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With genomic testing being increasingly integrated into every day clinical practice and a wide range of practitioners ordering genetic tests, it is important that the scope of the genetic counselling role continues to evolve alongside these changes. We present an exemplary role for genetic counsellors in a highly specialised service within England's National Health Service for people who have or are suspected to have rare genetic types of Ehlers Danlos syndrome. The service employs genetic counsellors and consultants from the fields of genetics and dermatology. The service also works closely with other specialists and related charities and patient organisations. The genetic counsellors in the service provide routine genetic counselling such as diagnostic and predictive testing, but their role also includes the writing of patient literature and emergency and well-being resources, delivering workshops and talks, and the development of qualitative and quantitative research on the patient experience. Data from such research has informed the development of patient self-advocacy and supportive resources, raised awareness amongst healthcare professionals and enhanced the standard of care and outcomes for patients. The service aims to be an example of innovation and accessibility and provides a model that can be potentially adopted by other highly specialised services of rare genetic diseases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Adolescent idiopathic scoliosis (AIS) often correspond with hypo thoracic kyphosis (TK) or even lordosis. The aim of this study was to analyze the influence of posterior instrumentation in thoracic AIS., Methods: Analysis of prospectively collected AIS-data with structural thoracic curves (Lenke type 1 & 2), operated 2010-2019 with pedicle screw dual rod systems in one scoliosis center. Follow-up (FU) minimum 24 months. Coronal and sagittal angles measured based on standing long-cassette-X-rays: thoracic major (MC), proximal thoracic (PC) and lumbar curve (LC), TK, lumbar lordosis (LL)., Statistical Analysis: values as mean ± SD, differences by student's t-test (significancy a = 0.05), Pearson's correlation, sub-analysis with sagittal modifier (-, N, +)., Results: A total of 127 AIS could be identified (63% type 1, 37% type 2). Mean FU 32.2 ± 16.6 months, mean age 14 ± 1.5 years. Mean Correction of MC 73 ± 12%, PC 51 ± 17%, LC 69 ± 21% with a significantly better correction of PC in Lenke 2 curves(p < 0.05). On average, TK (FU-preop) decreased by -2.1 ± 12.1°(p < 0.05) in all AIS. Whereas TK in type 1 was unchanged (p = 0.9), TK significantly decreased by - 6.0 ± 12.7°(p < 0.05) in type 2. No significant difference in LL. TK in hypokyphotic cases increased by 9.5 ± 5.5°(p < 0.05), stayed almost unchanged (- 1.4 ± 9.1°,p = 0.2) in normokyphotic, decreased by - 17.2 ± 14.2°(p < 0.05) in hyperkyphotic cases. Only hypokyphotic cases had a moderately strong correlation between correction of LC (r = 0.6) and PC (r = - 0.4) (frontal plane) and change from pre- to postoperative TK (sagittal plane) (r = 0.6). No relevant correlations for normo- and hyperkyphotic AIS. Postoperative hypokyphosis was significantly more often in Lenke 2 (16.3% vs. 2.6%, p < 0.05). Rod diameter (5,5 mm versus 6 mm) had no significant influence., Conclusion: Significant correction of hypo- and hyperkyphosis can be achieved with posterior spinal fusion (pedicle screw dual rod systems), whereas normokyphotic spines stay unchanged. However, Lenke 2 curves have a significantly higher risk for a postoperative thoracic hypokyphosis., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Adolescent idiopathic scoliosis (AIS) is often associated with thoracic hypokyphosis or even lordosis., Objectives: To analyze the influence of posterior correction and fusion in thoracic, structurally double-curved AIS., Material and Methods: Out of 127 thoracic AIS (Lenke types 1 and 2) recorded prospectively, idiopathic double thoracic curve AIS were analyzed retrospectively. Surgery 2010-2019 with pedicle screw double rod systems in a scoliosis center. Follow-up (FU) at least 2 years. Frontal and sagittal angles (whole-spine radiographs, 2 planes): thoracic curve (MK), proximal-thoracic curve (PK) and lumbar curve (LK), thoracic kyphosis (TK), lumbar lordosis (LL)., Statistical Analysis: values as MW ± SD, students t‑test (significance a = 0.05), Pearson's correlation, sub-analysis with sagittal modifiers (-, N, +)., Results: A total of 47 AIS-double thoracic curve were identified, mean FU 29.3 ± 12.2 months, mean age 14 ± 1.5 years. The mean correction (FU-preop) of MK was 67%, PK 53%, LK 73%, each significant, (p < 0.05). On average, TK (FU-preop) decreased by -6.5 ± 11.6° (p < 0.05), no significant change from FU (p = 0.6). TK (FU-preop) increased by 8.6 ± 5.0° (p < 0.05) in hypokyphotic cases, significantly decreased by -4.8 ± 9.6° in normokyphotic AIS and -25.3 ± 11.1° in hyperkyphotic cases, respectively (p < 0.05). In hypokyphosis: moderately strong correlation between correction PK (r = -0.5) and spontaneous correction LK (r = 0.8) (frontal plane) and change from pre- to postop TK (sagittal plane) (p < 0.05). Moderate correlation for hyperkyphosis: correction PK (r = -0.5) and postop TK (p < 0.05). No relevant correlations for normokyphosis. 17% had postop hypokyphosis, of which 0% had preop hypokyphosis. Rod diameter (5.5 mm vs. 6 mm) had no significant effect on TC., Conclusions: Posterior instrumented correction and fusion (pedicle screw dual rod systems) can significantly correct both lateral curves in idiopathic double thoracic curves, although it is associated with an increased risk of postop thoracic hypokyphosis, especially in preoperatively normokyphotic patients., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Inflammasomes are intracellular protein complexes that promote an inflammatory host defense in response to pathogens and damaged or neoplastic tissues and are implicated in inflammatory disorders and therapeutic-induced toxicity. We investigated the mechanisms of activation for inflammasomes nucleated by NOD-like receptor (NLR) protiens. A screen of a small-molecule library revealed that several tyrosine kinase inhibitors (TKIs)-including those that are clinically approved (such as imatinib and crizotinib) or are in clinical trials (such as masitinib)-activated the NLRP3 inflammasome. Furthermore, imatinib and masitinib caused lysosomal swelling and damage independently of their kinase target, leading to cathepsin-mediated destabilization of myeloid cell membranes and, ultimately, cell lysis that was accompanied by potassium (K + ) efflux, which activated NLRP3. This effect was specific to primary myeloid cells (such as peripheral blood mononuclear cells and mouse bone marrow-derived dendritic cells) and did not occur in other primary cell types or various cell lines. TKI-induced lytic cell death and NLRP3 activation, but not lysosomal damage, were prevented by stabilizing cell membranes. Our findings reveal a potential immunological off-target of some TKIs that may contribute to their clinical efficacy or to their adverse effects.

Background: The widely used Swiss neighbourhood index of socioeconomic position (Swiss-SEP 1) was based on data from the 2000 national census on rent, household head education and occupation, and crowding. It may now be out of date., Methods: We created a new index (Swiss-SEP 2) based on the 2012-2015 yearly micro censuses that have replaced the decennial house-to-house census in Switzerland since 2010. We used principal component analysis on neighbourhood-aggregated variables and standardised the index. We also created a hybrid version (Swiss-SEP 3), with updated values for neighbourhoods centred on buildings constructed after the year 2000 and original values for the remaining neighbourhoods., Results: A total of 1.54 million neighbourhoods were included. With all three indices, the mean yearly equivalised household income increased from around 52,000 to 90,000 CHF from the lowest to the highest index decile. Analyses of mortality were based on 33.6 million person-years of follow-up. The age- and sex-adjusted hazard ratios of all-cause mortality comparing areas in the lowest Swiss-SEP decile with areas of the highest decile were 1.39 (95% confidence interval [CI] 1.36-1.41), 1.31 (1.29-1.33) and 1.34 (1.32-1.37) using the old, new and hybrid indices, respectively., Discussion: The Swiss-SEP indices capture area-based SEP at a high resolution and allow the study of SEP when individual-level SEP data are missing or area-level effects are of interest. The hybrid version (Swiss-SEP 3) maintains high spatial resolution while adding information on new neighbourhoods. The index will continue to be useful for Switzerland's epidemiological and public health research.

Background & Aims: CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans., Methods: We conducted a clinical trial in stable liver transplant recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (ClinicalTrials.gov NCT02949492). One month after LDIL-2 was initiated, those exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months., Results: All participants achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression., Conclusions: The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance., Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT02949492)., Impact and Implications: The administration of low-dose IL-2 is an effective way of increasing the number of circulating regulatory T cells (Tregs), an immunosuppressive lymphocyte subset that is key for the establishment of immunological tolerance, but its use to promote allograft tolerance in the setting of clinical liver transplantation had not been explored before. In liver transplant recipients on tacrolimus monotherapy, low-dose IL-2 effectively expanded circulating Tregs but did not increase the number of Tregs with donor specificity, nor did it promote their trafficking to the transplanted liver. Low-dose IL-2 did not facilitate the discontinuation of tacrolimus and elicited, as an off-target effect, an IFNγ-orchestrated inflammatory response in the liver that resembled T cell-mediated rejection. These results, supporting an unexpected role for IL-2 in regulating the immunogenicity of the liver, highlight the need to carefully evaluate systemic immunoregulatory strategies with investigations that are not restricted to the blood compartment and involve target tissues such as the liver., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME). The TME, a heterogeneous population of differentiated and progenitor cells, plays a critical role in regulating tumor development, growth, invasion, metastasis and therapy resistance. In this context, cytokines from cancer cells and cells of the TME influence each other, eliciting an inflammatory milieu that can either enhance or suppress tumor growth and metastasis. Additionally, several lines of evidence exist that the composition of the microbiota regulates inflammatory processes, controlled by cytokine secretion, that play a role in carcinogenesis and tumor progression. In this review, we discuss the cytokine networks between cancer cells and the TME and microbiome in colorectal cancer and the related treatment strategies, with the goal to discuss cytokine-mediated strategies that could overcome the common therapeutic resistance of CRC tumors.

Study Design: A retrospective single center cohort study with prospective collected data from an institutional spine registry., Objectives: To determine whether restoration of lordosis L5/S1 is possible with both anterior lumbar interbody fusion (ALIF) and transforaminal lumbar interbody fusion (TLIF) and to find out which technique is superior to recreate lordosis in L5/S1., Methods: Seventy-seven patients with ALIF and seventy-nine with TLIF L5/S1 were included. Operation time, estimated blood loss), and complications were evaluated. Segmental lordosis L5/S1 and L4/5, overall lordosis, and proximal lordosis (L1 to L4) were measured in X-rays before and after surgery. Oswesery disability index and EQ-5D were assessed before surgery, and 3 and 12 months after surgery., Results: Mean operation time was 176.9 minutes for ALIF and 195.7 minutes for TLIF (p = 0.048). Estimated blood loss was 249.2 cc for ALIF and 362.9 cc for TLIF (p = 0.005). In terms of complications, only a difference in dural tears were found (TLIF 6, ALIF none; p = 0.014). Lordosis L5/S1 increased in the ALIF group (15.8 to 24.6°; p < 0.001), whereas no difference was noted in the TLIF group (18.4 to 19.4°; p = 0.360). Clinical results showed significant improvement in the Oswesery disability index (ALIF: 43 to 21.9, TLIF: 45.2 to 23.0) and EQ-5D (ALIF: 0.494 to 0.732, TLIF: 0.393 to 0.764) after 12 months in both groups, without differences between the groups., Conclusion: ALIF and TLIF are comparable methods for performing fusion at L5/S1, with good clinical outcomes and comparable rates of complications. However, there is only a limited potential for recreating lordosis at L5/S1 with a TLIF., Competing Interests: M. Quante hat einen Beratervertrag mit der Fa. Silony und erhält Honorare für Vorträge von der Fa. Nuvasive Inc. sowie der Fa. Silony. B. Thomsen hat eine Beratungstätigkeit für die Fa. Silony. M. Köszegvary hat einen Beratervertrag mit der Fa. Silony und erhält Honorare für Vorträge von der Fa. Nuvasive Inc. H. Halm hat einen Beratervertrag mit Patentvergütungskomponente mit der Fa. Nuvasive. Die Fa. Silony finanziert darüber hinaus eine Studienleiterin („study nurse“). C. Berlin, N. Bürger, F. Pecsi und U. Platz geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Radon is a radioactive noble gas naturally found in the earth crust that can accumulate in buildings. In addition to lung cancer, alpha particles emitted by radon may contribute to the risk of skin cancer. We evaluated the association between residential radon exposure and skin cancer mortality, over a fifteen year period, taking residential ultra-violet (UV) exposure into account., Methods: We included 4.9 million adults from the Swiss National Cohort. Hazard ratios for melanoma mortality were estimated using Cox proportional hazard models (20+ years old; follow-up 2001-2015). Long-term modelled residential radon and ambient UV exposures were assigned at baseline, and included together in the Cox models. With age as a time scale, models were adjusted for calendar time, sex, marital status, education, mother tongue, socioeconomic position, and occupational environment with potential for UV exposure. Age specific hazard ratios were derived. Effect modification, sensitivity analyses and the shape of the exposure response, as well as secondary analysis using other outcome definitions, were investigated., Results: During follow-up (average of 13.6 years), 3,979 melanoma deaths were observed. Associations declined with age, with an adjusted hazard ratio per 100 Bq/m 3 radon at age 60 of 1.10 (95% CI: 0.99, 1.23). The dose-response showed an approximate linear trend between the minimum and mean radon exposure of 75 Bq/m 3 . Having outdoor occupation significantly increased the risk of melanoma mortality associated with UV exposure compared to indoor jobs. Analysis restricted to the last five years of follow-up showed similar results compared to the main analysis. Similar associations were found for mortality from melanoma and non-melanoma skin cancer combined., Conclusion: With double the follow-up time, this study confirmed the previously observed association between residential radon exposure and melanoma and non-melanoma skin cancer mortality in Switzerland. Accumulation of radon indoors is preventable and of public health importance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Ltd.)

The SARS-CoV-2 (COVID-19) pandemic has accelerated the development and use of digital health platforms to support individuals with health-related challenges. This is even more frequent in the field of cancer care as the global burden of the disease continues to increase every year. However, optimal implementation of these platforms into the clinical setting requires careful planning and collaboration. An implementation project was launched between the Centre intégré universitaire de santé et de services sociaux (CIUSSS) du Centre-Ouest-de-I'Île-de-Montreal and BELONG-Beating Cancer Together-a person-centred cancer navigation and support digital health platform. The goal of the project was to implement content and features specific to the CIUSSS, to be made available exclusively for individuals with cancer (and their caregivers) treated at the institution. Guided by Structural Model of Interprofessional Collaboration, we report on implementation processes involving diverse stakeholders including clinicians, hospital administrators, researchers and local community/patient representatives. Lessons learned include earlier identification of shared goals and clear expectations, more consistent reliance on virtual means to communicate among all involved, and patient/caregiver involvement in each step to ensure informed and shared decision making.

Postoperative shoulder imbalance (PSI) is a common complication following adolescent idiopathic scolio- sis (AIS) surgery. There is little data available in literature on prediction of PSI. Prospectively collected data of AIS with thoracic curve (Lenke 2), operated in 2014-2018 at a single scoliosis-center, were analyzed retrospectively using X-rays of whole spine and traction films (TA): age, Cobb-angle of proximal (PC), major thoracic (MC) and lumbar curve (LC), shoulder height [mm], clavicle angle [°], T1-tilt [°], plumb line [mm]. Results as mean ± standard deviation. Change over time (postOP- FU) compared using t-test (≥=0.05). Correlation of preOP parameters and curve correction with PSI (|≥|15mm) was analyzed by correlation (Pearson)- and regression-classification-analysis. 32 AIS, average age of 14±1.3 yrs. FU 16 months (84%). Curve correction was 52.5% (PC), 70.1% (MC), 69.9% (LC), significant change in FU for PC (-2.4°, p>0.05), not for MC, LC (p=0.2, p=0.6). Shoulder height was negative if right- side up: 2.9±15.1mm (preOP), 5.5±15.0 mm (TA), 17.9±14.9mm (postOP), 17.4±8.4mm (FU). 28% had preOP shoulder imbalance, 69% postOP and 44% FU had PSI. Shoulder height on TA correlated to change preOP to FU (r=0.62) and preOP shoulder height (r=-0.85), clavicle angle had strong correlation (r=- 0.81). Regression-classification-analysis: correction of MC>62.4%, 81.5% of cases had PSI; with correction of MC>64.9% and LC>93.2%, 51.9% of cases had PSI. PSI is a common in Lenke2 AIS. In preOP planning TA, shoulder position and clavicle angle should be considered to prevent PSI. Correction of MC should be moderate, overcorrection of the LC avoided.

Objectives: This article aims to measure the willingness of the Swiss public to participate in personalised health research, and their preferences regarding data management and governance., Setting: Results are presented from a nationwide survey of members of the Swiss public., Participants: 15 106 randomly selected Swiss residents received the survey in September 2019. The response rate was 34.1% (n=5156). Respondent age ranged from 18 to 79 years, with fairly uniform spread across sex and age categories between 25 and 64 years., Primary and Secondary Outcome Measures: Willingness to participate in personalised health research and opinions regarding data management and governance., Results: Most respondents preferred to be contacted and reconsented for each new project using their data (39%, 95% CI: 37.4% to 40.7%), or stated that their preference depends on the project type (29.4%, 95% CI: 27.9% to 31%). Additionally, a majority (52%, 95% CI: 50.3% to 53.8%) preferred their data or samples be stored anonymously or in coded form (43.4%, 95% CI: 41.7% to 45.1%). Of those who preferred that their data be anonymised, most also indicated a wish to be recontacted for each new project (36.8%, 95% CI: 34.5% to 39.2%); however, these preferences are in conflict. Most respondents desired to personally own their data. Finally, most Swiss respondents trust their doctors, along with researchers at universities, to protect their data., Conclusion: Insight into public preference can enable Swiss biobanks and research institutions to create management and governance strategies that match the expectations and preferences of potential participants. Models allowing participants to choose how to interact with the process, while more complex, may increase individual willingness to provide data to biobanks., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Currently, the proportion of women in academic education and residency is predominant, but specialty-specific distribution of leading positions is partly reciprocal (orthopedics/surgery). Are there any differences that indicate a gender-dependent redistribution in leadership positions already in the selection of postgraduate training?, Methods: Online survey with orthopedics/trauma surgery (OUC) and neurosurgery (NCH) residents. Comparison with gynecology (GYN). Statistical analysis, mean in percent, statistical differences using t‑ or chi 2 -test (significance level α = 0,05)., Results: Returned questionnaire = 277, complete participation = 250. Female residents: OUC:52%, NCH:57%, GYN:85%. A total of 49% were told in medical school that a subject was inappropriate for gender reasons (f57-76%, m10-33%). The most frequent reason for a subject: all = "operating activity". The second most frequent reason: OUC-f = "good working atmosphere", OUC-m = "establishment", NCH-f = "career" and "good working atmosphere", NCH-m = "good working atmosphere", GYN-f = "establishment", GYN-m = "career". The most frequent reason against: OUC/GYN = "hardly any possibility to become established", NCH = "negative leadership style by superiors". For female residents in OUC/NCH, work/family balance had the smallest influence on the choice of specialty. Their subjective evaluation of compatibility was significantly the worst, and overall OUC/NCH was significantly worse than GYN. Although female residents in NCH were more likely to justify the specialty choice based on career goals, male residents in OUC/NCH were more likely to aim for a higher hierarchical position., Discussion: The results of this study emphasize that disciplines receive a gender-specific conditioning already at the undergraduate level, which has a clear impact on the choice of specialty. The image in this regard needs to be reconsidered, as even surgical subjects will predictably have to rely on more female specialists., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

More than half of all patients with colorectal cancer (CRC) develop distant metastasis and, depending on the local stage of the primary tumor, up to 48% of patients present peritoneal carcinomatosis (PC). PC is often considered as a widespread metastatic disease, which is almost resistant to current systemic therapies like chemotherapeutic and immunotherapeutic regimens. Here we could show that tumor cells of PC besides being senescent also exhibit stem cell features. To investigate these surprising findings in more detail, we established a murine model based on tumor organoids that resembles the clinical setting. In this murine orthotopic transplantation model for peritoneal carcinomatosis, we could show that the metastatic site in the peritoneum is responsible for senescence and stemness induction in tumor cells and that induction of senescence is not due to oncogene activation or therapy. In both mouse and human PC, senescence is associated with a senescence-associated secretory phenotype (SASP) influencing the tumor microenvironment (TME) of PC. SASP factors are able to induce a senescence phenotype in neighbouring cells. Here we could show that SASP leads to enhanced immunosenescence in the TME of PC. Our results provide a new immunoescape mechanism in PC explaining the resistance of PC to known chemo- and immunotherapeutic approaches. Therefore, senolytic approaches may represent a novel roadmap to target this terminal stage of CRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Braumüller, Mauerer, Berlin, Plundrich, Marbach, Cauchy, Laessle, Biesel, Holzner and Kesselring.)

Objective: While surgical decompression is an important treatment modality for cervical spondylotic myelopathy (CSM), it remains unclear if the severity of preoperative myelopathy status affects potential benefit from surgical intervention and when maximum postoperative improvement is expected. This investigation sought to determine if retrospective analysis of prospectively collected patient-reported outcomes (PROs) following surgery for CSM differed when stratified by preoperative myelopathy status. Secondary objectives included assessment of the minimal clinically important difference (MCID)., Methods: A total of 1151 patients with CSM were prospectively enrolled from the Quality Outcomes Database at 14 US hospitals. Baseline demographics and PROs at baseline and 3 and 12 months were measured. These included the modified Japanese Orthopaedic Association (mJOA) score, Neck Disability Index (NDI), quality-adjusted life-years (QALYs) from the EQ-5D, and visual analog scale from the EQ-5D (EQ-VAS). Patients were stratified by preoperative myelopathy severity using criteria established by the AO Spine study group: mild (mJOA score 15-17), moderate (mJOA score 12-14), or severe (mJOA score < 12). Univariate analysis was used to identify demographic variables that significantly varied between myelopathy groups. Then, multivariate linear regression and linear mixed regression were used to model the effect of severity and time on PROs, respectively., Results: For NDI, EQ-VAS, and QALY, patients in all myelopathy cohorts achieved significant, maximal improvement at 3 months without further improvement at 12 months. For mJOA, moderate and severe myelopathy groups demonstrated significant, maximal improvement at 3 months, without further improvement at 12 months. The mild myelopathy group did not demonstrate significant change in mJOA score but did maintain and achieve higher PRO scores overall when compared with more advanced myelopathy cohorts. The MCID threshold was reached in all myelopathy cohorts at 3 months for mJOA, NDI, EQ-VAS, and QALY, with the only exception being mild myelopathy QALY at 3 months., Conclusions: As assessed by statistical regression and MCID analysis, patients with cervical myelopathy experience maximal improvement in their quality of life, neck disability, myelopathy score, and overall health by 3 months after surgical decompression, regardless of their baseline myelopathy severity. An exception was seen for the mJOA score in the mild myelopathy cohort, improvement of which may have been limited by ceiling effect. The data presented here will aid surgeons in patient selection, preoperative counseling, and expected postoperative time courses.

Background: Postoperative shoulder imbalance is a common complication in adolescent idiopathic scoliosis and may impair patient satisfaction. The little data in the literature on the prediction and treatment of postoperative shoulder imbalance is incongruous. According to some studies, postoperative shoulder imbalance depends on the superior instrumented vertebral bodies, skeletal maturity, extent of correction and flexibility of the major curve., Question: Can preoperative radiological parameters from X-ray and traction films as well as correction of the curves be used to identify a factor impacting on postoperative shoulder imbalance?, Material and Methods: Prospective data in adolescent idiopathic scoliosis with thoracic curve (Lenke type 1), operated on between 2015 and 2018 at a scoliosis centre, were analysed retrospectively based on full-length X-rays of the spine (pre-/postOP and follow-up (FU)) and preoperative-traction films: age; correction of proximal, main and lumbar curve; shoulder height [mm]; clavicle angle [°]; T1 tilt [°]; coronal plumb line deviation [mm]. The findings were expressed as means with standard deviation. Changes in parameters over time (postOP-FU) were compared by t test (significance level α = 0.05). The correlation between preOP parameters and extent of correction with postoperative shoulder imbalance (≥ 15 mm) was determined by Pearson correlation and regression classification analysis., Outcomes: 55 patients with adolescent idiopathic scoliosis, mean age of 15 ± 1.4 years. The FU-rate after a mean of 15 months was 80% (n = 44). Correction of proximal, main and lumbar curve: 47.0%, 75.8% and 68.8%, respectively, without statistically significant change (Δ) in FU (p > 0.05). Shoulder height was - 11.0 ± 12.7 mm (preOP), 15.5 ± 13.4 mm (postOP), 10.1 ± 10.6 mm (FU) (p < 0.05). 38% of those with adolescent idiopathic scoliosis had preOP right shoulder elevation; 55% (postOP) and 32% (FU) respectively had postoperative shoulder imbalance (left shoulder elevation). Strong statistical correlation was found for Δshoulder position (FU-preOP) with pre-OP shoulder position (r = - 0.7), and Δshoulder position (pre-OP traction films) (r = 0.5) with pre-OP clavicle angle (r = - 0.5). On regression classification analysis, 81.8% of cases did display postoperative shoulder imbalance if proximal curve correction was ≤ 64.4%; main and lumbar curve correction, Δshoulder elevation (preOP traction films) played a secondary role., Discussion: One common complication even in Lenke type 1 adolescent idiopathic scoliosis is postoperative shoulder imbalance. Preoperative planning should include traction films, preoperative shoulder position and clavicle angle to avoid postoperative shoulder imbalance. Moderate correction of proximal curve is critical for postoperative shoulder balance., Competing Interests: C. Berlin, M. Quante and E. von Richthofen declare no conflict of interest. H. Halm. has a consulting and patent remuneration contract with the Nuvasive Inc. and a consulting contract with Silony. Silony also finances a study nurse./C. Berlin, M. Quante und E. von Richthofen geben an, dass kein Interessenkonflikt besteht. H. Halm. hat einen Beratervertrag mit Patentvergütungskomponente mit der Firma Nuvasive Inc. sowie einen Beratervertrag mit der Firma Silony. Die Firma Silony finanziert darüber hinaus eine Studienleiterin (study nurse)., (Thieme. All rights reserved.)

Aims: Underrepresentation of migrants, women, and older adults in cardiovascular disease (CVD) trials may contribute to disparate care and survival. Among patients who underwent percutaneous coronary intervention (PCI), we aimed to investigate the associations of (i) underrepresented groups with major adverse cardiac events (MACE), CVD mortality, and non-CVD mortality, (ii) underrepresented groups with cardiac rehabilitation (CR) uptake, and (iii) CR uptake with outcomes., Methods and Results: We included 15 211 consecutive patients from the CARDIOBASE Bern PCI registry (2009-18). In multi-state models comparing transition probabilities of events, sex was not associated with increased risk of any event. For each year increase in age, the increased risk of non-CVD and CVD mortality was 8% [95% confidence interval (CI) 6-9%]. Being migrant was associated with a lower risk of non-CVD mortality [hazard ratio (HR) (95% CI) 0.49 (0.27-0.90)] but not with CVD mortality. In logistic regression analysis, CR uptake was lower among women [odds ratio (95% CI) = 0.72 (0.57-0.86)] and older adults [0.32 (0.27-0.38)], but not among migrants. In cox regression, CR was independently associated with lower all-cause [HR (95% CI) = 0.12 (0.03-0.37)] and CVD mortality [0.1 (0.02-0.7)], but not with MACE [1.08 (0.8-1.4)]., Conclusion: Among underrepresented groups undergoing PCI, age, but not migration status nor sex, contributed to disparities in mortality. Migrant status did not result in lower attendance of CR. Considering the protective associations of CR on CVD mortality independent of age, sex, and migration status, the lower uptake in women and older adults is noteworthy., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Research Question: How are perinatal outcomes of live-born singletons after stimulated and unstimulated IVF different from perinatal outcomes in (i) children born in a tertiary centre and (ii) all children born in Switzerland?, Methods: This cohort study compared the perinatal outcomes of two birth cohorts and the national live birth registry. Relative risks were calculated using modified Poisson regression and clustering for siblings and adjustment for maternal age, parity and childs sex., Results: Of the 636,639 live births, 311 were in the Bern IVF Cohort (144 stimulated, 167 unstimulated), 2332 in the tertiary centre and 633,996 in the Swiss Live Birth Registry (SLBR). Perinatal outcomes following IVF did not differ compared with births in the SLBR (adjusted relative risk [aRR]; 95% confidence interval [CI]), with the exception of the increased risk of small for gestational age (1.31; 1.01 to 1.70, P = 0.04; aRR 1.12; 0.87 to 1.45, P = 0.39). Children born following stimulated IVF had a higher risk of low birthweight (2.17; 1.27 to 3.69, P < 0.01; aRR 1.72; 1.01 to 2.93, P = 0.05), and of being small for gestational age (1.50; 1.05 to 2.14, P = 0.03; aRR 1.31; 0.92 to 1.87; P = 0.13), whereas children born after unstimulated IVF had no increased risks compared with the SLBR. Higher Caesarean rate after IVF was mainly associated with higher maternal age., Conclusion: Singletons in the Bern IVF Cohort do not show less favourable perinatal outcomes. Gonadotrophin stimulation seems to have an effect, because lower risks were associated with unstimulated IVF., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Excess mortality quantifies the overall mortality impact of a pandemic. Mortality data have been accessible for many countries in recent decades, but few continuous data have been available for longer periods., Objective: To assess the historical dimension of the COVID-19 pandemic in 2020 for 3 countries with reliable death count data over an uninterrupted span of more than 100 years., Design: Observational study., Setting: Switzerland, Sweden, and Spain, which were militarily neutral and not involved in combat during either world war and have not been affected by significant changes in their territory since the end of the 19th century., Participants: Complete populations of these 3 countries., Measurements: Continuous series of recorded deaths (from all causes) by month from the earliest available year (1877 for Switzerland, 1851 for Sweden, and 1908 for Spain) were jointly modeled with annual age group-specific death and total population counts using negative binomial and multinomial models, which accounted for temporal trends and seasonal variability of prepandemic years. The aim was to estimate the expected number of deaths in a pandemic year for a nonpandemic scenario and the difference in observed and expected deaths aggregated over the year., Results: In 2020, the number of excess deaths recorded per 100 000 persons was 100 (95% credible interval [CrI], 60 to 135) for Switzerland, 75 (CrI, 40 to 105) for Sweden, and 155 (CrI, 110 to 195) for Spain. In 1918, excess mortality was 6 to 7 times higher. In all 3 countries, the peaks of monthly excess mortality in 2020 were greater than most monthly excess mortality since 1918, including many peaks due to seasonal influenza and heat waves during that period., Limitation: Historical vital statistics might be affected by minor completeness issues before the beginning of the 20th century., Conclusion: In 2020, the COVID-19 pandemic led to the second-largest infection-related mortality disaster in Switzerland, Sweden, and Spain since the beginning of the 20th century., Primary Funding Source: Foundation for Research in Science and the Humanities at the University of Zurich, Swiss National Science Foundation, and National Institute of Allergy and Infectious Diseases.

Colorectal cancer is among the leading causes of cancer-associated deaths worldwide. Treatment failure and tumor recurrence due to survival of therapy-resistant cancer stem/initiating cells represent major clinical issues to overcome. In this study, we identified lysine methyltransferase 9 (KMT9), an obligate heterodimer composed of KMT9α and KMT9β that monomethylates histone H4 at lysine 12 (H4K12me1), as an important regulator in colorectal tumorigenesis. KMT9α and KMT9β were overexpressed in colorectal cancer and colocalized with H4K12me1 at promoters of target genes involved in the regulation of proliferation. Ablation of KMT9α drastically reduced colorectal tumorigenesis in mice and prevented the growth of murine as well as human patient-derived tumor organoids. Moreover, loss of KMT9α impaired the maintenance and function of colorectal cancer stem/initiating cells and induced apoptosis specifically in this cellular compartment. Together, these data suggest that KMT9 is an important regulator of colorectal carcinogenesis, identifying KMT9 as a promising therapeutic target for the treatment of colorectal cancer. SIGNIFICANCE: The H4K12 methyltransferase KMT9 regulates tumor cell proliferation and stemness in colorectal cancer, indicating that targeting KMT9 could be a useful approach for preventing and treating this disease., (©2021 American Association for Cancer Research.)

In manufacturing companies, cognitive processing is required from assembly workers to perform correct and timely assembly of complex products, often with varied specifications and high quality demands. This paper explores assembly operators' perceptions of cognitive/mental workload to provide a holistic understanding of the work conditions that affect cognitive demands and performance. While the physical loading aspects of assembly work are well known, most empirical literature dealing with cognitive/mental loading in manufacturing tends to examine a few particular aspects, rather than address the issue with a holistic system view. This semi-structured interview study, involving 50 industrial assembly operators from three Swedish companies, explores how assemblers perceive that their cognitive performance and well-being is influenced by a wide variety of factors within the context of mechanical product assembly. The interview transcripts were analysed using a priori coding, followed by bottom-up Thematic Analysis. The results indicate that a variety of systemic effects on assemblers' cognitive performance can be classified as job demands or resources. Quite often, the absence of a resource mirrors a related demand, and "good assembly conditions", as described by the interviewees, often re-frame demands as desirable challenges that foster motivation and positive feelings towards the work. The identified demands and resources stem from task design, timing, physical loading, intrinsic and extrinsic motivators, social teamwork and the product's "interface" design. Despite organisational differences and conditions between the three companies that took part in the study, the results are largely consistent.

Corrective surgery remains a definitive treatment for adult spinal deformity, improving pain and disability. With these cases, instrumentation to the pelvis with iliac fixation is recommended. Whether iliac or S2-Alar-Iliac (S2AI) trajectories are used, sacroiliac joint pain and long-term sacroilitis can be common after long-fusion constructs.1-3 Sacroiliac fusion with triangular titanium implants during fusion can reduce back pain associated with sacroiliac joint degeneration,3 provides reduction in sacroiliac joint motion and stress when added to S2AI screws, and potentially enhances mechanical stability of fusion constructs.4 Here, we present a technique for placing triangular titanium sacroiliac implants (iFuse BedrockTM; SI-BONE Inc, Santa Clara, California) alongside S2AI screws using a robotic platform (Mazor X; Medtronic Sofamor Danek, Medtronic Inc, Dublin, Ireland). Navigated robotics allows reduction in human error with implant placement, and potentially decreased operative time/fluoroscopy.5-7 Key surgical steps include placement of K wires for S2AI and bilateral SI-implants, tapping, replacing SI-implant K wires with guide pins, placing S2AI screws, and finally placing the SI-implant. Final placement is verified with intraoperative fluoroscopy. The patient described is a 61-yr-old woman with worsening adult degenerative scoliosis, lower back pain, left leg radicular pain, and mild right leg pain who failed conservative treatment. Examination revealed diminished strength in both legs. Imaging was significant for moderate sigmoid scoliosis, discogenic disease, and osteoarthritis at all levels. She consented to undergo corrective surgery. Postoperatively, the patient experienced resolution of her leg weakness and pain. Imaging demonstrated appropriate positioning of hardware. Prospective studies on the efficacy of the SI-implant are underway., (© Congress of Neurological Surgeons 2021.)

Background: In the operative treatment of idiopathic scoliosis, posterior correction and fusion in freehand technique is a proven procedure and is frequently performed. Malpositioned pedicle screws can result in serious neurovascular complications. Intraoperative fluoroscopy and neurophysiological measurements are performed to ensure the correct position of pedicle screws. Newer procedures with fluoroscopic- and computertomographic-assisted navigation are advertised as less dangerous and with a more accurate screw position., Hypothesis: Is the freehand technique used in the surgical treatment of idiopathic scoliosis safer than other methods with regard to complications caused by screw malposition and intraoperative radiation exposure?, Material and Methods: Register data of 34 consecutive idiopathic scoliosis patients with two structural curves (Lenke 3 and 6) were collected prospectively in our scoliosis center and were retrospectively analyzed. The following parameters were evaluated: total radiation product, time of fluoroscopy, number of fused segments, time of operation, blood loss, screw-related complications and number of instrumented pedicle screws. All values were given as mean ± standard deviation and statistically analyzed. Finally, our data were compared on accuracy of screw placement and radiation exposure to data from literature with screw placement under navigation., Results: Average age at the time of surgery was 23.6 ± 12 years. The average thoracic curve was 69.2 ± 14.2° preoperatively and 21.7 ± 12.8° postoperatively (correction 69.9%), the average lumbar curve was 64.3° ± 10.8° preoperatively and corrected to 15.6 ± 10.4° postoperatively (correction 76.2%). The total radiation product per patient was 145.7 ± 86.1 cGy*cm², the time of fluoroscopy 31.7 ± 23.5 s (11.5 segments), the time of operation 267.2 ± 64.1 min and the blood loss 700.4 ± 522.3 ml. A total of 803 pedicle screws were placed. No screw-associated complications were detected in the entire collective. The comparison of our data with freehand placement of pedicle screws to literature data showed a noticeable higher radiation exposure for the patient during fluoroscopic- and computertomographic-assisted navigation., Discussion: The results showed that positioning of pedicle screws with freehand technique in patients with idiopathic scoliosis is accompanied with considerably lower intraoperative radiation exposure compared to fluoroscopic- or computertomographic-assisted navigation. An increased radiation exposure of these typically young patients is associated with an increased long-term risk for the occurrence of radiation-induced malignant diseases. With appropriate surgical experience, placement of pedicle screws in freehand technique is safe and effective and with similar accuracy than screws placed under navigation, but produces significantly less radiation exposure to the patients., Competing Interests: C. Berlin and U. Platz confirm that there are no conflicts of interest. M. Quante has a consultancy contract with the Silony company and receives fees for lectures from Nuvasive Inc. and the Silony company. B. Thomsen does consultancy work for the Silony company. M. Köszegvary has a consultancy contract with the Silony company and receives fees for lectures from Nuvasive Inc. M. Halm has a consultancy contract with, and receives fees for lectures from, Nuvasive Inc. and has a consultancy contract with the Silony company. The Silony company also finances a study leader (study nurse)./C. Berlin und U. Platz geben an, dass kein Interessenkonflikt besteht. M. Quante hat einen Beratervertrag mit der Firma Silony und erhält Honorare für Vorträge von der Firma Nuvasive Inc. sowie der Firma Silony. B. Thomsen hat eine Beratungstätigkeit für die Firma Silony. M. Köszegvary hat einen Beratervertrag mit der Firma Silony und erhält Honorare für Vorträge von der Firma Nuvasive Inc. H. Halm. hat einen Beratervertrag mit Patentvergütungskomponente mit der Firma Nuvasive Inc. sowie einen Beratervertrag mit der Firma Silony. Die Firma Silony finanziert darüber hinaus eine Studienleiterin (study nurse)., (Thieme. All rights reserved.)

Purpose: The mean potential of lordosis restoration by transforaminal lumbar interbody fusion (TLIF) is supposed to be low in general. In contrast, clinical experience shows a wide range of segmental lordosis correction. In this study, the predictability of lordosis correction should be investigated., Methods: Prospectively collected register data were analyzed retrospectively. One hundred twenty-one consecutive patients (2014-2016) operated with single-level TLIF L4/5 (10°-lordotic cage). Segmental lordosis (L4/5) and overall lordosis (L1-S1) were measured on lumbar X-rays: preoperatively (pre), after 3-5 days (post), at least 24 months postoperatively (2yFU). Outcome and satisfaction of patients were assessed. Parameters were statistically compared by students t-tests (a = 0.05). In addition, predictors of correction were analyzed., Results: Age was 60.7 years, rate of 2yFU 41.3% (n = 50). Lordosis correction L4/5 was statistically significant with (post-pre) 4.9 ± 5.7° (p < 0.01), but not significant for L1-S1 (post-pre) 1.6 ± 8.0° (p = 0.3). A strong-moderate correlation of lordosis L4/5 (pre) and lordosis correction L4/5 (post-pre) was shown (r =  - 0.6, p < 0,01). In a rising range of preoperative lordosis L4/5 from 15-30° the likelihood of lordosis loss increased. In 2yFU correction, L4/5 was significant with (post-pre) 5.4 ± 5.4° (p < 0.01), no significant long-term change (2yFU-postop)  - 1.5 ± 4.9° (p = 0.2). No correlation (r =  - 0.1) of correction and ODI. VAS-B improved by means of 2.9, VAS-L by 2.5, ODI by 19.1% (pre vs. 2yFU), each statistically significant (p < 0.01)., Conclusion: Significant segmental relordosation can be performed by TLIF L4/5. The potential of correction strongly correlates with preoperative lordosis. Therefore, TLIF technique should be considered carefully in cases with a preoperative segmental lordosis of more than 15° and additional need of lordosation.

This paper reports survey findings on the Swiss public's willingness, attitudes, and concerns regarding personalized health research participation by providing health information and biological material. The survey reached a sample of 15,106 Swiss residents, from which we received 5,156 responses (34.1% response rate). The majority of respondents were aware of research using human biological samples (71.0%) and held a positive opinion towards this type of research (62.4%). Of all respondents, 53.6% indicated that they would be willing to participate in a personalized health research project. Willingness to participate was higher in younger, higher educated, non-religious respondents with a background in the health sector. Respondents were more willing to provide 'traditional' types of health data, such as health questionnaires, blood or biological samples, as opposed to social media or app-related data. All respondents valued the return of individual research results, including risk for diseases for which no treatment is available. Our findings highlight that alongside general positive attitudes towards personalized health research using data and samples, respondents have concerns about data privacy and re-use. Concerns included potential discrimination, confidentiality breaches, and misuse of data for commercial or marketing purposes. The findings of this large-scale survey can inform Swiss research institutions and assist policymakers with adjusting practices and developing policies to better meet the needs and preferences of the public. Efforts in this direction could focus on research initiatives engaging in transparent communication, education, and engagement activities, to increase public understanding and insight into data sharing activities, and ultimately strengthen personalized health research efforts., Competing Interests: The authors have declared that no competing interests exist.

Residential radon exposure is a major public health issue in Switzerland due to the known association between inhaled radon progeny and lung cancer. To confirm recent findings of an association with skin cancer mortality, an updated national radon model is needed. The aim of this study was to derive the best possible residential radon prediction model for subsequent epidemiological analyses. Two different radon prediction models were developed (linear regression model vs. random forest) using ca. 80,000 measurements in the Swiss Radon Database (1994-2017). A range of geographic predictors and building specific predictors were considered in the 3-D models (x,y, floor of dwelling). A five-fold modelling strategy was used to evaluate the robustness of each approach, with models developed (80% measurement locations) and validated (20%) using standard diagnostics. Random forest consistently outperformed the linear regression model, with higher Spearman's rank correlation (51% vs. 36%), validation coefficient of determination (R 2 31% vs. 15%), lower root mean square error (RMSE) and lower fractional bias. Applied to the population of 5.4 million adults in 2000, the random forest resulted in an arithmetic mean (standard deviation) of 75.5 (31.7) Bq/m 3 , and indicated a respective 16.1% and 0.1% adults with predicted radon concentrations exceeding the World Health Organization (100 Bq/m 3 ) and Swiss (300 Bq/m 3 ) reference values., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: We studied time trends in seasonal influenza vaccination and associations with socioeconomic and health-related determinants in Switzerland, overall and in people aged ≥65 years., Design: Three cross-sectional surveys., Participants: Individuals who participated in the Swiss Health Surveys 2007, 2012 and 2017. We calculated the proportion reporting influenza vaccination in the last 12 months, and performed multivariable logistic regression analyses., Results: We included 51 582 individuals in this analysis. The median age was 49 years (IQR 25-64), and 27 518 were women (53.3%). The proportion of reporting a history of influenza vaccination overall was 31.9% (95% CI 31.4 to 32.4); and dropped from 34.5% in 2007 to 28.8% in 2017. The uptake of vaccination within the past 12 months was 16% in 2007 and similar in 2012 and 2017 (around 14%). In people with chronic disease, uptake dropped from 43.8% in 2007 to 37.1% in 2012 and to 31.6% in 2017 (p<0.001). In people aged ≥65 years, uptake dropped from 47.8% in 2007 to 38.5% in 2012 to 36.2% in 2017 (p<0.001). In logistic regression, self-reported vaccination coverage decreased in the 65-75 years old (adjusted OR (aOR) 0.56, 95% CI 0.48 to 0.66 between 2007 and 2012; aOR 0.89, 95% CI 0.77 to 1.03 between 2012 and 2017). Uptake was positively associated with the ≥65 age group, living in French-speaking and urban areas, history of smoking, bad self-reported health status, private/semiprivate health insurance, having a medical profession and having any underlying chronic disease., Conclusion: Influenza vaccination coverage was low in older and chronically ill persons. Significant efforts are required in preparing for the influenza season 2020/2021 to reduce the double burden of COVID-19 and seasonal influenza. These efforts should include campaigns but also novel approaches using social media., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Background: With the enhanced use of chemotherapy and the advent of increased patient survival rates, there are an increasing number of cancer survivors living with chemotherapy-induced cognitive impairment. A growing number of clinical studies have brought to light the association of agents like methotrexate in generating these neurological sequelae, although mechanisms remain unclear., Methods: Here, we use a clinically relevant regimen of several cycles of methotrexate and leucovorin rescue to develop a model of chemotherapy-induced cognitive impairment, and investigate the in vivo long-term (16 mo) impact of high-dose systemic methotrexate on white matter cellular dynamics as assessed by stereology, animal behavior, and diffusion tensor imaging., Results: Our results indicate that at 6 and 16 months post-chemotherapy, methotrexate-treated rats exhibit a significant and permanent decrease in the number of oligodendrocytes and their progenitors in the white matter, in corpus callosum volumes, and myelin basic protein. These findings are associated with mostly delayed deficits in performance on Morris Water Maze and Novel Object Recognition tasks. Diffusion tensor imaging demonstrates significantly decreased fractional anisotropy values in the callosum genu, body, and splenium, as well as previously unassessed areas like the fimbria. Interestingly, these white matter changes are preceded by an earlier, transient decrement in white matter microglia at 3 months, and hippocampal neural progenitors at 3 and 6 months., Conclusion: These results demonstrate a significant negative impact of methotrexate on the oligodendrocyte compartment and white matter, associated with cognitive impairment. The data also support the use of diffusion tensor imaging in monitoring white matter integrity in this context., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: A proven and frequently used surgical procedure in patients with idiopathic scoliosis (IS) is posterior transpedicular corrective spondylodesis using the freehand technique. Novel procedures with fluoroscopically and computed tomography (CT)-assisted navigation are presumed to be less risky and more accurate., Objective: Is the freehand technique for IS safe with respect to screw-associated complications and intraoperative radiation exposure?, Material and Methods: Prospectively collected data (2017-2018) from 39 consecutive patients (average age 18.7 years) with thoracic single curvature IS (61.7° ± 13.9°) from a specialized scoliosis center were evaluated for the following parameters (mean ± standard deviation): total radiation product, fluoroscopy time, fused segments, operative time, blood loss and screw-associated complications. A comparison with data from the literature on intraoperative radiation exposure using navigation procedures was carried out., Results: The total radiation product per patient was 71.7 ± 44.0 cGy*cm 2 , fluoroscopy time 17.4 ± 8.6 s. (7.8 segments), operative time 183.5 ± 54.2 min and blood loss 379.5 ± 183 ml. There were no screw-associated complications in the entire collective. Correction of the main curvature was 75.7%. Comparison of the data with index data from the literature showed a 1.25-12.5-fold higher radiation exposure for patients with fluoroscopically assisted navigation and 9.25-12.3-fold higher radiation exposure with CT-assisted procedures compared to the present results., Conclusion: The results of this study showed that with appropriate experience freehand positioning of pedicle screws is associated with comparable accuracy and less radiation exposure for patients than navigation procedures. With respect to the young age of patients, a radiation-induced long-term risk for malignant diseases should be taken into consideration.

Purpose: In surgical correction of scoliosis with pedicle screw dual-rod systems, frequently used freehand technique of screw positioning is challenging due to 3D deformity. Screw malposition can be associated with serious complications. Image-guided technologies are already available to improve accuracy of screw positioning and decrease radiation to surgeon. This study was conducted to measure intraoperative radiation to patients in freehand technique, evaluate screw-related complications and compare radiation values to published studies using navigation techniques., Methods: Retrospective analysis of prospectively collected data of 73 patients with idiopathic scoliosis, who underwent surgical correction with pedicle screw dual-rod system. Evaluated parameters were age, effective radiation dose (ED), fluoroscopy time, number of fused segments, correction and complications. Parameters were compared with regarding single thoracic curve (SC) and double thoracic and lumbar curves (DC), adolescent (10-18 years) or adult (> 18 years) idiopathic scoliosis, length of instrumentation. ED was compared with values for navigation from online database., Results: Average age was 21.0 ± 9.7 years, ED was 0.17 ± 0.1 mSv, time of fluoroscopy was 24.1 ± 18.6 s, 9.5 ± 1.9 fused segments. Average correction for SC was 75.7%, for DC 69.9% (thoracic) and 76.2% (lumbar). No screw-related complications. ED was significantly lower for SC versus DC (p < 0.01), short versus long fusions (p < 0.01), no significant difference for age (p = 0.1). Published navigation data showed 6.5- to 8.8-times higher radiation exposure for patients compared to our results., Conclusion: Compared to navigation procedures, freehanded positioning of pedicle screws in experienced hands is a safe and effective method for surgical correction of idiopathic scoliosis with a significant decrease in radiation exposure to patients.

Objectives: More than 20 people die each year in snow avalanches in Switzerland. Previous studies have primarily described these victims, but were not population based. We investigated sociodemographic factors for avalanche mortality between 1995 and 2014 in the entire Swiss resident population., Design and Methods: Within the Swiss National Cohort we ascertained avalanche deaths by anonymous data linkage with the avalanche accident database at the Swiss WSL Institute of Snow and Avalanche Research SLF. We calculated incidence rates, by dividing the number of deaths from avalanches by the number of person-years, and hazard ratios (HRs) for sociodemographic and economic characteristics using Cox proportional hazard models., Results: The data linkage yielded 250 deaths from avalanche within the SNC population for the 20 years 1995 to 2014. The median distance between the place of residence and the place of the event (avalanche) was 61.1 km. Male gender, younger age (15-45 years), Swiss nationality, living in the Alpine regions, higher education, living in the highest socioeconomic quintile of neighbourhoods, being single, and living in a household with one or more children were associated with higher avalanche mortality rates. Furthermore, for younger persons (<40 years) the hazard of dying in an avalanche between 2005 and 2014 was significantly lower than in the years 1995 to 2004 (HR = 0.56, 95%-CI: 0.36-0.85)., Conclusion: Over a 20-year period in Switzerland, higher rates of dying in an avalanche were observed in men, in younger age groups, and persons with tertiary education, living in the highest socioeconomic quintile of neighbourhoods, and living in an Alpine region. For younger persons (<40 years), the hazard declined during the study period., Competing Interests: The authors have declared that no competing interests exist.

Purpose: 4D and 2D phase-contrast MRI (2D Flow MRI, 4D Flow MRI, respectively) are increasingly being used to noninvasively assess pulmonary hypertension (PH). The goals of this study were i) to evaluate whether established quantitative parameters in 2D Flow MRI associated with pulmonary hypertension can be assessed using 4D Flow MRI; ii) to compare results from 4D Flow MRI on a digital broadband 3T MR system with data from clinically established MRI-techniques as well as conservation of mass analysis and phantom correction and iii) to elaborate on the added value of secondary flow patterns in detecting PH., Methods: 11 patients with PH (4f, 63 ± 16y), 15 age-matched healthy volunteers (9f, 56 ± 11y), and 20 young healthy volunteers (13f, 23 ± 2y) were scanned on a 3T MR scanner (Philips Ingenia). Subjects were examined with a 4D Flow, a 2D Flow and a bSSFP sequence. For extrinsic comparison, quantitative parameters measured with 4D Flow MRI were compared to i) a static phantom, ii) 2D Flow acquisitions and iii) stroke volume derived from a bSSFP sequence. For intrinsic comparison conservation of mass-analysis was employed. Dedicated software was used to extract various flow, velocity, and anatomical parameters. Visualization of blood flow was performed to detect secondary flow patterns., Results: Overall, there was good agreement between all techniques, 4D Flow results revealed a considerable spread. Data improved after phantom correction. Both 4D and 2D Flow MRI revealed concordant results to differentiate patients from healthy individuals, especially based on values derived from anatomical parameters. The visualization of a vortex, indicating the presence of PH was achieved in 9 /11 patients and 2/35 volunteers., Discussion: This study confirms that quantitative parameters used for characterizing pulmonary hypertension can be gathered using 4D Flow MRI within clinically reasonable limits of agreement. Despite its unfavorable spatial and lesser temporal resolution and a non-neglible spread of results, the identification of diseased study participants was possible., Competing Interests: The authors have declared that no competing interests exist.

Objective: To compare proton density-weighted short-tau inversion recovery (PD-STIR) and T2-weighted fat-suppressed turbo spin echo (T2-FS) sequences for detecting osteitis lesions of the sacroiliac joints (SIJ) in patients with chronic low back pain (CLBP)., Methods: This prospective study included 110 patients with CLBP and suspected spondyloarthritis and 18 healthy controls. All 128 participants (age range: 19-57 yrs) underwent 3.0 Tesla magnetic resonance imaging (MRI) of the SIJ including PD-STIR and T2-FS. Two readers independently scored PD-STIR and T2-FS images for osteitis in separate sessions. Sum scores and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Images were further analyzed as to whether they fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criterion of a positive MRI (MRI+). Interreader agreement was calculated using intraclass correlation coefficients., Results: Average osteitis sum scores were higher for T2-FS images (mean sum score of 4.10 in T2-FS vs 2.55 in PD-STIR, p = 0.017). Mean SNR was 16.54 for PD-STIR and 37.30 for T2-FS (p = 0.0289). Mean CNR was 4.14 for PD-STIR and 20.20 for T2-FS (p = 0.0212). For both readers, the ASAS MRI+ definition was more often fulfilled by T2-FS than by PD-STIR images, resulting in more patients being classified as having axial spondyloarthritis (axSpA): 68 patients using T2-FS versus 58 patients using PD-STIR. Interreader intraclass correlation coefficients were very good for both PD-STIR (0.91) and T2-FS (0.86)., Conclusion: T2-FS sequences improve image quality and hence the detection of osteitis compared to the PD-STIR sequence. More patients were classified as axSpA based on a positive MRI by T2-FS.

In the U.S., privately owned wells are not subject to any regulatory testing requirements. Well owners must have sufficient environmental health literacy (EHL) to understand and interpret information that contain complex terms and labels to manage their water quality. The objective of this paper is to assess the performance and validity of a new EHL screening tool. The Water Environmental Literacy Level Scale (WELLS) is based on the Newest Vital Sign (NVS) and contains six questions on comprehension, calculations and application of information. Content validity was assessed from expert review. Criterion-related and construct validity were evaluated using an online, convenience sample of adults ( n = 869). Percent of correct responses for items ranged from 53% to 96% for NVS and from 41% to 97% for WELLS. Completion time, mean scores, distributions, and internal consistency were equivalent between both scales. Higher scores suggest higher EHL. The scales were moderately correlated (ρ = 0.47, p < 0.001). Kappa agreement was 74%. Bland-Altman plots depicted little mean difference between the scales. Education and income level were positively associated with EHL. WELLS showed criterion-validity with NVS and construct validity with education and income. In practice or research, WELLS could quickly screen individuals for low EHL.

Supermarket food sales data might serve as a simple indicator of population-level dietary habits that influence the prevalence of excess weight in local environments. To test this possibility, we investigated how variation in store-level food sales composition across Switzerland is associated with the mean Body Mass Index (BMI) of young men (Swiss Army conscripts) living near the stores. We obtained data on annual food sales (2011) for 553 stores from the largest supermarket chain in Switzerland, identified foods commonly regarded as "healthy" or "unhealthy" based on nutrient content, and determined their contribution to each store's total sales (Swiss francs). We found that the sales percentages of both "healthy" and "unhealthy" food types varied by 2- to 3-fold among stores. Their balance ranged from -15.3% to 18.0% of total sales; it was positively associated with area-based socioeconomic position ( r = 0.63) and negatively associated with the mean BMI of young men in the area ( r = -0.42). Thus, even though we compared supermarkets from a single chain, different shopping behaviors of customers caused stores in privileged areas to sell relatively more healthy food. Knowledge about such patterns could help in designing in-store interventions for healthier nutrition and monitoring their effects over time., Competing Interests: The authors declare no conflict of interest

Purpose: Increase in in situ breast cancer (BCIS) incidence has been reported across Europe and the USA. However, little is known about the trends in BCIS incidence in regions without population-based mammographic screening programs. We set out to investigate these trends in Zurich, Switzerland, where only opportunistic mammographic screening exists., Methods: Data from 989 women diagnosed with a primary BCIS between 2003 and 2014 were used in our analyses. Age-standardized incidence rates per 100,000 person-years (ASR) were computed per year. Additional analyses by BCIS subtype, by age group at diagnosis and by incidence period were conducted. Incidence trends over time were assessed using joinpoint regression analysis., Results: The overall BCIS ASR was 10.7 cases per 100,000 person-years with an increasing trend over the study period. A similar trend was observed for the ductal carcinoma in situ (DCIS) ASR, while the lobular carcinoma in situ (LCIS) ASR decreased. Age-specific analyses revealed that the 50-59 year age group had the highest BCIS ASR. The highest increase in BCIS ASR, even though not statistically significant, was observed for the < 40 year age group., Conclusions: BCIS ASR increased linearly over a 12-year period. The increase was reflected by an increase in DCIS ASR, whereas LCIS ASR decreased over time. The highest increase in BCIS ASR over the study period was observed for the < 40 year age group, even though not statistically significant. Patient and tumor characteristics of this group that may be associated with BCIS development warrant further investigation.

Objective: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity., Methods: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined., Results: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects., Conclusions: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

Aims: We studied time trends in seasonal influenza vaccination and assessed associations with socioeconomic and health-related determinants in Switzerland (overall and people aged &ge;65 years)., Methods: We used data from the Swiss Health Surveys of 2007 and 2012. We calculated the proportion of the population (overall and those &ge;65 years old) reporting influenza vaccination in the last 12 months, and performed multivariate logistic regression analyses, presented as adjusted odds ratios (aORs)., Results: The average overall frequency of people reporting having been vaccinated for influenza in the previous 12 months was 15.2% (95% confidence interval [CI] 14.7&ndash;15.7); frequency decreased from 16.4% in 2007 to 14.1% in 2012 (p &lt;0.001). In elderly people (&ge;65 years) the frequency declined from 47.8 to 38.5% (p &lt;0.001). The decline was more pronounced in both the 15 to 19 age group (aOR 0.5, 95% CI 0.3&ndash;1.0) and those 65 to 75 years old (aOR 0.6, 95% CI 0.5&ndash;0.7), and in those with less education (aOR 0.6, 95% CI 0.4&ndash;0.7). Pregnant women had the lowest frequency for influenza vaccination (2.3%, 95% CI 0.6&ndash;7.9), but the frequency increased between 2007 and 2012 (aOR 4.5, 95% CI 1.0&ndash;20.5). Influenza vaccination in the last 12 months was positively associated with the &ge;65 age group, living in French-speaking and urban areas, history of smoking, bad self-reported health status, health insurance for private/semiprivate hospital stays and working in healthcare professions., Conclusions: Influenza vaccination coverage was low overall and declined over time. To increase influenza vaccine uptake and reach the European target of 75% in people aged &ge;65 years, more efforts should be put into novel intervention approaches.

Background: Workplace Ergonomics and Human Factors (E/HF) remains as relevant and important as ever to respond to contemporary workplace design challenges. Therefore, E/HF expertise must be involved in early and appropriate phases of the workplace design process, in order to leverage user needs and requirements to constrain the proposed design solution. In this process, design decisions are made., Objective: The aim of this article is to describe the use of a systems-theoretical framework as a guide in collaborative workplace design, focussing on planning and documenting which decisions and activities should involve E/HF expertise., Methods: As this is a conceptual paper, its method is to synthesise a framework from a combination of design process methodology-, general systems theory- and sociotechnical systems literature., Results: The framework organises the design decisions to be made into hierarchical abstraction levels and cross-cuts them into five perspectives from which the design problem can be viewed holistically., Conclusions: The ACD3 framework is intended as an enabler of many types of design, including the design of work systems. It provides a framework that allows all stakeholders to converge around design decisions that ensure that the work system is optimised to human characteristics and the activity to be performed.

Objective: The aim is assessing the in vivo efficacy of annulus fibrosus (AF) cells seeded into collagen by enhancing the reparative process around annular defects and preventing further degeneration in a rat-tail model., Summary of Background Data: Treating disc herniation with discectomy may relieve the related symptoms but does not address the underlying pathology. The persistent annular defect may lead to re-herniation and further degeneration. We recently demonstrated that riboflavin crosslinked high-density collagen gels (HDC) can facilitate annular repair in vivo., Methods: 42 rats, tail disc punctured with an 18-gauge needle, were divided into 3 groups: untreated (n = 6), injected with crosslinked HDC (n = 18), and injected with AF cell-laden crosslinked HDC (n = 18). Ovine AF cells were mixed with HDC gels prior to injection. X-rays and MRIs were conducted over 5 weeks, determining disc height index (DHI), nucleus pulposus (NP) size, and hydration. Histological assessments evaluated the viability of implanted cells and degree of annular repair., Results: Although average DHIs of both HDC gel groups were higher than those of the puncture control group at 5 weeks, the retention of disc height, NP size and hydration at 1 and 5 weeks was significant for the cellular group compared to the punctured, and at 5 weeks to the acellular group. Histological assessment indicated that AF cell-laden HDC gels have accelerated reparative sealing compared to acellular HDC gels., Conclusions: AF cell-laden HDC gels have the ability of better repairing annular defects than acellular gels after needle puncture., Statement of Significance: This project addresses the compelling demand of a sufficient treatment strategy for degenerative disc disease (DDD) perpetuated by annulus fibrosus (AF) injury, a major cause of morbidity and burden to health care systems. Our study is designed to answer the question of whether injectable, photo-crosslinked, high density collagen gels can seal defects in the annulus fibrosus of rats and prevent disc degeneration. Furthermore, we investigated whether the healing of AF defects will be enhanced by the delivery of AF cells (fibrochondrocytes) to these defects. The use of cell-laden collagen gels in spine surgery holds promise for a wide array of applications, from current discectomy procedures to future nucleus pulposus reparative therapies, and our group is excited about this potential., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To determine the prevalence of fat metaplasia and other structural lesions of the sacroiliac joints associated with axial spondyloarthritis in a nonrheumatological patient population., Methods: Magnetic resonance imaging examinations that included the pelvis and were performed in patients without known rheumatological disease were used for this retrospective cross-sectional study. These images were evaluated for sacroiliac fat metaplasia, sclerosis, osteophytes, and joint space alterations such as erosions or ankylosis. Patients were divided into 7 age groups (15-24 to ≥ 75 yrs). Prevalence of lesions across age groups was calculated. Possible clinical confounders (e.g., status post radiation, suspected inflammatory bowel disease) were investigated regarding their effect on lesion prevalence and extent, to exclude bias., Results: A total of 485 patients were enrolled. Fat metaplasia was very common and increased with age, from a prevalence of 50.6% in the age groups < 45, to 94.4% in patients ≥ 75 years. Erosions were uncommon: 0.6% of patients < 45, and 2.6% of the entire study population exhibited this feature, with no detectable age-dependent increase. Sclerosis and osteophytes were detected in 13.7% and 37.0% of patients, respectively. None of the investigated clinical confounders had a significant effect on lesion prevalence., Conclusion: Our study shows a very high prevalence of fat metaplasia adjacent to the sacroiliac joint in asymptomatic patients, while erosions are extremely uncommon.

Aims: Breast cancer is the most common cancer in women worldwide. We assessed changes in the use of breast cancer screening 2007-2012 in Switzerland, and associations with socioeconomic and health-related determinants., Methods: We used the nationwide and representative data from the Swiss Health Surveys 2007 and 2012. We analysed the self-reported use of mammography in the last 12 months (proportion of population) among women aged 40-79 years, and opportunistic (without clinical symptoms, initiated by the woman or a physician) and programmatic screening mammography (as part of a systematic screening programme). We performed multivariate logistic regression analyses (presented as adjusted odds ratios, aORs)., Results: The use of any mammography in the last 12 months declined from 19.1% (95% confidence interval [CI] 17.7-20.5%) in 2007 to 11.7% (95% CI 10.7-12.6%) in 2012. This decline was more pronounced in regions with a long-standing or no cantonal breast cancer screening programme (aOR 0.5, 95% CI 0.4-0.6, and aOR 0.5, 95% CI 0.4-0.6, respectively), but remained relatively stable in regions with a recently introduced programme (aOR 0.9, 95% CI 0.6-1.3, p-value from test for interaction 0.01). Opportunistic screening dropped from 12.0% (95% CI 10.9-13.2%) in 2007 to 6.2% (95% CI 5.5-6.9%; p <0.001) in 2012, whereas the use of programmatic mammography remained stable at 3.1% (95% CI 2.6-3.7%). Use of any mammography was higher in women aged 50-69 years, residing in a region with a systematic screening programme in place, and women having a private hospital stay insurance, but was not associated with education level and non-Swiss citizenship., Conclusions: Overall attendance of breast cancer screening is low in Switzerland and decreased between 2007 and 2012, despite expanding cantonal mammography screening programmes. Many factors may have contributed to this decline, including the ongoing scientific and public debates on the value of breast cancer screening.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare. The methods need to be specific and account for multiplicity to avoid false positive signals when the list of known adverse drug reactions is long. To apply them as part of a routine process, the methods also have to cope with very diverse drugs (increasing or decreasing number of cases over time, seasonal patterns, very safe drugs versus drugs for life-threatening diseases). In this paper, we develop new nonparametric signal detection methods, directed at detecting differences between a reporting and a reference period, or trends within a reporting period. These methods are based on bootstrap and permutation distributions, and they combine statistical significance with clinical relevance. We conducted a large simulation study to understand the operating characteristics of the methods. Our simulations show that the new methods have good power and control the family-wise error rate at the specified level. Overall, in all scenarios that we explored, the method performs much better than our current standard in terms of power, and it generates considerably less false positive signals as compared to the current standard., (Copyright © 2018 John Wiley & Sons, Ltd.)

Background: Lack of health insurance claims (HIC) in the last year of life might indicate suboptimal end-of-life care, but reasons for no HIC are not fully understood because information on causes of death is often missing. We investigated association of no HIC with characteristics of individuals and their place of residence., Methods: We analysed HIC of persons who died between 2008 and 2010, which were obtained from six providers of mandatory Swiss health insurance. We probabilistically linked these persons to death certificates to get cause of death information and analysed data using sex-stratified, multivariable logistic regression. Supplementary analyses looked at selected subgroups of persons according to the primary cause of death., Results: The study population included 113,277 persons (46% males). Among these persons, 1199 (proportion 0.022, 95% CI: 0.021-0.024) males and 803 (0.013, 95% CI: 0.012-0.014) females had no HIC during the last year of life. We found sociodemographic and health differentials in the lack of HIC at the last year of life among these 2002 persons. The likelihood of having no HIC decreased steeply with older age. Those who died of cancer were more likely to have HIC (adjusted odds ratio for males 0.17, 95% CI: 0.13-0.22; females 0.19, 95% CI: 0.12-0.28) whereas those dying of mental and behavioural disorders (AOR males 1.83, 95% CI:1.42-2.37; females 1.65, 95% CI: 1.27-2.14), and males dying of suicide (AOR 2.15, 95% CI: 1.72-2.69) and accidents (AOR 2.41, 95% CI: 1.96-2.97) were more likely to have none. Single, widowed, and divorced persons also were more likely to have no HIC (AORs in range of 1.29-1.80). There was little or no association between the lack of HIC and characteristics of region of residence. Patterns of no HIC differed across main causes of death. Associations with age and civil status differed in particular for persons who died of cancer, suicide, accidents and assaults, and mental and behavioural disorders., Conclusions: Particular groups might be more likely to not seek care or not report health insurance costs to insurers. Researchers should be aware of this aspect of health insurance data and account for persons who lack HIC.

Study Design: Ovine in vivo study., Objective: To perform lateral approach lumbar surgery in an ovine model to administer an injectable riboflavin cross-linked high-density collagen (HDC) gel and to assess its ability to mitigate intervertebral disc (IVD) degeneration after induced annulus fibrosus (AF) injury., Summary of Background Data: Biological-based injectable gels have shown efficacy in restoring biomechanical, radiographic, and histological parameters in IVD-injured animal models. Riboflavin cross-linked HDC gel has previously demonstrated retention of nucleus pulposus (NP) tissue, reduced loss of disc height, and prevention of terminal cellular degenerative changes in rat-tail spines. However, this biological therapy has never been tested in large animal models., Methods: Forty lumbar IVDs were accessed from eight sheep via lateral approach surgery. IVDs were randomly assigned to healthy control, injury and HDC treatment, or negative control with injury and no treatment. IVD injury was carried out using a drill-bit through the AF followed by needle puncture of the NP. Sheep were followed for 16 weeks and underwent qualitative/quantitative magnetic resonance imaging, x-ray, and histological analyses of collagen and proteoglycan content., Results: The lateral approach to the ovine lumbar spine to deliver HDC gel proved to be safe and reproducible. IVDs treated with the HDC gel revealed less degenerative changes at the microscopic level based on AF and NP histology. However, mean Pfirrmann grade, T2 relaxation time, NP voxel size, and disc height index were not significantly different between the two injury groups., Conclusion: Injectable HDC gel can be administered safely via lateral approach surgery in an ovine AF injury model. IVDs treated with HDC gel demonstrated less degeneration at the microscopic level though radiographic changes were slight when comparing treated to untreated IVDs. Future studies will need to elucidate the role of injury technique and time frame for follow-up in correlating histological and radiographical outcomes., Level of Evidence: N /A.

Study Design: This is a retrospective single-center study., Objective: The aim of the study was to evaluate the impact of cage characteristics and position toward clinical and radiographic outcome measures in patients undergoing extreme lateral interbody fusion (ELIF)., Summary of Background Data: ELIF is utilized for indirect decompression and minimally invasive surgical treatment for various degenerative spinal disorders. However, evidence regarding the influence of cage characteristics in patient outcome is minimal., Materials and Methods: Patients undergoing ELIF between 2007 and 2011 were included in a retrospective study. Demographic and perioperative data, as well as cage characteristics and side of approach were extracted. Radiographic parameters including lumbar lordosis, foraminal height, and disc height as well as clinical outcome parameters (Oswestry Disability Index and Visual Analog Scale) were measured preoperatively, postoperatively, and at the latest follow-up examination. Cage dimensions, in situ position, and type were correlated with radiographic and clinical outcome parameters., Results: In total, 84 patients with a total of 145 functional spinal units were analyzed. At the last follow-up of 17.7 months, radiographic and clinical outcome measures revealed significant improvement compared with before surgery with both, 18 and 22 mm cage anterior-posterior diameter subgroups (P≤0.05). Among cage characteristics, 22 mm cages presented superior restoration of foraminal and disc heights compared with 18 mm cages (P≤0.05). Neither position of the cage (anterior vs. posterior), nor the type (parallel vs. lordotic) had a significant impact on restoration of foraminal height and lumbar lordosis. Moreover, the side of surgical approach did not influence the amount of foraminal height increase., Conclusions: Cage anterior-posterior diameter is the determining factor in restoration of foraminal height in ELIF. Cage height, type, positioning, and side of approach do not have a determining role in radiographic outcome in the present study. Sustainable foraminal height restoration is achieved by implantation of wider cages., Level of Evidence: Level 3.