Fat embolism syndrome in Duchenne muscular dystrophy: Report on a novel case and systematic literature review.

We report a non-ambulatory 13-year-old boy with Duchenne muscular dystrophy who experienced severe acute respiratory distress syndrome and cerebral fat embolism following elective soft tissue surgery. Post-surgery radiological examination revealed bilateral femoral fractures and marked osteopenia that were believed to have caused disseminated pulmonary and cerebral fat embolism. The patient had never been on glucocorticoid treatment. Five months post-surgery, he remained in a state of minimal consciousness. A literature review was performed and eleven publications included, providing case reports of a total number of 23 patients with Duchenne muscular dystrophy with fat embolism syndrome. The most common causes were falls from the wheelchair that predominantly resulted in femoral fractures. Median age at the event was around 14 years. Seven patients succumbed to complications of fat embolism. No event was described in the context of surgery. We want to raise awareness that spontaneous unnoticed fractures may occur especially in adolescents with DMD from traumatic injury of large bones and also during elective surgery with a high risk of causing fat embolism with severe sequelae.

Distribution of RET proto-oncogene variants in children with appendicitis.

BACKGROUND: In addition to patient-related systemic factors directing the immune response, the pathomechanisms of appendicitis (AP) might also include insufficient drainage leading to inflammation caused by decreased peristalsis. Genetic predisposition accounts for 30%-50% of AP. M. Hirschsprung (HSCR), also characterized by disturbed peristalsis, is associated with variants in the RET proto-oncogene. We thus hypothesized that RET variants contribute to the etiology of AP. METHODS: DNA from paraffin-embedded appendices and clinical data of 264 children were analyzed for the RET c.135A>G variant (rs1800858, NC_000010.11:g.43100520A>G). In 46 patients with gangrenous or perforated AP (GAP), peripheral blood DNA was used for RET sequencing. RESULTS: Germline mutations were found in 13% of GAP, whereas no RET mutations were found in controls besides the benign variant p.Tyr791Phe (NC_000010.11:g.43118460A>T). In GAP, the polymorphic G-allele in rs2435352 (NC_000010.11:g.43105241A>G) in intron 4 was underrepresented (p = 0.0317). CONCLUSION: Our results suggest an impact of the RET proto-oncogene in the etiology of AP. Mutations were similar to patients with HSCR but no clinical features of HSCR were observed. The pathological phenotypes in both populations might thus represent a multigenic etiology including RET germline mutations with phenotypic heterogeneity and incomplete penetrance.

Improving the Affordability of Anticancer Medicines Demands Evidence-Based Policy Solutions.

The high cost of many new anticancer medicines significantly impedes breakthrough discoveries from reaching patients. A commonly heard refrain is that high prices are necessary to compensate for the high costs of research and development (R&D). Yet, there are promising policy proposals aimed at improving affordability without compromising innovation. In seeking new policy solutions, we argue for a shift away from entrenched opinion toward an evidence-based discourse that is grounded in experiments and real-world pilot studies. We offer a novel perspective and practical recommendations on how empirical evidence could and should be gathered to inform evidence-based policy interventions that lead to sustainable medicine prices in oncology.See related article by Franzen et al. (Cancer Res Commun 2022;2:39-47).

Affordable Prices Without Threatening the Oncological R&D Pipeline-An Economic Experiment on Transparency in Price Negotiations.

The high prices of innovative medicines endanger access to care worldwide. Sustainable prices need to be affordable while sufficiently incentivizing research and development (R&D) investments. A proposed solution is increased transparency. Proponents argue that price and R&D cost confidentiality are drivers of high prices. On the contrary, supporters of confidentiality claim that confidentiality enables targeted discounts which make treatments affordable; moreover, pharmaceutical companies argue that R&D investments would suffer with more transparency. Despite the political relevance, limited empirical evidence exists on the effects of transparency regulations. We contribute to fill this gap with an experiment where we replicate the EU pharmaceutical market in a laboratory setting. In a randomized controlled study, we analyzed how participants, 400 students located in four European countries, negotiated in the current system of Price Secrecy in comparison with innovative bargaining settings where either prices only (Price Transparency) or prices and R&D costs (Full Transparency) were made transparent to buyers. We found that Price transparency had no statistically significant effect on average prices or number of patients treated and made R&D investments significantly smaller (-16.86%; P: 0.0024). On the other hand, Full Transparency reduced prices (-26%; P: 0.0004) and held the number of patients constant at the level of Price Secrecy. It produced price convergence between countries with low and high health budgets, and, despite lower prices, had no effect on R&D investments. Our findings provide novel evidence that combining price and R&D cost transparency could be an effective policy to contribute to sustainable medicine prices. See related article by Franzen et al. (Cancer Discov 2022;12:299-302).

Osteosynthesis of the Mandibular Condyle With Magnesium-Based Biodegradable Headless Compression Screws Show Good Clinical Results During a 1-Year Follow-Up Period.

PURPOSE: The use of titanium-based implants in mandibular condyle fractures can require implant removal because of screw penetration through the condylar surface. The use of biodegradable implants can avoid a second operation for implant removal and the associated possible complications. We investigated the clinical and radiologic outcomes of osteosynthesis of mandibular condyle fractures (MCFs) with biodegradable magnesium-based compression screws. MATERIALS AND METHODS: We performed a retrospective observational study of 6 patients who had been treated at our department. We recorded the changes in jaw movements over time, occlusion, and possible complications at defined intervals of 1, 3, 6, and 12 months postoperatively. We also compared the preoperative computed tomography (CT) scans with the postoperative cone-beam CT (CBCT) scans at 6 and 12 months postoperatively to evaluate mandibular condyle healing and screw degradation. RESULTS: Of the 6 patients, 4 were men and 2 were women, with a mean age of 43.2 years (range, 30 to 66 years). All 6 patients had unilateral MCFs. All the patients showed well-restored function of the temporomandibular joint with significant improvement in mouth opening (46.17 ± 6.49 mm), right (10.67 ± 1.03 mm) and left (10.67 ± 1.97 mm) laterotrusion, and protrusion (10.17 ± 1.33 mm) distances to physiologic values. The CBCT scans showed the remodeling processes of the mandibular condyle and a few radiolucencies indicating the magnesium-based screws. Although penetration of 1 screw tip through the condylar surface had occurred, no implant removal was necessary owing to biodegradation of the implant. CONCLUSIONS: The results of the present study have shown that biodegradable magnesium-based compression screws provide good clinical results and avoid implant removal.

CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension.

OBJECTIVE: To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. METHODS: Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. RESULTS: Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. CONCLUSION: High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.

Conformational Plasticity of HLA-B27 Molecules Correlates Inversely With Efficiency of Negative T Cell Selection.

The development of autoimmune disorders is incompletely understood. Inefficient thymic T cell selection against self-peptides presented by major histocompatibility antigens (HLA in humans) may contribute to the emergence of auto-reactive effector cells, and molecular mimicry between foreign and self-peptides could promote T cell cross-reactivity. A pair of class I subtypes, HLA-B2705 and HLA-B2709, have previously been intensely studied, because they are distinguished from each other only by a single amino acid exchange at the floor of the peptide-binding groove, yet are differentially associated with the autoinflammatory disorder ankylosing spondylitis. Using X-ray crystallography in combination with ensemble refinement, we find that the non-disease-associated subtype HLA-B2709, when presenting the self-peptide pGR (RRRWHRWRL), exhibits elevated conformational dynamics, and the complex can also be recognized by T cells. Both features are not observed in case of the sequence-related self-peptide pVIPR (RRKWRRWHL) in complex with this subtype, and T cell cross-reactivity between pGR, pVIPR, and the viral peptide pLMP2 (RRRWRRLTV) is only rarely observed. The disease-associated subtype HLA-B2705, however, exhibits extensive conformational flexibility in case of the three complexes, all of which are also recognized by frequently occurring cross-reactive T cells. A comparison of the structural and dynamic properties of the six HLA-B27 complexes, together with their individual ability to interact with T cells, permits us to correlate the flexibility of HLA-B27 complexes with effector cell reactivity. The results suggest the existence of an inverse relationship between conformational plasticity of peptide-HLA-B27 complexes and the efficiency of negative selection of self-reactive cells within the thymus.

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

BACKGROUND: Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy. METHODS: We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702). FINDINGS: Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported. INTERPRETATION: Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort. FUNDING: None.

Diagnostic utility of small fiber analysis in skin biopsies from children with chronic pain.

INTRODUCTION: Small fiber neuropathies (SFN) are associated with a reduction in quality of life. In adults, epidermal nerve fiber density (END) analysis is recommended for the diagnosis of SFN. In children, END assessment is not often performed. We analyzed small nerve fiber innervation to elucidate the potential diagnostic role of skin biopsies in young patients with pain. METHODS: Epidermal nerve fiber density and sudomotor neurite density (SND) were assessed in skin biopsies from 26 patients aged 7 to 20 years (15 female patients) with unexplained chronic pain. The results were compared with clinical data. RESULTS: Epidermal nerve fiber density was abnormal in 50% and borderline in 35% of patients. An underlying medical condition was found in 42% of patients, including metabolic, autoimmune, and genetic disorders. DISCUSSION: Reduction of epidermal nerve fibers can be associated with treatable conditions. Therefore, the analysis of END in children with pain may help to uncover a possible cause and guide potential treatment options.

Pulsed Electromagnetic Field Therapy Improves Osseous Consolidation after High Tibial Osteotomy in Elderly Patients-A Randomized, Placebo-Controlled, Double-Blind Trial.

Extremely low-frequency pulsed electromagnetic field (ELF-PEMF) therapy is proposed to support bone healing after injuries and surgical procedures, being of special interest for elderly patients. This study aimed at investigating the effect of a specific ELF-PEMF, recently identified to support osteoblast function in vitro, on bone healing after high tibial osteotomy (HTO). Patients who underwent HTO were randomized to ELF-PEMF or placebo treatment, both applied by optically identical external devices 7 min per day for 30 days following surgery. Osseous consolidation was evaluated by post-surgical X-rays (7 and 14 weeks). Serum markers were quantified by ELISA. Data were compared by a two-sided t-test (α = 0.05). Device readouts showed excellent therapy compliance. Baseline parameters, including age, sex, body mass index, wedge height and blood cell count, were comparable between both groups. X-rays revealed faster osseous consolidation for ELF-PEMF compared to placebo treatment, which was significant in patients ≥50 years (∆mean = 0.68%/week; p = 0.003). Findings are supported by post-surgically increased bone-specific alkaline phosphatase serum levels following ELF-PEMF, compared to placebo (∆mean = 2.2 µg/L; p = 0.029) treatment. Adverse device effects were not reported. ELF-PEMF treatment showed a tendency to accelerate osseous consolidation after HTO. This effect was stronger and more significant for patients ≥50 years. This ELF-PEMF treatment might represent a promising adjunct to conventional therapy supporting osseous consolidation in elderly patients.

Comparison of SCAphoid fracture osteosynthesis by MAGnesium-based headless Herbert screws with titanium Herbert screws: protocol for the randomized controlled SCAMAG clinical trial.

BACKGROUND: Scaphoid fractures are the most common carpal fractures. They often need to be treated by surgery, where the use of a compression screw is the globally accepted gold standard. Surgeons may choose between different implant materials including titanium alloys, which remain in the body or are removed after healing. An alternative are biodegradable magnesium-based implants. Properties of magnesium alloys include high stability, osteoconductivity, potential reduction of infections and few artifacts in magnetic resonance imaging (MRI). The aim of this trial is to demonstrate non-inferiority of magnesium-based compression screws compared with titanium Herbert screws for scaphoid fractures. METHODS: The trial is designed as a multicenter, blinded observer, randomized controlled parallel two-group post market trial. Approximately 190 patients will be randomized (1:1) with stratification by center either to titanium or magnesium-based compression screws. Follow-up is 1 year per patient. Surgical procedures and aftercare will be performed according to the German treatment guideline for scaphoid fractures. The first primary endpoint is the patient-rated wrist evaluation (PRWE) score after 6 months. The second primary endpoint is a composite safety endpoint including bone union until 6 months, no adverse device effect (ADE) during surgery or wound healing and no serious ADE or reoperation within 1 year. The third primary endpoint is the difference in change MRI artifacts over time. Non-inferiority will be investigated for primary endpoints 1 (t-test confidence interval) and 2 (Wilson's score interval) using both the full analysis set (FAS) and the per protocol population at the one-sided 2.5% test-level. Superiority of magnesium over titanium screws will be established using the FAS at the two-sided 5% test-level (Welch test) only if non-inferiority has been established for both primary endpoints. Secondary endpoints include quality of life. DISCUSSION: This study will inform care providers whether biodegradable magnesium-based implants are non-inferior to standard titanium Herbert screws for the treatment of scaphoid fractures in terms of wrist function and safety. Furthermore, superiority of magnesium-based implants may be demonstrated using MRI, which is used as surrogate endpoint for screw degradation. TRIAL REGISTRATION: DRKS, DRKS00013368 . Registered Dec 04, 2017.

Hallux valgus correction utilising a modified short scarf osteotomy with a magnesium biodegradable or titanium compression screws - a comparative study of clinical outcomes.

BACKGROUND: Biodegradable implants reduce the likelihood of further surgery for hardware removal and reduce the risks of associated infection and allergy. The purpose of this study is to evaluate the clinical efficacy and determine the comparability of biodegradable magnesium alloy MgYREZr (MAGNEZIX® CS) compression screw fixation compared with standard titanium screw fixation in the surgical treatment of hallux valgus deformity. METHODS: Eleven patients undergoing corrective surgery for hallux valgus utilising biodegradable magnesium screws and a control group of 25 patients undergoing corrective hallux valgus surgery with standard titanium screws were reviewed at a median of 19 months (range 12-30 months). PROM scores (Manchester-Oxford Foot Questionnaire (MOXFQ), Foot and Ankle Outcomes Instrument (FAOI) and the EQ-5D-3 L) were recorded preoperatively and at latest follow-up. RESULTS: The results between the two groups were broadly similar, with the Magnesium and Titanium patients showing similar patterns in the various domains in the MOXFQ, the FAOI and the EQ-5D-3 L. Most patients reported a near full shoe comfort score, and EQ-5D-3 L scores were significantly improved in both patient groups (with most patients reporting a full score). Foot pain and foot function improved irrespective of the scoring systems and patients in both groups demonstrated significantly improved scores following the surgery (p < 0.05). Notably, there were no significant differences when comparing the post-operative scores between the groups for any individual scoring parameter. No impairment to quality of life was recorded. There were no intra or post-operative complications. There were no problems encountered through the use of the bioabsorbable screws. CONCLUSION: Biodegradable magnesium-based compression screws appeared to be safe in this study and are an effective fixation device in the treatment of hallux valgus deformity with clinical outcomes similar to standard titanium screw fixation.

Metal-triggered conformational reorientation of a self-peptide bound to a disease-associated HLA-B*27 subtype.

Conformational changes of major histocompatibility complex (MHC) antigens have the potential to be recognized by T cells and may arise from polymorphic variation of the MHC molecule, the binding of modifying ligands, or both. Here, we investigated whether metal ions could affect allele-dependent structural variation of the two minimally distinct human leukocyte antigen (HLA)-B*27:05 and HLA-B*27:09 subtypes, which exhibit differential association with the rheumatic disease ankylosing spondylitis (AS). We employed NMR spectroscopy and X-ray crystallography coupled with ensemble refinement to study the AS-associated HLA-B*27:05 subtype and the AS-nonassociated HLA-B* 27:09 in complex with the self-peptide pVIPR (RRKWRRWHL). Both techniques revealed that pVIPR exhibits a higher degree of flexibility when complexed with HLA-B*27:05 than with HLA-B*27:09. Furthermore, we found that the binding of the metal ion Cu2+ or Ni2+, but not Mn2+, Zn2+, or Hg2+, affects the structure of a pVIPR-bound HLA-B*27 molecule in a subtype-dependent manner. In HLA-B*27:05, the metals triggered conformational reorientations of pVIPR, but no such structural changes were observed in the HLA-B*27:09 subtype, with or without bound metal ion. These observations provide the first demonstration that not only major histocompatibility complex class II, but also class I, molecules can undergo metal ion-induced conformational alterations. Our findings suggest that metals may have a role in triggering rheumatic diseases such as AS and also have implications for the molecular basis of metal-induced hypersensitivities and allergies.

Safety and efficacy of mTOR inhibitor treatment in patients with tuberous sclerosis complex under 2 years of age - a multicenter retrospective study.

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem disease with prominent neurologic manifestations such as epilepsy, cognitive impairment and autism spectrum disorder. mTOR inhibitors have successfully been used to treat TSC-related manifestations in older children and adults. However, data on their safety and efficacy in infants and young children are scarce. The objective of this study is to assess the utility and safety of mTOR inhibitor treatment in TSC patients under the age of 2 years. RESULTS: A total of 17 children (median age at study inclusion 2.4 years, range 0-6; 12 males, 5 females) with TSC who received early mTOR inhibitor therapy were studied. mTOR inhibitor treatment was started at a median age of 5 months (range 0-19 months). Reasons for initiation of treatment were cardiac rhabdomyomas (6 cases), subependymal giant cell astrocytomas (SEGA, 5 cases), combination of cardiac rhabdomyomas and SEGA (1 case), refractory epilepsy (4 cases) and disabling congenital focal lymphedema (1 case). In all cases everolimus was used. Everolimus therapy was overall well tolerated. Adverse events were classified according to the Common Terminology Criteria of Adverse Events (CTCAE, Version 5.0). Grade 1-2 adverse events occurred in 12 patients and included mild transient stomatitis (2 cases), worsening of infantile acne (1 case), increases of serum cholesterol and triglycerides (4 cases), changes in serum phosphate levels (2 cases), increase of cholinesterase (2 cases), transient neutropenia (2 cases), transient anemia (1 case), transient lymphopenia (1 case) and recurrent infections (7 cases). No grade 3-4 adverse events were reported. Treatment is currently continued in 13/17 patients. Benefits were reported in 14/17 patients and included decrease of cardiac rhabdomyoma size and improvement of arrhythmia, decrease of SEGA size, reduction of seizure frequency and regression of congenital focal lymphedema. Despite everolimus therapy, two patients treated for intractable epilepsy are still experiencing seizures and another one treated for SEGA showed no volume reduction. CONCLUSION: This retrospective multicenter study demonstrates that mTOR inhibitor treatment with everolimus is safe in TSC patients under the age of 2 years and shows beneficial effects on cardiac manifestations, SEGA size and early epilepsy.

Novel variants and clinical symptoms in four new ALG3-CDG patients, review of the literature, and identification of AAGRP-ALG3 as a novel ALG3 variant with alanine and glycine-rich N-terminus.

ALG3-CDG is one of the very rare types of congenital disorder of glycosylation (CDG) caused by variants in the ER-mannosyltransferase ALG3. Here, we summarize the clinical, biochemical, and genetic data of four new ALG3-CDG patients, who were identified by a type I pattern of serum transferrin and the accumulation of Man5 GlcNAc2 -PP-dolichol in LLO analysis. Additional clinical symptoms observed in our patients comprise sensorineural hearing loss, right-descending aorta, obstructive cardiomyopathy, macroglossia, and muscular hypertonia. We add four new biochemically confirmed variants to the list of ALG3-CDG inducing variants: c.350G>C (p.R117P), c.1263G>A (p.W421*), c.1037A>G (p.N346S), and the intron variant c.296+4A>G. Furthermore, in Patient 1 an additional open-reading frame of 141 bp (AAGRP) in the coding region of ALG3 was identified. Additionally, we show that control cells synthesize, to a minor degree, a hybrid protein composed of the polypeptide AAGRP and ALG3 (AAGRP-ALG3), while in Patient 1 expression of this hybrid protein is significantly increased due to the homozygous variant c.160_196del (g.165C>T). By reviewing the literature and combining our findings with previously published data, we further expand the knowledge of this rare glycosylation defect.

[Impact of delayed presentation of patients with hand infections to hand surgeons: a retrospective single-centre study of 379 patients]. / Auswirkung der verspäteten Vorstellung von Handinfektionen beim Handchirurgen ­ eine retrospektive Single-Center-Studie von 379 Patienten.

OBJECTIVE: This study investigates the impact of the presentation time of patients with hand infections to hand surgeons on hospital stay and the frequency of necessary operations. PATIENTS AND METHODS: 379 patients with hand infections treated in our clinic from 2007 to 2014 were evaluated retrospectively for time of presentation to hand surgeon, time of trauma, length of stay, and frequency of necessary operations. RESULTS: On average, a surgical presentation delayed by more than one day extended the hospital stay by 1.22 days (KHVD) (95 % CI: 1.20-1.25, p < 0.001). Also, the odds of having to undergo surgery increased by 13.59 % each day (95 % CI 4.01 % -25.43 %, p < 0.001). KHVD also increased by a factor of 1.09 (95 % CI: 1.03-1.15, p < 0.001) with delayed antibiotic challenge. However, the time antibiotics were administered did not correlate with the need to undergo surgery (yes/no) (p = 0.11). CONCLUSION: Late presentation of patients with hand infections leads to a longer inpatient stay and a higher number of necessary operations. Early presentation of hand infections to an experienced hand surgeon is important to avoid complicated patient pathways that add costs to the healthcare system.

Necrotizing enterocolitis and high intestinal iron uptake due to genetic variants.

BackgroundIntestinal iron is a nutritional compound, which is essential for enteric microbiota. We evaluated the hypothesis that polymorphisms, which are known modifiers of intestinal iron uptake in adults, are associated with necrotizing enterocolitis (NEC) in preterm infants.MethodsPreterm infants (birth weight below 1,500 g) were studied. Single-nucleotide polymorphisms with known effects on serum iron levels (rs1800562, rs1799945, and rs855791) were determined using PCR. The effects of polymorphisms on NEC surgery were tested by Mendelian randomization. Outcome data were compared with χ2-test, Fisher's exact test, t-test, and Cochran-Armitage test for trend and multiple logistic regression analysis.ResultsComplete genotyping data were available for 11,166 infants. High serum iron levels due to rs855791 genotype were associated with a significantly reduced risk of NEC surgery (odds ratio (OR) 0.265; 95% confidence interval (CI) 0.11-0.65; adjusted P=0.011). Carriers of the rs855791 A-allele not receiving prophylactic probiotics had a higher risk of NEC surgery (OR 1.12, 95% CI 1.08-1.70, nominal P=0.002). Prophylactic treatment with probiotics was associated with a reduced risk of NEC surgery in carriers of the rs855791 A-Allele. No differences were found with regard to other short- or long-term outcome data.ConclusionPolymorphisms inducing lower intestinal iron uptake like the rs855791 A-allele might be an underestimated risk factor for NEC.

Transcriptome-Wide Analysis Identifies Novel Associations With Blood Pressure.

Hypertension represents a major cardiovascular risk factor. The pathophysiology of increased blood pressure (BP) is not yet completely understood. Transcriptome profiling offers possibilities to uncover genetics effects on BP. Based on 2 populations including 2549 individuals, a meta-analyses of monocytic transcriptome-wide profiles were performed to identify transcripts associated with BP. Replication was performed in 2 independent studies of whole-blood transcriptome data including 1990 individuals. For identified candidate genes, a direct link between long-term changes in BP and gene expression over time and by treatment with BP-lowering therapy was assessed. The predictive value of protein levels encoded by candidate genes for subsequent cardiovascular disease was investigated. Eight transcripts (CRIP1, MYADM, TIPARP, TSC22D3, CEBPA, F12, LMNA, and TPPP3) were identified jointly accounting for up to 13% (95% confidence interval, 8.7-16.2) of BP variability. Changes in CRIP1, MYADM, TIPARP, LMNA, TSC22D3, CEBPA, and TPPP3 expression associated with BP changes-among these, CRIP1 gene expression was additionally correlated to measures of cardiac hypertrophy. Assessment of circulating CRIP1 (cystein-rich protein 1) levels as biomarkers showed a strong association with increased risk for incident stroke (hazard ratio, 1.06; 95% confidence interval, 1.03-1.09; P=5.0×10-5). Our comprehensive analysis of global gene expression highlights 8 novel transcripts significantly associated with BP, providing a link between gene expression and BP. Translational approaches further established evidence for the potential use of CRIP1 as emerging disease-related biomarker.

Hypo-fractionated SBRT for localized prostate cancer: a German bi-center single treatment group feasibility trial.

BACKGROUND: For prostate cancer treatment, treatment options with minimal side effects are desired. External beam radiation therapy (EBRT) is non-invasive, standard of care and delivered in either conventional fractionation over 8 weeks or with moderate hypo-fractionation over about 5 weeks. Recent advances in radiotherapy technology have made extreme hypo-fractionated stereotactic body radiation therapy (SBRT) of prostate cancer feasible, which has not yet been introduced as a standard treatment method in Germany. Initial results from other countries are promising, but long-term results are not yet available. The aim of this study is to investigate feasibility and effectiveness of SBRT for prostate cancer in Germany. METHODS/DESIGN: This German bi-center single group trial (HYPOSTAT) is designed to evaluate feasibility and effectiveness, as measured by toxicity and PSA-response, respectively, of an extreme hypo-fractionated SBRT regimen with five fractions of 7 Gy in treatment of localized low and intermediate risk prostate cancer. The target volume includes the prostate with or without the base of seminal vesicles depending on risk stratification and uncertainty margins that are kept at 3-5 mm. SBRT treatment is delivered with the robotic CyberKnife system, which was recently introduced in Germany. Acute and late toxicity after one year will be evaluated according to Common Terminology Criteria for Adverse Events (CTCAE v. 4.0), Radiation Therapy Oncology Group (RTOG) and International Prostate Symptom Score (IPSS) Scores. The quality of life will be assessed before and after treatment with the EORTC QLQ C30 questionnaire. Hypothesizing that the proportion of patients with grade 2 side effects or higher is less or equal than 2.8%, thus markedly lower than the standard EBRT percentage (17.5%), the recruitment target is 85 patients. DISCUSSION: The HYPOSTAT trial aims at demonstrating short term feasibility of extreme hypo-fractioned SBRT for the treatment of prostate cancer and might be used as the pilot study for a multi-center multi-platform or for randomized-controlled trials comparing conventional radiotherapy with SBRT for localized prostate cancer in the future. The study concept of patient enrollment, follow up and evaluation by multiple public university clinics and actual patient treatment in dedicated private radiosurgery practices with high-tech radiation equipment is unique for clinical trials. STUDY STATUS: The study is ongoing and currently recruiting patients. TRIAL REGISTRATION: Registration number: NCT02635256 ( clinicaltrials.gov ). Registered 8 December 2015.