Inheritance and genetics in idiopathic scoliosis

Idiopathic scoliosis is the most common spine deformity, affecting approximately 3% of children and adolescents. Its aetiology is still unknown. However, relatives of individuals with idiopathic scoliosis have a higher risk of developing scoliosis compared to the general population. The aim of this thesis was to improve our understanding of the hereditary and genetic background of idiopathic scoliosis. Self - reported data on scoliosis in twins (n=64,578) in the population - based Swedish Twin Registry were an alysed to estimate the relative importance of genetic effects on the phenotypic variance – that is, the heritability of scoliosis. Using structural equation model ing, we estimated that 38% of the phenotypic variance of scoliosis is due to additive genetic effects and 62% to unique environmental effects. In ScoliGeneS, an ongoing multi - centre study, we included individuals with idiopathic scoliosis and controls. The importance of a family history of scoliosis wa s investigated in 1,463 individuals with idiop athic scoliosis . Among those treated with a brace or surgery for scoliosis, 53% reported one or more relatives with scoliosis compared to 46% of the untreated, indicating a higher risk of treatment in the presence of a family history of scoliosis (odds rat io 1.32; 95% confidence interval 1.06 – 1.64). The prevalence of back problems was investigated in 1,069 adults with idiopathic scoliosis and in 1 58 controls. B ack problems were reported in 64% of the individuals with scoliosis compared to 29% of the control s (p<0.001, adjusted for sex, age and smoking). No differences betwee n untreated and treated individuals with idiopathic scoliosis regarding the prevalence of back problems in adulthood were seen. Four common single - nucleotide variants, previously shown to be associated with idiopathic scoliosis, were genotyped in 1,739 individuals with idiopathic scoliosis from the ScoliGeneS cohort and in 1,812 controls. In addition, the protein - coding regions of the genome – the exome – was sequenced in pooled samples (10x10) from 100 surgically treated patients in the ScoliGeneS cohort. We found a strong associ ation of idiopathic scoliosis with a common previously known variant downstream of the LBX1 gene (OR=1.5 3; p=7.0x 10 - 18 ). We identified twenty novel variants by exome sequencing after filtering and an initial genotyping validation. No significant association was f ound with idiopathic scoliosis in the large cohort of 1,739 cases and 1,812 controls. In summary, inherited factors are of importance in the development and progression of idiopathic scoliosis. A genetic variant downstream of the LBX1 gene is strongly associated with idiopathic scoliosis. We were unable to find genes of similar or stronger effect

An observational study on the outcome after surgery for lumbar disc herniation in adolescents compared to adults based on the Swedish Spine Register

BACKGROUND CONTEXT: Disc-related sciatica has a prevalence of about 2% in adults, but is rare in adolescents. If conservative treatment is unsuccessful, surgery is an option. PURPOSE: The aim of this study was to compare the outcomes of surgery for lumbar disc herniation in adolescents with adults in the Swedish Spine Register. STUDY DESIGN/SETTING: This is a prospective observational study: National Quality Register. PATIENT SAMPLE: This study included 151 patients, 18 years or younger, 4,386 patients, 19-39 years, and 6,078 patients, 40 years or older, followed for 1-2 years after surgery. OUTCOME MEASURES: The primary outcomes were patient satisfaction and global assessment of leg and back pain. Secondary outcomes were Visual Analog Scale ( VAS) leg pain, VAS back pain, Oswestry disability index (ODI), and EuroQol-5 dimensions (EQ-5D). METHODS: Statistical analyses were performed with the Welch F test, the chi-square test, and the Wilcoxon signed-rank test. RESULTS: At follow-up, 86% of the adolescents were satisfied compared with 78% in the younger adults and 76% in the older adults group (p < .001). According to the global assessment, significantly decreased leg pain was experienced by 87% of the adolescents, 78% of the younger adults, and 71% of the older adults (p < .001). Corresponding figures for back pain were 88%, 73%, and 70%, respectively (p < .001). All groups experienced significant postoperative improvement of VAS leg pain, VAS back pain, ODI, and EQ-5D (all p < .001). CONCLUSIONS: The adolescent age group was more satisfied with the treatment than the adult groups. There was a significant improvement in all age groups after surgery.Financial support has been received from the Swedish Society of Spine Surgeons.Accepte

Investigation of rare and low-frequency variants using high-throughput sequencing with pooled DNA samples

High-throughput sequencing using pooled DNA samples can facilitate genome-wide studies on rare and low-frequency variants in a large population. Some major questions concerning the pooling sequencing strategy are whether rare and low-frequency variants can be detected reliably, and whether estimated minor allele frequencies (MAFs) can represent the actual values obtained from individually genotyped samples. In this study, we evaluated MAF estimates using three variant detection tools with two sets of pooled whole exome sequencing (WES) and one set of pooled whole genome sequencing (WGS) data. Both GATK and Freebayes displayed high sensitivity, specificity and accuracy when detecting rare or low-frequency variants. For the WGS study, 56% of the low-frequency variants in Illumina array have identical MAFs and 26% have one allele difference between sequencing and individual genotyping data. The MAF estimates from WGS correlated well (r = 0.94) with those from Illumina arrays. The MAFs from the pooled WES data also showed high concordance (r = 0.88) with those from the individual genotyping data. In conclusion, the MAFs estimated from pooled DNA sequencing data reflect the MAFs in individually genotyped samples well. The pooling strategy can thus be a rapid and cost-effective approach for the initial screening in large-scale association studies.Peer reviewe

The role of diseases, risk factors and symptoms in the definition of multimorbidity:a systematic review

<p>Objective is to explore how multimorbidity is defined in the scientific literature, with a focus on the roles of diseases, risk factors, and symptoms in the definitions. Design: Systematic review. Methods: MEDLINE (PubMed), Embase, and The Cochrane Library were searched for relevant publications up until October 2013. One author extracted the information. Ambiguities were resolved, and consensus reached with one co-author. Outcome measures were: cut-off point for the number of conditions included in the definitions of multimorbidity; setting; data sources; number, kind, duration, and severity of diagnoses, risk factors, and symptoms. We reviewed 163 articles. In 61 articles (37%), the cut-off point for multimorbidity was two or more conditions (diseases, risk factors, or symptoms). The most frequently used setting was the general population (68 articles, 42%), and primary care (41 articles, 25%). Sources of data were primarily self-reports (56 articles, 42%). Out of the 163 articles selected, 115 had individually constructed multimorbidity definitions, and in these articles diseases occurred in all definitions, with diabetes as the most frequent. Risk factors occurred in 98 (85%) and symptoms in 71 (62%) of the definitions. The severity of conditions was used in 26 (23%) of the definitions, but in different ways. The definition of multimorbidity is heterogeneous and risk factors are more often included than symptoms. The severity of conditions is seldom included. Since the number of people living with multimorbidity is increasing there is a need to develop a concept of multimorbidity that is more useful in daily clinical work. Key Points</p><p>The increasing number of multimorbidity patients challenges the healthcare system. The concept of multimorbidity needs further discussion in order to be implemented in daily clinical practice.</p><p>Many definitions of multimorbidity exist and most often a cut-off point of two or more is applied to a range of 4–147 different conditions.</p><p>Diseases are included in all definitions of multimorbidity.</p><p>Risk factors are often included in existing definitions, whereas symptoms and the severity of the conditions are less frequently included.</p><p></p> <p>The increasing number of multimorbidity patients challenges the healthcare system. The concept of multimorbidity needs further discussion in order to be implemented in daily clinical practice.</p> <p>Many definitions of multimorbidity exist and most often a cut-off point of two or more is applied to a range of 4–147 different conditions.</p> <p>Diseases are included in all definitions of multimorbidity.</p> <p>Risk factors are often included in existing definitions, whereas symptoms and the severity of the conditions are less frequently included.</p

CELSR2 is a candidate susceptibility gene in idiopathic scoliosis

A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c. G6859A change in exon 21 (NM_001408), leading to a predicted p. V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.Peer reviewe

Deficiency of SARS-CoV-2 T-cell responses after vaccination in long-term allo-HSCT survivors translates into abated humoral immunity

Recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematological diseases are at risk of severe disease and death from COVID-19. To determine the safety and immunogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines, samples from 50 infection-naive allo-HSCT recipients (median, 92 months from transplantation, range, 7-340 months) and 39 healthy controls were analyzed for serum immunoglobulin G (IgG) against the receptor binding domain (RBD) within spike 1 (S1) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; anti–RBD-S1 IgG) and for SARS-CoV-2–specific T-cell immunity, reflected by induction of T-cell–derived interferon-g in whole blood stimulated ex vivo with 15-mer SI-spanning peptides with 11 amino acid overlap S1-spanning peptides. The rate of seroconversion was not significantly lower in allo-transplanted patients than in controls with 24% (12/50) and 6% (3/50) of patients remaining seronegative after the first and second vaccination, respectively. However, 58% of transplanted patients lacked T-cell responses against S1 peptides after 1 vaccination compared with 19% of controls (odds ratio [OR] 0.17; P 5 .009, Fisher’s exact test) with a similar trend after the second vaccination where 28% of patients were devoid of detectable specific T-cell immunity, compared with 6% of controls (OR 0.18; P 5 .02, Fisher’s exact test). Importantly, lack of T-cell reactivity to S1 peptides after vaccination heralded substandard levels (,100 BAU/mL) of anti–RBD-S1 IgG 5 to 6 months after the second vaccine dose (OR 8.2; P 5 .007, Fisher’s exact test). We conclude that although allo-HSCT recipients achieve serum anti–RBD-S1 IgG against SARS-CoV-2 after 2 vaccinations, a deficiency of SARS-CoV-2–specific T-cell immunity may subsequently translate into insufficient humoral responses

Nurses' experience of meeting relatives after sudden death in emergency care : a literature review

ABSTRACT Every year approximately 90,500 people die in Sweden, about 19 000 of these die suddenly. A large portion dies in the hospital and many times the death comes unexpected. It is the health professionals task to find and support the relatives. Nurses working with emergency care, almost daily come in contact with relatives who have lost a loved one and they are expected to manage the related parties grief in a professional manner. Some of the people have undergone a preparation time, while others may experience a more unexpected and sudden death of their relatives. The aim of this literature overview was to examine nurses' experiences to meet and take care of the relatives after a sudden death in emergency care. The method has been implemented as a literature review with descriptive design that is to say that the result is based on an already published research, which the author has compiled into an elaborated text in the results section. The literature review is based on fourteen scientific articles. Articles were searched in approved scientific databases and all the articles included was of good quality according to the guidelines from Sophiahemmets quality control and all the included articles were relevant to the literature review purpose. The result is based on three main categories that were developed during the data analysis. The main categories were the nurse's perspective, factors influencing the meeting with the relatives and the effect of care relationship when meeting with the relatives. The nurse's obvious task was to support and see and meet the needs of the related parties. To do so required a good care relationship. The articles gave examples of what the nurses were considered to be part of and the difficulty in the meeting with the relatives who have suddenly lost a loved one. Articles highlights the nurses own feelings and experiences, but also the organization behind the nurses, both the good and bad sides. The nurses also noticed a deficiency in their education and that they lacked the knowledge and guidance of activities in the area. The discussion shows that in situations where relatives lose their loved one suddenly and unexpectedly, often perceived as a difficulty by nurses. In some cases nurses are experiencing emotional difficulties and discomfort that causes that they feel that they are not enough for the family and their needs and expectations. Which means that the nurses are unsure whether they satisfy the related enough in these situations. From previous studies it is seen that nurses' experiences is that the training and knowledge of the subject is, and inadequate grounds. In order to prevent their negative thought patterns and their uncertainty in the care of relatives who unexpectedly lost a loved one, it will need more knowledge and theoretical knowledge given space in practice. Conclusion of the literature is that emergency nurse would strengthen their working profession in the care of relatives who have suddenly lost a loved one through more knowledge and then with both theoretical and practical teaching, better structure and clearer guidelines. Keywords: Sudden death, relatives, emergency care, nurse and experiences.Varje år dör det cirka 90 500 människor i Sverige, cirka 19 000 av dessa dör plötsligt. En stor del avlider på sjukhuset och många gånger mycket oväntat. Det är vårdpersonalens uppgift att finnas och stötta de närstående. Sjuksköterskor som arbetar inom akutsjukvård kommer nästan dagligen i kontakt med närstående som förlorat en anhörig och förväntas kunna hantera de närståendes sorg på ett professionellt sätt. En del närstående har genomgått en förberedelse tid medan andra får uppleva en mer oväntad och plötsligt bortgång av sina anhöriga. Syftet med litteraturöversikten var att belysa sjuksköterskors upplevelser av att möta och ta hand om de närstående efter ett plötsligt dödsfall inom akutsjukvård. Metoden har genomförts som en litteraturöversikt med deskriptiv design det vill säga att resultatet bygger på ett redan publicerat forskningsresultat som författaren har sammanställt till en genomarbetad text i resultatdelen. Litteraturöversikten bygger på 14 vetenskapliga artiklar. Artiklarna söktes i vetenskapliga godkända databaser och alla artiklar som inkluderades höll god kvalitet enligt riktlinjer från Sophiahemmets kvalitetsgranskning och alla inkluderade artiklar var relevanta till litteraturöversiktens syfte. Resultatet grundar sig på tre huvudkategorier som arbetades fram under dataanalysen. Huvudkategorierna var sjuksköterskans perspektiv, faktorer som påverkar möte med närstående och vårdrelationens betydelse i mötet med närstående. Sjuksköterskans tydligaste arbetsuppgift var att stödja och se och tillmötesgå de närståendes behov. För att kunna göra det krävdes en god vårdrelation. Artiklarna gav exempel på vad sjuksköterskorna ansågs vara en del av svårigheten i att möta närstående som förlorat en anhörig plötsligt. Artiklarna lyfter framförallt fram sjuksköterskornas egna känslor och erfarenheter men även verksamheterna och då både bra respektive dåliga orsaker. Sjuksköterskorna upplevde även en bristfällighet i deras grundutbildning och att de saknade kunskap och riktlinjer från verksamheten inom området. Diskussionen visar att i situationer där närstående förlora sin anhörig plötsligt och oväntat många gånger upplevs som en svårighet av sjuksköterskorna. I vissa fall upplever sjuksköterskorna känslomässiga svårigheter och obehag som leder till att de upplever en känsla av att de inte räcker till för de närstående och deras behov och förväntningar. Det leder till att sjuksköterskorna är osäkra på om de tillgodoser de närstående tillräckligt i dessa situationer. Tidigare studier visar att sjuksköterskor upplever att grundutbildningen är bristfällig, utbildningen erbjuder inte tillräckligt med kunskap om vården av närstående. För att förhindra deras negativa tankemönster och osäkerhet vid omvårdnaden av närstående som plötsligt har förlorat en anhörig, behövs mer kunskap och att den teoretiska kunskapen får utrymme i praktiken. Slutsatsen är att akutsjuksköterskan skulle stärka sin yrkesprofession i omhändertagandet av närstående som plötsligt har förlorat en anhörig genom mer kunskap och då med både teoretiskt och praktiskt undervisning, bättre struktur och tydligare riktlinjer ute i verksamheten

Patienters förmåga till livsstilsförändringar : En litteraturstudie om informationens betydelse för livsstilsförändringar hos patienter som överlevt en hjärtinfarkt

Bakgrunden visar att en hjärtinfarkt kan påverkar hela människans syn på livet. Hjärtsjukdomar påverkas både av människans genetiska arvsmassa samt av varje individs livsstil. En hjärtinfarkt kan innebära en akut livskris både för patienterna och för deras närstående. De drabbas ofta av oro, ångest och osäkerhet, som ofta är ett resultat av patienternas livsstil, och deras tankar om att insjukna igen senare i framtiden. Dagens korta vårdtid kan innebära att patienterna har svårt att ta emot all information som ges. Syftet var att belysa om den information som sjuksköterskan ger till patienter med hjärtinfarkt under vårdtiden kan påverka deras inställning till livsstilsförändringar. Metoden som valdes var en systematisk litteraturstudie där resultatet är hämtat från åtta stycken kvalitativa artiklar respektive två kvantitativa artiklar som svarade mot arbetets syfte. Artiklarna analyserades utifrån Granheim &amp; Lundman (2004) beskrivningsmodell av kvalitativ innehållsanalys. Resultatet visade att många patienter upplever osäkerhet och rädsla samt att de känner sig oförberedda när hemgången börjar närma sig. Patienterna tycker det är svårt att fortsätta med livsstilsförändringarna i hemmiljön på grund av okunskap och minskad motivation, vilket leder till att de nöjer sig med den medicinska behandlingen. Patienterna efterfrågar även individuellt anpassad information om medicinsk behandling, faktorer som kan förändra deras livsstil. Slutsatsen tyder på att all information mellan sjuksköterskan och patienterna bör ske mer individuellt och att livsstilsförändringar bör prioriteras mer. Patienterna får inte bara lita till den medicinska behandlingen. Författarna tycker att återbesök och samarbete mellan primärvården och sjukhusvården bör ingå som en del av vårdandets yttersta mål

Malawi efter Banda : förändringar i landet där tystnad rådde

Malawi är ett av de fattigaste länderna i världen, och styrdes med järnhand av Dr Hastings Banda i 30 år. Denna skrift ger en beskrivning av Malawi under Bandas styre och redovisar den ekonomiska och politiska utvecklingen sedan den nya regimen tillträdde efter flerpartivalet 1994

NOX2-Derived Reactive Oxygen Species in Cancer

The formation of reactive oxygen species (ROS) by the myeloid cell NADPH oxidase NOX2 is critical for the destruction of engulfed microorganisms. However, recent studies imply that ROS, formed by NOX2+ myeloid cells in the malignant microenvironment, exert multiple actions of relevance to the growth and spread of neoplastic cells. By generating ROS, tumor-infiltrating myeloid cells and NOX2+ leukemic myeloid cells may thus (i) compromise the function and viability of adjacent cytotoxic lymphocytes, including natural killer (NK) cells and T cells, (ii) oxidize DNA to trigger cancer-promoting somatic mutations, and (iii) affect the redox balance in cancer cells to control their proliferation and survival. Here, we discuss the impact of NOX2-derived ROS for tumorigenesis, tumor progression, regulation of antitumor immunity, and metastasis. We propose that NOX2 may be a targetable immune checkpoint in cancer