis (p = 0.02). Tumours with strong FXYD-3 expression had less tumour necrosis (p = 0.02) after radiotherapy. FXYD-3 expression in the primary tumour was increased compared to normal mucosa (p=0.008). We concluded that FXYD-3 expression was a prognostic factor in patients receiving preoperative radiotherapy for rectal cancer. Study II investigated FXYD-3 expression in tumours that developed local recurrences following surgery and compared this with expression in tumours that did not develop local recurrences. There was no difference in the expression of FXYD-3 between the group that developed local recurrences and the group that did not develop local recurrences. There was no difference in survival between those with strong or weak FXYD-3 expression. We concluded that this study could not confirm the findings from study 1 i.e. that FXYD-3 expression has prognostic significance in rectal cancer. Study III was a register-based study on the incidence and effects of complete response to neoadjuvant treatment. Eight per cent of the patients with adequate CRT to achieve complete response also had a complete histological response of the luminal tumor in the resected bowel. Sixteen per cent of that group had remaining lymph node metastases in the operative specimen. Chemotherapy together with radiotherapy doubled the chance of complete response in the luminal tumour. Patients with remaining lymph node metastases had a lower survival rate compared to those without. We concluded that residual nodal involvement after neoadjuvant treatment was an important factor for reduced survival after complete response in the luminal tumour. Study IV followed up the results from the previous study by re-evaluating magnetic resonance imaging (MRI)- images in patients with complete tumour response. Two experienced MRI radiologists performed blinded re-staging of post CRT MR- images from patients with complete response in the luminal tumour. One group with lymph node metastases and another one without were studied and the results compared with the pathology reports. The sensitivity, specificity, and positive and negative predicted values for correct staging of positive lymph nodes was 37%, 84%, 70% and 57%. The size of the largest lymph node (4.5 mm, p=0.04) seemed to indicate presence of a tumour positive lymph node. We concluded that MRI couldn’t correctly stage patients for lymph node metastases in patients with complete response to CRT in the luminal tumour.

The starting point of the present thesis is nurses’ reported experiences of disagreements with physicians for pushing life sustaining treatment too far. The overall aim was to describe and compare nurses’ and physicians’ perspectives on the boundaries for life-sustaining treatment and to evaluate whether ethics rounds could promote mutual understanding and stimulate ethical reflection. A mixed methods design with qualitative and quantitative data was used, including interviews and questionnaires. The health professionals’ experiences/perceptions were based on known patients foremost from general wards, but also intensive care units, at four Swedish hospitals. The first two studies treated the perspective on boundaries for life-sustaining treatment and the last two evaluated philosopher- ethicist led ethics rounds. Analysis of data was performed using a phenomenological approach and content analysis as well as comparative and descriptive non-parametric statistics. In the first study, the essence of the physicians’ decision-making process to limit life-sustaining treatment for ICU patients, was a process of principally medical considerations in discussions with other physicians. In the second study, there were more similarities than differences between nurses’ and physicians’ opinions regarding the 714 patients studied. The physicians considered limited treatment as often as the nurses did. The ethics rounds studies generated mixed experiences/perceptions. It seemed that more progress was made toward the goal of promoting mutual understanding than toward the goal of stimulating ethical reflection. Above all, the rounds seemed to meet the need for a forum for crossing over professional boundaries. The most salient finding was the insight to enhance team collaboration, that the interprofessional dialogue was sure to continue. Predominating new insights after rounds were interpreted as corresponding to a hermeneutic approach. One of nurses’ negative experiences of the ethics rounds was associated with the lack of solutions. Based on the present findings, one suggestion for improvement of the model of ethics rounds is made with regard to achieving a balance between ethical analyses, conflict resolution and problem solving. In conclusion, the present thesis provides strong evidence that differences in opinions regarding boundaries for life-sustaining treatment are not associated with professional status. The findings support the notion of a collaborative team approach to end-of-life decision-making for patients with diminished decisionmaking capacity. There is an indication that stimulation of ethical reflection in relation to known patients may foremost yield psychosocial insights. This could imply that social conflicts may overshadow ethical analysis or that ethical conflicts and social conflicts are impossible to distinguish.

Abdominal Aortic Aneurysm (AAA) is a disease that mainly affects elderly men, and ruptured AAA (rAAA) is associated with a mortality of &gt; 80%. AAA seldom gives any symptoms prior to rupture. The aims of this thesis were to investigate different aspects of how to affect mortality from rAAA. In Study I, we identified 849 patients treated for rAAA during 1987-2004, and studied the 30-day survival after surgery, depending on whether they came directly to the treating hospital (one-stop) or were transferred via another hospital (two-stop). A two-stop referral pattern resulted in a 27% lower population-based survival rate for patients 65-74 years of age. However, the consequences would be small even if a one-stop referral pattern could be generally accomplished, due to the huge over-all mortality related to rAAA, hence an argument to find and treat AAA before rupture, e.g. by screening. In Study II, we examined the AAA-prevalence and the risk factors for AAA among 70-year-old men. The screening-detected AAA-prevalence was 2.3%, thus less than half the predicted. The most important risk factor was smoking. In Study III, we compared the screening-detected AAA-prevalence, the attendance rate, and the rate of opportunistic detection of AAA, between almost 8000 65- and 6000 70-year-old men. There was no difference in the screening-detected prevalence; probably due to the fact that almost 40% of the AAAs among the 70-year-old were already known prior to screening, compared to roughly 25% in the 65-year-old. The attendance rate was higher among the 65-year-old men, 85.7% compared 84.0% in the 70-year-old. Thus, there is no benefit of screening for AAA among 70- instead of 65-year-old men. In Study IV, a cost-effectiveness analysis, we found that screening for AAA still appears to be cost-effective, despite profound changes in disease pattern and AAA-management. In conclusion, we found that mortality from rAAA is not affected in any substantial way by different referral patterns and hence centralisation of services for AAA/rAAA is not a solution. A better alternative is to prevent rupture through early detection by screening. Screening 65-year-old men for AAA still appears to be cost-effective, despite profound changes in disease pattern and AAA-management during the last decade. Screening 70- instead of 65-year-old men will not increase the efficacy of screening.

Bakgrund: Inför ett kirurgiskt ingrepp erhålls information kring pre/intra/post – operativa rutiner. Det är inte helt klarlagt hur patienter uppfattar och kan ta till sig denna information. Syfte: Att beskriva patienters erfarenheter av preoperativ information inför kolo-rektal cancer kirurgi. Design: Kvalitativ deskriptiv studie med semi-strukturerade intervjuer. Kontext: Intervjuerna genomfördes på en vårdavdelning tillhörande ett universitetssjukhus i Sverige. Deltagare: 14 deltagare tillfrågades att delta i studien varav sju accepterade att delta. Metod: Intervjuerna spelades in på band och transkriberades ordagrant, insamlad data analyserades efter latent innehåll utefter Graneheim och Lundmans modell för innehållsanalys. Resultat: Huvudtema: Personcentrerad omvårdnad, och fyra teman: 1. Betydelsen av individuellt anpassad information. 2. Tydliga besked och bra bemötande främjar trygghet. 3. Stöd av närstående är betydelsefullt. 4. Väntan på svar främjar ovisshet. Deltagarna var sammantaget nöjda med erhållen preoperativ information. Några av deltagarna hade dock svårigheter att minnas all information som givits. Att leva i ovisshet kring fortsatt prognos samt framtiden gav känslor av otrygghet och oro. Betydelsen av närstående och anhöriga var stor, dels för att uppfatta informationen korrekt, för att minnas den samt för emotionellt stöd. Behov av ytterligare information gällde biverkningar av läkemedel, kostråd efter kirurgi, provsvar, peroperativa förlopp samt information kring livet efter sjukhusvistelsen. Slutsats: : Att utgå från en personcentrerad vård, där patientens egna berättelse är i fokus, kan bidra till att ge en mer individbaserad preoperativ information, och på så sätt stärka patientens egna resurser under vårdtiden. / Background: Information regarding the pre/intra/post – operative routines is given prior to surgical interventions. It is not entirely clarified how patients perceive this information. Objective: To explore patients´ experiences regarding preoperative information before undergoing colo-rectal cancer surgery. Design: Qualitative descriptive study with semi-structured interviews. Setting: Interviews were conducted in a hospital ward on a university hospital in Sweden. Participants: 14 participants were asked to participate and seven accepted to participate in the study. Method: Interviews were tape recordered and collected data were transcribed verbatim and analyzed for latent content using Graneheim and Lundman´s outline for content analysis. Results: Main theme: Person-centered nursing care. Four themes were identified: 1. The meaning of individual-based information. 2. Explicit notifications and warm receptions promote feelings of safety. 3. Support from next of kin are meaningfull. 4. Waiting for answers promotes feelings of uncertainty. All of the participants were satisfied with acquired preoperative information. However, a few of the participants had difficulties remembering all of the information given. Feelings of uncertainty about the prognosis and the future were present and were experienced as to somewhat burdensome. The importance of relatives and next of kin were very important in regard of understanding and memorizing given information, but also for emotional support. The need for further desired information included pharmacological side effects, dietary advice following surgery, test results, perioperative complications and information regarding life after discharge. Conclusions: Providing person-centered care based on the narrative from the patient can help healthcare professionals to provide more accurate and individual based preoperative information.

Bakgrund: Under 1800-talet fick Florence Nightingale ner dödligheten efter kirurgi bland annat genom att hålla en renare operationsmiljö. De medicinska framstegen har tagit exponentiella kliv och omvårdnaden försöker hålla takten. Studier visar dock att hälso- och sjukvårdspersonalens följsamhet till hygienriktlinjer är bristande. För att vårdrelaterade infektioner såsom postoperativ sårinfektion inte ska ta fäste, urholka sjukvårdsbudgeten och orsaka patienten vårdlidande behöver samtlig operationspersonal ta hygienfrågan på största allvar, utan undantag. Syfte: Syftet var att studera operationspersonalens följsamhet till hygienriktlinjer på två sjukhus i södra Sverige. Metod: Studien var en kvantitativ observationsstudie som genomfördes med ett strukturerat protokoll. I protokollet fanns faktorer som särskilt studerade om allt av personalens hår och skägg var täckt med operationsmössan vid allmän- och infektionskänslig kirurgi. Det observerades även om personalen använde skor med hel ovansida som var avtorkningsbar. Resultat: Resultatet visade en näst intill fullständig följsamhet till hygienriktlinjer vid infektionskänslig kirurgi. Vid allmän kirurgi fanns förbättringar att genomföra av samtlig operationspersonal. Personal som inte arbetade i operationssåret var den population som hade sämst följsamhet till de utvalda riktlinjerna. Slutsats: Kunskap och ansvar till hygienriktlinjer kan leda till ökad patientsäkerhet och minskat lidande för patienten. / Background: Florence Nightingale saved lives by keeping the environment clean before, during and after surgery in the mid-19th century. The knowledge in medicine has developed in exponential steps and the nursing care is trying to keep up. Studies show that compliance to hygiene guidelines are low. The routines to prevent surgical site infections need to be taken seriously, without exceptions, to prevent the infections to cause suffering both for individuals and the hospitals budgets. Aim: The purpose of this study was to study the OR staff´s compliance to hygiene guidelines at two south Swedish hospitals. Method: The study was a quantitative observational study. Data have been collected at two different southern Swedish hospitals during 152 surgeries. The observation was structured and followed a special protocol that observed if hair and beard is covered with a hood/other coverage and what type of shoes that the staff wear in the OR. It was also observed if surgeries that need ultraclean environment, as implant surgery, was respected with the extended guidelines. Results: The results showed that there where almost complete compliance to the hygiene guidelines during ultraclean surgeries. During other surgeries it showed that improvements could have been done by all staff in the OR. The staff that was working in the OR but not in the wound, close to the patient had lowest compliance. Conclusion: Knowledge and discipline to hygiene rules may lead to improvement in patient safety and diminished patient suffering.