A predictive non-invasive SNP-based biomarker signature in resectable pancreatic cancer: protocol for a prospective validation study.

BACKGROUND: Single nucleotide polymorphisms (SNPs) are inherited genetic variants that can be easily determined in everyday clinical practice using a simple blood or even saliva test. They have the potential to serve as non-invasive biomarkers to predict cancer-specific patient outcomes after resection of pancreatic ductal adenocarcinoma (PDAC). Specifically, two recent analyses led to the identification and validation of three SNPs in the CD44 and CHI3L2 genes (SNPrs187115, SNPrs353630, SNPrs684559) that can be utilised as predictive biomarkers to help select patients who are likely to benefit from pancreatic resection. Those variants associate with an over 2-fold increased risk for tumour-related death in three independent PDAC study cohorts from Europe and U.S., including the publicly available Cancer Genome Atlas (TCGA) database (p-value up to 1x10-8). However, those analyses are limited by their retrospective study design with its inherent biases, such as selection and publication bias, which limits the utilization of these promising biomarkers in guiding PDAC therapy. OBJECTIVE: In order to overcome the limitations of the previous, retrospectively-designed studies and translate the findings into clinical practice, we aim to utilise a cohort of PDAC patients who undergo pancreatic resection to prospectively validate the association of the identified SNPs with PDAC survival after resection in a controlled clinical setting. METHODS: All patients with PDAC who undergo pancreatic resection at three participating hospitals in Switzerland and fulfil the inclusion criteria will be included consecutively. The SNP genotypes will be determined using standard genotyping techniques from patient blood samples. For each genotyped locus, log-rank and Cox multivariate regression tests will be performed, accounting for the relevant covariates AJCC-stage and resection-status. Clinical follow-up data will be collected for at least 3 years. Sample size calculation resulted in a number of 150 patients. RESULTS: The follow-up data collection has started in August 2019 and the estimated end of data collection will be in May 2027. The study is still recruiting participants and 142 patients have been recruited as of November 2023. The DNA extraction and genotyping of the SNPs will be done after the inclusion of the last patient. Since no SNP genotypes have been determined, no data analysis has been performed yet. The results are expected to be published in 2027. CONCLUSIONS: This is the first prospective study of the CD44 and CHI3L2 gene SNP-based biomarker signature in PDAC. A prospective validation of this signature would enable its utilization as a non-invasive, predictive biomarker of survival after pancreatic resection that is readily available at the time of diagnosis and assist in guiding PDAC therapy. The results of this study may help individualize treatment decisions and potentially improve patient outcomes. CLINICALTRIAL: Not listed in a registry, because no results of a health care intervention are reported.

Surgery Within 24 Hours Reduces Mortality and General Complication Rates in Patients Who Have Periprosthetic Femoral Fractures at the Hip.

BACKGROUND: In patients who have hip fractures, treatment within 24 hours reduces mortality and complication rates. A similar relationship can be assumed for patients who have hip periprosthetic femoral fractures (PPFs) owing to the similar baseline characteristics of the patient populations. This monocentric retrospective study aimed to compare the complication and mortality rates in patients who had hip PPF treated within and after 24 hours. METHODS: In total, 350 consecutive patients who had hip PPF in a maximum-care arthroplasty and trauma center between 2006 and 2020 were retrospectively evaluated. The cases were divided into 2 groups using a time to surgery (TTS) of 24 hours as the cutoff value. The primary outcome variables were operative and general complications as well as mortalities within 1 year. RESULTS: Overall, the mean TTS was 1.4 days, and the 1-year mortality was 14.6%. The TTS ≤ 24 hours (n = 166) and TTS > 24 hours (n = 184) groups were comparable in terms of baseline characteristics and comorbidities. Surgical complications were equally frequent in the 2 groups (16.3 versus 15.2%, P = .883). General complications occurred significantly more often in the late patient care group (11.4 versus 28.3%, P < .001). In addition, the 30-day mortality (0.6 versus 5.5%, P = .012), and 1-year mortality (8.3 versus 20.5%, P = .003) rates significantly increased in patients who had TTS > 24 hours. Cox regression analysis yielded a hazard ratio of 4.385 (P < .001) for the TTS > 24 hours group. CONCLUSIONS: Prompt treatment is required for patients who have hip PPF to reduce mortality and overall complications.

European Academy of Neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European Reference Network for Neuromuscular Diseases (ERN EURO-NMD).

BACKGROUND: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS). METHODS: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available. RESULTS: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management. CONCLUSIONS: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available.

Cervical and thoracic spinal cord gray matter atrophy is associated with disability in patients with amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis (ALS), there is an unmet need for more precise patient characterization through quantitative, ideally operator-independent, assessments of disease extent and severity. Radially sampled averaged magnetization inversion recovery acquisitions (rAMIRA) magnetic resonance imaging enables gray matter (GM) and white matter (WM) area quantitation in the cervical and thoracic spinal cord (SC) with optimized contrast. We aimed to investigate rAMIRA-derived SC GM and SC WM areas and their association with clinical phenotype and disability in ALS. METHODS: A total of 36 patients with ALS (mean [SD] age 61.7 [12.6] years, 14 women) and 36 healthy, age- and sex-matched controls (HCs; mean [SD] age 63.1 [12.1] years, 14 women) underwent two-dimensional axial rAMIRA imaging at the inter-vertebral disc levels C2/3-C5/C6 and the lumbar enlargement level Tmax . ALS Functional Rating Scale-revised (ALSFRS-R) score, muscle strength, and sniff nasal inspiratory pressure (SNIP) were assessed. RESULTS: Compared to HCs, GM and WM areas were reduced in patients at all cervical levels (p < 0.0001). GM area (p = 0.0001), but not WM area, was reduced at Tmax . Patients with King's Stage 3 showed significant GM atrophy at all levels, while patients with King's Stage 1 showed significant GM atrophy selectively at Tmax . SC GM area was significantly associated with muscle force at corresponding myotomes. GM area at C3/C4 was associated with ALSFRS-R (p < 0.001) and SNIP (p = 0.0016). CONCLUSION: Patients with ALS assessed by rAMIRA imaging show significant cervical and thoracic SC GM and SC WM atrophy. SC GM area correlates with muscle strength and clinical disability. GM area reduction at Tmax may be an early disease sign. Longitudinal studies are warranted.

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study.

Background: Evidence for the efficacy of nusinersen in adults with 5q-associated spinal muscular atrophy (SMA) has been demonstrated up to a period of 16 months in relatively large cohorts but whereas patients reach a plateau over time is still to be demonstrated. We investigated the efficacy and safety of nusinersen in adults with SMA over 38 months, the longest time period to date in a large cohort of patients from multiple clinical sites. Methods: Our prospective, observational study included adult patients with SMA from Germany, Switzerland, and Austria (July 2017 to May 2022). All participants had genetically-confirmed, 5q-associated SMA and were treated with nusinersen according to the label. The total Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores, and 6-min walk test (6 MWT; metres), were recorded at baseline and 14, 26, and 38 months after treatment initiation, and pre and post values were compared. Adverse events were also recorded. Findings: Overall, 389 patients were screened for eligibility and 237 were included. There were significant increases in all outcome measures compared with baseline, including mean HFMSE scores at 14 months (mean difference 1.72 [95% CI 1.19-2.25]), 26 months (1.20 [95% CI 0.48-1.91]), and 38 months (1.52 [95% CI 0.74-2.30]); mean RULM scores at 14 months (mean difference 0.75 [95% CI 0.43-1.07]), 26 months (mean difference 0.65 [95% CI 0.27-1.03]), and 38 months (mean difference 0.72 [95% CI 0.25-1.18]), and 6 MWT at 14 months (mean difference 30.86 m [95% CI 18.34-43.38]), 26 months (mean difference 29.26 m [95% CI 14.87-43.65]), and 38 months (mean difference 32.20 m [95% CI 10.32-54.09]). No new safety signals were identified. Interpretation: Our prospective, observational, long-term (38 months) data provides further real-world evidence for the continuous efficacy and safety of nusinersen in a large proportion of adult patients with SMA. Funding: Financial support for the registry from Biogen, Novartis and Roche.

Influence of avascular necrosis of the femoral head on hip prosthesis integration: a radiological analysis.

BACKGROUND: Avascular osteonecrosis of the femoral head (AVN) often results in total hip arthroplasty (THA). The cause for increased THA revision rates among patients with AVN is not yet fully understood. PURPOSE: To perform a comparative radiological analysis of implant integration between patients with AVN and osteoarthritis (OA). MATERIAL AND METHODS: After a matched pair analysis of 58 patients, 30 received THA due to OA, 28 due to AVN. X-ray images were evaluated after one week ("baseline") and on average 37.58 months postoperatively ("endline"). The prosthesis was grouped into 10 regions of interest (ROI): seven femoral and three acetabular. Incidence, width, and extent of "radiolucent lines" were measured within each zone. RESULTS: Between baseline and endline, width and extent progressed more noticeably in all femoral and acetabular zones among patients with AVN. In femoral ROI 1, the width increased in 40% of AVN cases compared to 6.7% of OA cases. For acetabular ROI 3, the width increased in 26.7% of AVN cases compared to no perceived changes in the OA group. No signs of prosthetic loosening were found in the AVN group. CONCLUSION: The increase of width and extent of radiolucent lines over time in patients with AVN could be a sign of lack of osteointegration. However, prosthetic loosening in absence of clinical symptoms cannot be deduced from radiological findings after medium-term postoperative follow-up. Further long-term studies are required to monitor how radiolucent lines develop in respect to long-term implant loosening. Dependent on bone quality, individually adapted reaming and broaching of the implant site are recommended.

Bone Mineral Density is Associated With Adverse Events but not Patient-Reported Outcomes in Total Hip and Knee Arthroplasty.

BACKGROUND: Although osteoporosis is common in patients undergoing elective total hip arthroplasty (THA) and total knee arthroplasty (TKA), its impact on postoperative outcomes has been inadequately studied. The purpose of this study was to evaluate the impact of bone mineral density (BMD) on adverse events and patient-reported outcomes in THA and TKA. METHODS: A series of 1,306 THA and 1,046 TKA patients who had received osteodensitometry were analyzed retrospectively. Rates of readmission, complication, transfusion, and patient-reported outcome were correlated with BMD. Multivariable logistic regression models were used to assess the relationship between osteoporosis and adverse events. RESULTS: Osteoporosis patients showed higher rates of 90-day readmission (THA: 8.5% versus 4.0%, P = .02; TKA: 8.9% versus 4.4%, P = .04) and transfusion (THA: 6.8% versus 1.2%, P < .001; TKA: 5.4% versus 1.5%, P = .005). After THA, rates of complications requiring intensive care management (5.1% versus 0.7%, P < .001) and rates of medical complications (3.5% versus 0.6%, P = .001) were increased. After TKA, rates of surgical complications (2.8% versus 0.8%, P = .04) were increased. Postoperatively, osteoporosis patients improved to comparable patient-reported outcomes as patients who had normal BMD. Multivariable logistic regression analyses revealed osteoporosis as an independent risk factor for readmissions, complications, and transfusions. CONCLUSION: Osteoporosis is a risk factor for adverse events after THA and TKA. Affected patients show similar improvement of patient-reported outcome compared to patients who have normal BMD. As osteoporosis is modifiable, a systematic screening of patients scheduled for THA or TKA should be discussed.

Rapid desorption and analysis for illicit drugs and chemical profiling of fingerprints by SICRIT ion source.

Forensic analysis can encompass a wide variety of analytes from biological samples including DNA, blood, serum, and fingerprints to synthetic samples like drugs and explosives. In order to analyze this variety, there are various sample preparation techniques, which can be time-consuming and require multiple analytical instruments. With recent advancements in ambient ionization mass spectrometry (MS), plasma-based dielectric barrier discharge ionization (DBDI) sources have demonstrated to cover a wide range of these analytes. The flow-through design of this source also allows for easy connection to a thermal desorption type of sample introduction. We present an in-house built thermal desorption device where the sample is introduced via a glass slide, which gets heated and transferred to the DBDI-MS with nitrogen for identification and semi-quantification. Using a glass slide as an inexpensive sampling device, detection limits as low as 20 pg for fentanyl are demonstrated. Additionally, a very precise (>96% accuracy) identification of persons based on the chemical profile of their fingerprints is possible, establishing a direct analytical link of the drug trace to the individual in one measurement. We compared the DAG, TAG, sterol, and (semi-)volatile region of the averaged fingerprint spectra over multiple days, showing the best model accuracy for identification based on the DAG region. The combination of thermal desorption and DBDI-MS minimized sample preparation, leading to an ultrasensitive and rapid analysis of illicit drug traces and the identification of underlying personas based on fingerprints.

[Outcome of joint replacement in patients with underlying rheumatoid disease]. / Outcome nach Gelenkersatz bei Patienten mit rheumatoider Grunderkrankung.

BACKGROUND: Artificial joint replacement is a meaningful treatment option for patients with advanced rheumatic degenerative joint diseases. The aim of this study was to investigate the influence of the underlying rheumatic diseases on postoperative complications and patient-reported outcome (PRO) after elective total joint replacement (TJR). MATERIAL AND METHODS: In a retrospective analysis of 9149 patients with elective total knee or total hip arthroplasty (TKR and THR), complication rates and PRO of patients with and without rheumatic diseases (RD) were compared. Multivariate logistic regression models were used to determine whether the underlying rheumatic disease was an independent risk factor for various complications. RESULTS: In the univariate analyses the RD patients had an increased risk of medical complications (7.1% vs. 5.2%; p = 0.028) and Clavien-Dindo grade IV complications (2.8% vs. 1.8%; p = 0.048) after TJR. This was confirmed in multivariate statistical analyses (p < 0.034). The rates for operative revisions and surgical complications were comparable (2.5% vs. 2.4%; p = 0.485). Analysis of the PRO showed a higher responder rate in patients with RD after TKR (91.9% vs. 84.5%, p = 0.039). In contrast, the responder rate in patients with RD after THR was comparable (93.4% vs. 93.2%, p = 0.584). CONCLUSION: Despite increased postoperative complication rates, patients with underlying rheumatic diseases showed a comparable outcome 1 year after TJR. After TKR the RD patients showed even higher responder rates. Although RD patients are a vulnerable patient group, they can still benefit from joint replacement.

Comparison of two joint-preserving treatments for osteonecrosis of the femoral head: core decompression and core decompression with additional cancellous bone grafting.

OBJECTIVE: Femoral head necrosis (FHN) affects mostly young and active people. The most common operative therapy is core decompression (CD) with optional cancellous bone grafting (CBG). Because little information is available on the long-term results of these procedures, we investigated the effectiveness of CD and CD + CBG in patients with ARCO stage II FHN in terms of postoperative pain, range of motion, patient-reported outcome measures (Harris Hip Score, Hip Disability and Osteoarthritis Outcome Score, EuroQol 5D, and Short Form 36 Questionnaire), and disease progression. METHODS: We retrospectively compared 11 patients treated with CD alone 48.0 months (range, 26.3-68.5 months) postoperatively versus 11 patients treated with CD + CBG 69.2 months (range, 38.0-92.9 months) postoperatively. All patients were assessed according to a routine clinical protocol involving a clinical examination, questionnaires, and radiological imaging (X-ray and magnetic resonance imaging). RESULTS: The clinical and radiological results showed no significant differences between the two groups. Both interventions demonstrated equal results according to clinical scores. CONCLUSIONS: Our data may encourage application of the less invasive technique of CD alone without CBG, which is more surgically demanding. Further prospective studies with longer follow-up are necessary to clarify the risk factors for therapy failure.

[Treatment aspects of interprosthetic femur fractures-retrospective analysis of 70 patients]. / Therapieaspekte interprothetischer Femurfrakturen ­ retrospektive Analyse von 70 Patienten.

BACKGROUND: Interprosthetic femur fractures (IFF) are rare injuries, whose surgical treatment is basically with osteosynthesis or revision arthroplasty. Various therapy algorithms have been proposed based on very small study collectives. Factors influencing the outcome are not known. OBJECTIVES: The aim of the retrospective monocentric study is to derive a treatment algorithm based on a large number of cases and to identify factors influencing the outcome. MATERIALS AND METHODS: Between 2006 and 2020, 70 IFF were identified. The surgical treatment comprised 38 osteosyntheses, 30 revision arthroplasties and 2 amputations. With classification and time to surgery, 69 perioperative variables were recorded. General and operative complications, as well as mortality, were determined in the follow-up period of 1 year. RESULTS: ASA and Charlson score correlated with 1­year-mortality. In addition, preoperatively increased CRP levels, reduced hemoglobin and the CHA2DS2-VASc score were identified as factors influencing mortality. Surgery within 24 h showed a trend towards fewer general complications. Transferred patients indicated an increased mortality. Based on classification according to Pires et al. or Füchtmeier et al. no clear treatment decision could be made. Relevant criteria for the surgical treatment were fracture localization, implant stability, bone vitality, anchoring possibility of the revision stem, as well as general condition of the patient. CONCLUSIONS: The identified factors influencing the outcome correspond to those of patients with hip fractures. IFF should be treated timely. A treatment path was developed on the basis of the largest patient group to date.

No signs of check-list fatigue - introducing the StOP? intra-operative briefing enhances the quality of an established pre-operative briefing in a pre-post intervention study.

Background: The team timeout (TTO) is a safety checklist to be performed by the surgical team prior to incision. Exchange of critical information is, however, important not only before but also during an operation and members of surgical teams frequently feel insufficiently informed by the operating surgeon about the ongoing procedure. To improve the exchange of critical information during surgery, the StOP?-protocol was developed: At appropriate moments during the procedure, the leading surgeon briefly interrupts the operation and informs the team about the current Status (St) and next steps/objectives (O) of the operation, as well as possible Problems (P), and encourages questions of other team members (?). The StOP?-protocol draws attention to the team. Anticipating the occurrence of StOP?-protocols may support awareness of team processes and quality issues from the beginning and thus support other interventions such as the TTO; however, it also may signal an additional demand and contribute to a phenomenon akin to "checklist fatigue." We investigated if, and how, the introduction of the StOP?-protocol influenced TTO quality. Methods: This was a prospective intervention study employing a pre-post design. In the visceral surgical departments of two university hospitals and one urban hospital the quality of 356 timeouts (out of 371 included operation) was assessed by external observers before (154) and after (202) the introduction of the StOP?-briefing. Timeout quality was rated in terms of timeout completeness (number of checklist items mentioned) and timeout quality (engagement, pace, social atmosphere, noise). Results: As compared to the baseline, after the implementation of the StOP?-protocol, observed timeouts had higher completeness ratings (F = 8.69, p = 0.003) and were rated by observers as higher in engagement (F = 13.48, p < 0.001), less rushed (F = 14.85, p < 0.001), in a better social atmosphere (F = 5.83, p < 0.016) and less noisy (F = 5.35, p < 0.022). Conclusion: Aspects of TTO are affected by the anticipation of StOP?-protocols. However, rather than harming the timeout goals by inducing "checklist fatigue," it increases completeness and quality of the team timeout.

Marginal resection as a potential curative treatment option of infantile fibrosarcoma with good response after chemotherapy: A case report of an ETV6-NTRK3 positive infantile fibrosacroma of the distal tibia.

RATIONALE: The infantile fibrosarcoma (IFS) is a non-rhabdomyosarcoma soft tissue sarcoma with locally aggressive properties. State of the art therapy consists of neoadjuvant chemotherapy followed by wide resection according to the criteria of the musculoskeletal tumor society. DIAGNOSES: An ETV6-NTRK3 positive IFS of the distal tibia in a 21-months old child showed good response to chemotherapy. INTERVENTIONS: Due to refusal of amputation marginal resection completing the margins with a high speed drill and filling the space with bone cement was performed. OUTCOMES: At latest follow-up 10 years after surgery, no recurrence was observed. LESSONS: An individual therapy for surgical treatment of IIFS is recommended. This comprises marginal resection in instead of the golden standard "wide resection" in selected cases.

Intestinal IgA-positive plasma cells are highly sensitive indicators of alloreaction early after allogeneic transplantation and associate with both graft-versus-host disease and relapse-related mortality.

Intestinal immunoglobulin A (IgA) is strongly involved in microbiota homeostasis. Since microbiota disruption is a major risk factor of acute graft-versus-host disease (GvHD), we addressed the kinetics of intestinal IgA-positive (IgA+) plasma cells by immunohistology in a series of 430 intestinal biopsies obtained at a median of 1,5 months after allogeneic stem cell transplantation (allo-SCT) from 115 patients (pts) at our center. IgA+ plasma cells were located in the subepithelial lamina propria and suppressed in the presence of histological aGvHD (GvHD Lerner stage 0: 131+/-8 IgA+ plasma cells/mm2; stage 1-2: 108+/-8 IgA+ plasma cells/mm2; stage 3-4: 89+/-16 IgA+ plasma cells/mm2; P=0.004). Overall, pts with IgA+ plasma cells below median had an increased treatment related mortality (P=0.04). Time courses suggested a gradual recovery of IgA+ plasma cells after day 100 in the absence but not in the presence of GvHD. Vice versa IgA+ plasma cells above median early after allo-SCT were predictive of relapse and relapse-related mortality (RRM): pts with low IgA+ cells had a 15% RRM at 2 and at 5 years, while pts with high IgA+ cells had a 31% RRM at 2 years and more than 46% at 5 years; multivariate analysis indicated high IgA+ plasma cells in biopsies (hazard ratio =2.7; 95% confidence interval: 1.04-7.00) as independent predictors of RRM, whereas Lerner stage and disease stage themselves did not affect RRM. In contrast, IgA serum levels at the time of biopsy were not predictive for RRM. In summary, our data indicate that IgA+ cells are highly sensitive indicators of alloreaction early after allo-SCT showing association with TRM but also allowing prediction of relapse independently from the presence of overt GvHD.

How Relevant Is the Parallax Effect on Low Centered Pelvic Radiographs in Total Hip Arthroplasty.

The correct cup position in total hip arthroplasty (THA) is usually assessed on anteroposterior low centered pelvic radiographs, harboring the risk of misinterpretation due to projection of a three-dimensional geometry on a two-dimensional plane. In the current study, we evaluate the effect of this parallax effect on the cup inclination and anteversion in THA. In the course of a prospective clinical trial, 116 standardized low centered pelvic radiographs, as routinely obtained after THA, were evaluated regarding the impact of central beam deviation on the cup inclination and anteversion angles. Measurements of the horizontal and vertical beam offset with two different methods of parallax correction were compared with each other. Furthermore, the effect of parallax correction on the accuracy ofmeasuring the cup position was investigated. The mean difference between the two parallax correction methods was 0.2° ± 0.1° (from 0° to 0.4°) for the cup inclination and 0.1° ± 0.1° (from -0.1° to 0.2°) for the anteversion. For a typically intended cup position of a 45° inclination and 15° anteversion, the parallax effect led to a mean error of -1.5° ± 0.3° for the inclination and 0.6° ± 1.0° for the anteversion. Central beam deviation resulted in a projected higher cup inclination up to 3.7°, and this effect was more prominent in cups with higher anteversion. In contrast, the projected inclination decreased due to the parallax effect up to 3.2°, especially in cups with high inclination. The parallax effect on routinely obtained low centered pelvic radiographs is low and not clinically relevant due to the compensating effect of simultaneous medial and caudal central beam deviation.

Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications.

BACKGROUND: Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis. METHODS: In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87). RESULTS: Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P < .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P < .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1). CONCLUSIONS: Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.

Genetic variability in sporadic amyotrophic lateral sclerosis.

With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking. We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE. We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool. We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10-5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%. This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.