A multicentric study of the disease risks and first manifestations in hereditary transthyretin amyloidosis (ATTRv): insights for an earlier diagnosis.

BACKGROUND: In hereditary transthyretin amyloidosis (ATTRv), early manifestation and age at onset (AO) may vary strikingly. We assessed the disease'risk (penetrance), AO and initial features in ATTRv families to gain insights on the early disease presentation. METHODS: Genealogical information, AO and first disease manifestations were collected in ATTRv families, from Sweden, Italy (Sicily), Spain (Mallorca), France, Turkey, Brazil. Penetrance was computed using a non-parametric survival method. RESULTS: We analysed 258 TTRV30M kindreds and 84 carrying six other variants (TTRT49A, F64L, S77Y, S77F, E89Q, I107V). In ATTRV30M families, the earliest disease risk was found at age 20 years in the Portuguese and Mallorcan families and at age 30-35 years, in the French and Swedish groups. The risks were higher in men and in carriers of maternal descent. In families carrying TTR-nonV30M variants, the earliest disease risk ranged from 30 y-o in TTRT49A to 55 y-o in TTRI107V families. Peripheral neuropathy symptoms were the most frequent initial manifestations. Among patients carrying TTRnonV30M variants, about 25% had an initial cardiac phenotype, one third a mixed phenotype. CONCLUSION: Our work provided solid data on the risks and early features of ATTRv in a spectrum of families to enhance an early diagnosis and treatment.

'Do you feel well or unwell?' A study on children's experience of estimating their nausea using the digital tool PicPecc.

Research with childhood cancer has progressed greatly in recent years, resulting in much improved treatment that is more intensive. However, with this new treatment children often experience negative symptoms, and research shows that nausea is a symptom that most affects them. Pictorial support in person-centred care for children (PicPecc) is a digital picture-based tool for children who undergo treatment due to their cancer diagnosis and helps them more effectively communicate and self-report their symptoms and emotions. The aim of the study was to investigate children's experience of (i) using mHealth in nausea management and (ii) their acceptability of using an application (App). Semi-structured interviews were conducted with eight children aged five to fifteen years. Data were analysed with qualitative content analysis. The findings were presented in three categories: 1) Communicating feelings, 2) Playfulness generated in motivation and 3) App adaptable to children's capabilities. Using an App contributed to new opportunities for the children to participate in their care. They experienced their treatment in different ways and used different strategies to manage and distract themselves from their symptoms. Using the PicPecc App can increase healthcare staff's understanding of how children experience nausea when they undergo chemotherapy.

Metabolomics analysis for diagnosis and biomarker discovery of transthyretin amyloidosis.

Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p < .05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.

New data on the genetic profile and penetrance of hereditary Val30Met transthyretin amyloidosis in Sweden.

INTRODUCTION: Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden. METHODS: To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk. RESULTS: We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals. CONCLUSIONS: Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.

Quality of life of patients with hard-to-heal leg ulcers: a review of nursing documentation.

People with hard-to-heal leg ulcers experience reduced quality of life (QoL), including physical, mental and social aspects; this, in turn, negatively affects the wound healing process. QoL is often overlooked by health professionals treating those with hard-to-heal wounds, for whom the focus is instead on the wound itself and the healing process. This study aimed to investigate how the QoL of patients with hard-to-heal wounds is documented and followed up by nurses. The healthcare records of patients with hard-to-heal wounds were reviewed using an audit instrument. Data were collected retrospectively from 12 patient healthcare records. The nursing documentation included few notes related to patients' QoL. The nurses focused on issues such as nutrition, mobilisation and smoking, while the patients expressed concerns about anxiety/depressed mood, pain and sleeping difficulties. Only nine of the documented problems were approved according to the instrument. Most importantly, documentation of planned interventions and outcomes was missing. Documentation by nurses around the QoL of patients with hard-to-heal wounds is lacking, because of which QoL might be neglected and wound healing might not progress well.

Anorectal Function After Ileo-Rectal Anastomosis Is Better than Pelvic Pouch in Selected Ulcerative Colitis Patients.

BACKGROUND: With a lifelong perspective, 12% of ulcerative colitis patients will need a colectomy. Further reconstruction via ileo-rectal anastomosis or pouch can be affected by patients' perspective of their quality of life after surgery. AIM: To assess the function and quality of life after restorative procedures with either ileo-rectal anastomosis or ileal pouch-anal anastomosis in relation to the inflammatory activity on endoscopy and in biopsies. METHOD: A total of 143 UC patients operated with subtotal colectomy and ileo-rectal anastomosis or pouches between 1992 and 2006 at Linköping University Hospital were invited to participate. Those who completed the validated questionnaires (Öresland score, SF-36, Short Health Scale) were offered an endoscopic evaluation including multiple biopsies. Associations between anorectal function and quality of life with type of restorative procedure and severity of endoscopic and histopathologic grading of inflammation were evaluated. RESULTS: Some 77 (53.9%) eligible patients completed questionnaires, of these 68 (88.3%) underwent endoscopic evaluation after a median follow-up of 12.5 (range 3.5-19.4) years after restorative procedure. Patients with ileo-rectal anastomosis reported better overall Öresland score: median = 3 (IQR 2-5) for ileo-rectal anastomosis (n = 38) and 10 (IQR 5-15) for pouch patients (n = 39) (p < 0.001). Anorectal function (Öresland score) and endoscopic findings (Baron-Ginsberg score) were positively correlated in pouch patients (tau: 0.28, p = 0.006). CONCLUSION: Patients operated with ileo-rectal anastomosis reported better continence compared to pouches. Minor differences were noted regarding the quality of life. Ileo-rectal anastomosis is a valid option for properly selected ulcerative colitis patients if strict postoperative endoscopic surveillance is carried out.

Swedish Inflammatory Bowel Disease Register (SWIBREG) - a nationwide quality register.

Background: Inflammatory bowel disease (IBD) is a chronic, inflammatory relapsing disease with increasing incidence. IBD research and long-term follow-up of patients have, however, been hampered by lack of detailed data on disease phenotype, patient-reported outcome measures, Physician Global Assessment, disease activity, and hospital-administered drugs. Aim: To review the Swedish IBD quality register (SWIBREG). Methods: Review of SWIBREG including questionnaire data from users and patients. Results: SWIBREG was launched in 2005, and as of April 2019, contains 46,400 patients with IBD (Crohn's disease: n = 15,705, ulcerative colitis: n = 21,540, IBD unclassified and other colitis (including e.g., microscopic colitis): n = 9155). Of these IBD patients, 7778 had been diagnosed in childhood (16.8%). Earlier research has shown that combining SWIBREG and the Swedish National Patient Register (NPR) yields a positive predictive value of 100% (95%CI = 95-100%) for having a diagnosis of IBD. Moreover, out of all patients in the NPR with a diagnosis of IBD plus either IBD-related surgery or immunomodulatory/biological treatment during the past 18 months, SWIBREG covers 59.0%. SWIBREG records not only information on conventional therapies but also on biological treatment, surgery, smoking, disease activity, patient-reported outcome measures (PROMs), and patient-experienced measures (PREMs). Data are presented through a graphical decision support system. Conclusion: SWIBREG benefits patients with IBD, and offers an ideal opportunity for healthcare personnel and researchers to examine disease phenotype and activity, PROMs/PREMs, and hospital-administered drugs in patients with IBD.

Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type.

For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

Non-parametric estimation of survival in age-dependent genetic disease and application to the transthyretin-related hereditary amyloidosis.

In genetic diseases with variable age of onset, survival function estimation for the mutation carriers as well as estimation of the modifying factors effects are essential to provide individual risk assessment, both for mutation carriers management and prevention strategies. In practice, this survival function is classically estimated from pedigrees data where most genotypes are unobserved. In this article, we present a unifying Expectation-Maximization (EM) framework combining probabilistic computations in Bayesian networks with standard statistical survival procedures in order to provide mutation carrier survival estimates. The proposed approach allows to obtain previously published parametric estimates (e.g. Weibull survival) as particular cases as well as more general Kaplan-Meier non-parametric estimates, which is the main contribution. Note that covariates can also be taken into account using a proportional hazard model. The whole methodology is both validated on simulated data and applied to family samples with transthyretin-related hereditary amyloidosis (a rare autosomal dominant disease with highly variable age of onset), showing very promising results.

Associations Between Early Implant Failure, Patient Age, and Patient Mortality: A 15-Year Follow-Up Study on 2,566 Patients Treated with Implant-Supported Prostheses in the Edentulous Jaw.

PURPOSE: The aim of this study was to report the distribution of patients with early implant failures after implant treatment in the edentulous jaw with regard to age at surgery and association with patient mortality over a 15-year period. MATERIALS AND METHODS: All consecutively treated patients treated in the edentulous jaw at a single specialist clinic from 1986 to 1997 were included and followed up for 1 year for implant failures and for 15 years with regard to patient mortality. Patients were arranged into age groups, and life tables for patients and reference groups of patients with comparable age (based on national population data) were calculated. Log rank test was used to test differences in patient survival between those with reported early implant failures and those with no early failures. Mantel-Haenszel chi-square test was used to test association between proportions of implant failures and age groups. RESULTS: A total of 55 patients were excluded because they were not living in Sweden (nonresidents/emigrated). Altogether, 2,566 patients were included, with a mean age of 65 years (SD: 11). Of these, 988 patients were deceased during the 15 years of follow-up (38%), and 291 presented an early implant failure (11.3%), most of them before prosthesis placement (72%). Patients with early implant failures presented higher mortality rates than patients with no failures (P < .05), and failure rates decreased consistently from younger to higher age groups (P < .05). CONCLUSION: Patients in the younger age groups showed an increased mortality compared with the reference group (P < .05) and a higher prevalence of early failures compared with older patients (P < .05). Older patients showed an opposing pattern of lower mortality compared with reference groups of comparable age (P < .05), but both younger and older patients with early failures showed a higher mortality compared to patients with no failures (P < .05).

Early Implant Failures Related to Individual Surgeons: An Analysis Covering 11,074 Operations Performed during 28 Years.

BACKGROUND: Compared with knowledge on patient and implant component factors, little knowledge is available on surgeons' role in early implant failures. PURPOSE: To report incidence of early implant failures related to total number of operations performed by individual surgeons. MATERIALS AND METHODS: Early implant failures (≤1 year of implant prosthesis function) were reported after a total of 11,074 implant operations at one specialist clinic during 28 years of surgery. Altogether, 8,808 individual patients were treated by 23 different dentists, of whom 21 surgeons were specialists in oral surgery or periodontology. Recorded failures were related to total numbers of performed operations per surgeon, followed by statistical comparisons (χ2 ) between surgeons with regard to type of treated jaw and implant surface. RESULTS: Altogether, 616 operations were recorded with early implant failures (5.6%), most often observed in edentulous upper jaws after placing implants with a turned surface (p < .05). Significant differences between surgeons, gender of surgeon, type of treated jaws by the surgeon, and implant surface used by the surgeon could be observed (p < .05). CONCLUSIONS: Early implant failures are complex, multifactorial problems associated with many aspects in the surgical procedure. A stochastic variation of failures for individual surgeons could be observed over the years. Different levels of failure rate could be observed between the surgeons, occasionally reaching significant levels as a total or for different jaw situations (p < .05). The surgeons reduced their failure rates when using implants with moderately rough surfaces (p < .5), but the relationship of failure rate between the surgeons was maintained.

Similarities and differences in the experience of fatigue among people living with fibromyalgia, multiple sclerosis, ankylosing spondylitis and stroke.

AIMS AND OBJECTIVES: To elucidate the experience of fatigue across several long-term illnesses, focusing on the similarities and differences. BACKGROUND: Fatigue is common to many long-term illnesses, but it has been studied mainly within the context of a single illness; qualitative studies comparing the experience and its impact on daily life across different long-term illnesses are lacking. DESIGN: Qualitative design. METHODS: A secondary analysis was conducted of five original interview studies involving 95 persons with ankylosing spondylitis, fibromyalgia, multiple sclerosis or stroke. RESULTS: Similarities and differences concerning experiences of fatigue were found across the studied long-term illnesses. All patients expressed the perception of having an unfamiliar body. Fatigue was also commonly expressed as unpredictable, uncontrollable and invisible to others. Differences were related to a constant versus a varying condition, a sudden and an uncontrollable sleepiness, a mutual reinforcement with pain and increased stress sensitivity. A lack of energy and a need for sleep and rest were common experiences, as was the impact on social relationships. There were also similarities regarding how the patients managed their daily life. The search for practical solutions and attitude adjustment differed with the fatigue characteristics. All patients felt a lack of understanding and disbelief from others. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: Fatigue is commonly expressed by patients with long-term illnesses. Variations in experience are related to the type of diagnosis. The disparity between experiences influences how patients managed and adjusted to the conditions of everyday life. The illness-specific characteristics of fatigue warrant increased clinical awareness and may allow professionals to offer adequate information and establish effective methods of managing the condition. The feeling of invisibility and difficulty describing the experience of fatigue in particular highlights this need.

Incidence of First Implant Failure: A Retroprospective Study of 27 Years of Implant Operations at One Specialist Clinic.

BACKGROUND: Even though there are many studies available reporting on implant failures, there are few studies that follow implant failures over time in large populations. PURPOSE: The purpose of this article is to present an overview of the annual incidence of reported implant failures for patients and operations over a 28-year period. MATERIALS AND METHODS: A total of 8,528 patients were consecutively provided with 39,077 implants in 10,719 implant operations during a 27-year period (1986-2012) at one specialist clinic. All patients with reported failures of implants during a 28-year routine follow-up period (1986-2013) were included, and data from the patients' files were retrieved and reported. RESULTS: Altogether, 857 patients (882 jaws/operations) were identified with one or more failures (10.0% of patients/8.5% of operations). Mean annual incidence of first failure showed obvious variations between years, even between seemingly clinically similar situations. However, incidence of first implant failure was higher for upper than lower jaws (p < .05), within 1 year of surgery (69%) than after 1 year (p < .05), and for implants with a turned surface compared with implants with a moderately rough surface (p < .05). CONCLUSIONS: With regard to annual failure incidence in relation to total number of operations over time, obvious variations in failure rate can be observed between seemingly similar clinical situations, as well as significant differences in incidence of first implant failure between the first year after surgery and later time points, between upper and lower jaws using implants with turned surfaces, and between operations to install implants with turned surfaces and those to install implants with moderately rough surfaces.

Meanings of being received and met by others as experienced by women with fibromyalgia.

Fibromyalgia (FM) is a common chronic pain syndrome that mostly affects middle-aged women. Our aim with this study was to elucidate meanings of being received and met by others as experienced by women with FM. Interviews with a narrative approach were conducted with 9 women. We analyzed the transcribed interviews with a phenomenological hermeneutical interpretation. The findings revealed two themes: being seen as a malingerer and being acknowledged. Meanings of being received and met by others, as experienced by women with FM, can be understood as a movement between the two perspectives. When they were acknowledged, their feelings of security and trust increased, but the women could not rely on this because others received and met them in such an unpredictable manner.

Gene expression profile in hereditary transthyretin amyloidosis: differences in targeted and source organs.

INTRODUCTION: Hereditary transthyretin amyloidosis (ATTR) is a genetic disease caused by a point mutation in the TTR gene that causes the liver to produce an unstable TTR protein. The most effective treatment has been liver transplantation in order to replace the variant TTR producing liver with one that produces only wild-type TTR. ATTR amyloidosis patients' livers are reused for liver sick patients, i.e. the Domino procedure. However, recent findings have demonstrated that ATTR amyloidosis can develop in the recipients within 7-8 years. The aim of this study was to elucidate how the genetic profile of the liver is affected by the disease, and how amyloid deposits affect target tissue. METHODS: Gene expression analysis was used to unravel the genetic profiles of Swedish ATTR V30M patients and controls. Biopsies from adipose tissue and liver were examined. RESULTS AND CONCLUSIONS: ATTR amyloid patients' gene expression profile of the main source organ, the liver, differed markedly from that of the controls, whereas the target organs' gene expression profiles were not markedly altered in the ATTR amyloid patients compared to those of the controls. An impaired ER/protein folding pathway might suggest ER overload due to mutated TTR protein.

Frequency of the transthyretin Val30Met mutation in the northern Swedish population.

By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skellefteå and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skellefteå populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skellefteå and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skellefteå region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.

The significance of FM associations for women with FM.

PURPOSE: Living with fibromyalgia (FM) means living with a long-term pain syndrome that is invisible to others. Support and understanding from others seem to be important to managing the affected daily life. The aim of this study was to describe the significance of FM associations for women with FM. METHODS: Data collection was carried out through focus group discussions with seventeen women with FM. Data were analyzed through thematic content analysis. RESULTS: The findings show that women experienced associations for people with FM as important as they gave access to contacts with others with similar experiences. Their need of togetherness was fulfilled at the association and they described being strengthened by the support received. Because of the lack of information and knowledge about FM, the association was described as an important venue for getting and mediating information about the illness. CONCLUSIONS: At the association the women seem to be empowered, which increases their ability to manage their daily lives despite the limitations imposed by FM. Healthcare personnel could not satisfy the women's needs and to manage to support women with FM. There is a need for communication based on a shared understanding between the women and healthcare personnel. IMPLICATIONS FOR REHABILITATION: This study highlighted the need for communication based on a shared understanding between people with chronic illness and healthcare personnel to support and strengthen women with FM in their daily lives. The FM associations meet the needs for togetherness, confirmation, and information that the women with FM in this study described and healthcare personnel could not satisfy. Healthcare personnel can learn from FM associations how to empower women with FM in their everyday lives.

Meanings of feeling well for women with fibromyalgia.

The researchers' focus in this study was to elucidate meanings of feeling well for women with fibromyalgia (FM). We obtained narrative interviews with 13 women with FM and used a phenomenological-hermeneutic interpretation to analyze the interview texts. Our interpretation of the findings shows that for women with FM meanings of feeling well can be understood as having strength to be involved. The women's experiences of feeling well meant being in control, having power, finding one's own pace, and experiencing feelings of belonging.

Allele specific expression of the transthyretin gene in swedish patients with hereditary transthyretin amyloidosis (ATTR V30M) is similar between the two alleles.

BACKGROUND: Hereditary transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease characterized by extracellular deposits of amyloid fibrils composed of misfolded TTR. The differences in penetrance and age at onset are vast, both between and within populations, with a generally late onset for Swedish carriers. In a recent study the entire TTR gene including the 3' UTR in Swedish, French and Japanese ATTR patients was sequenced. The study disclosed a SNP in the V30M TTR 3' UTR of the Swedish ATTR population that was not present in either the French or the Japanese populations (rs62093482-C>T). This SNP could create a new binding site for miRNA, which would increase degradation of the mutated TTR's mRNA thus decrease variant TTR formation and thereby delay the onset of the disease. The aim of the present study was to disclose differences in allele specific TTR expression among Swedish V30M patients, and to see if selected miRNA had any effect upon the expression. METHODOLOGY/PRINCIPAL FINDINGS: Allele-specific expression was measured on nine liver biopsies from Swedish ATTR patients using SNaPshot Multiplex assay. Luciferase activity was measured on cell lines transfected with constructs containing the TTR 3' UTR. Allele-specific expression measured on liver biopsies from Swedish ATTR patients showed no difference in expression between the two alleles. Neither was there any difference in expression between cell lines co-transfected with two constructs with or without the TTR 3' UTR SNP regardless of added miRNA. CONCLUSIONS/SIGNIFICANCE: The SNP found in the 3' UTR of the TTR gene has no effect on degrading the variant allele's expression and thus has no impact on the diminished penetrance of the trait in the Swedish population. However, the 3' UTR SNP is unique for patients descending from the Swedish founder, and this SNP could be utilized to identify ATTR patients of Swedish descent.