A neutrophil response linked to tumor control in immunotherapy.

Neutrophils accumulate in solid tumors, and their abundance correlates with poor prognosis. Neutrophils are not homogeneous, however, and could play different roles in cancer therapy. Here, we investigate the role of neutrophils in immunotherapy, leading to tumor control. We show that successful therapies acutely expanded tumor neutrophil numbers. This expansion could be attributed to a Sellhi state rather than to other neutrophils that accelerate tumor progression. Therapy-elicited neutrophils acquired an interferon gene signature, also seen in human patients, and appeared essential for successful therapy, as loss of the interferon-responsive transcription factor IRF1 in neutrophils led to failure of immunotherapy. The neutrophil response depended on key components of anti-tumor immunity, including BATF3-dependent DCs, IL-12, and IFNγ. In addition, we found that a therapy-elicited systemic neutrophil response positively correlated with disease outcome in lung cancer patients. Thus, we establish a crucial role of a neutrophil state in mediating effective cancer therapy.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans.

BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+ or IL-2+ CD8+ and CD4+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.

Chromatin bridges, not micronuclei, activate cGAS after drug-induced mitotic errors in human cells.

Mitotic errors can activate cyclic GMP-AMP synthase (cGAS) and induce type I interferon (IFN) signaling. Current models propose that chromosome segregation errors generate micronuclei whose rupture activates cGAS. We used a panel of antimitotic drugs to perturb mitosis in human fibroblasts and measured abnormal nuclear morphologies, cGAS localization, and IFN signaling in the subsequent interphase. Micronuclei consistently recruited cGAS without activating it. Instead, IFN signaling correlated with formation of cGAS-coated chromatin bridges that were selectively generated by microtubule stabilizers and MPS1 inhibitors. cGAS activation by chromatin bridges was suppressed by drugs that prevented cytokinesis. We confirmed cGAS activation by chromatin bridges in cancer lines that are unable to secrete IFN by measuring paracrine transfer of 2'3'-cGAMP to fibroblasts, and in mouse cells. We propose that cGAS is selectively activated by self-chromatin when it is stretched in chromatin bridges. Immunosurveillance of cells that fail mitosis, and antitumor actions of taxanes and MPS1 inhibitors, may depend on this effect.

Effects of TP63 mutations on keratinocyte adhesion and migration.

The goal of this study was to investigate the molecular mechanisms responsible for the formation of skin erosions in patients affected by Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC). This ectodermal dysplasia is caused by mutations in the TP63 gene, which encodes several transcription factors that control epidermal development and homeostasis. We generated induced pluripotent stem cells (iPSC) from AEC patients and corrected the TP63 mutations using genome editing tools. Three pairs of the resulting conisogenic iPSC lines were differentiated into keratinocytes (iPSC-K). We identified a significant downregulation of key components of hemidesmosomes and focal adhesions in AEC iPSC-K compared to their gene-corrected counterparts. Further, we demonstrated reduced AEC iPSC-K migration, suggesting the possibility that a process critical for cutaneous wound healing might be impaired in AEC patients. Next, we generated chimeric mice expressing a TP63-AEC transgene and confirmed a downregulation of these genes in transgene-expressing cells in vivo. Finally, we also observed these abnormalities in AEC patient skin. Our findings suggest that integrin defects in AEC patients might weaken the adhesion of keratinocytes to the basement membrane. We propose that reduced expression of extracellular matrix adhesion receptors, potentially in conjunction with previously identified desmosomal protein defects, contribute to skin erosions in AEC.

What's the Harm in Cardiopulmonary Resuscitation?

In clinical ethics, there remains a great deal of uncertainty regarding the appropriateness of attempting cardiopulmonary resuscitation (CPR) for certain patients. Although the issue continues to receive ample attention and various frameworks have been proposed for navigating such cases, most discussions draw heavily on the notion of harm as a central consideration. In the following, I use emerging philosophical literature on the notion of harm to argue that the ambiguities and disagreement about harm create important and oft-overlooked challenges for the ethics of CPR. I begin by elucidating the standard account of harm, called the Counterfactual Comparative Account (CCA). I then show that three challenges to the CCA-preemptive harms, the harm of death, and non-experiential harms-are particularly salient when assessing potential harms for candidates of CPR and likely impact-related decision-making and communication. I extend this argument to explore how the ambiguities of harm might extend to other realms of clinical decision-making, such as the use and limitations of life-sustaining treatments. To address these challenges, I propose two strategies for identifying and minimizing the impact of such uncertainty: first, clinicians and ethicists ought to promote pluralistic conversations that account for different understandings of harm; second, they ought to invoke harm-independent considerations when discussing the ethics of CPR in order to reflect the nuances of such conversations. These strategies, coupled with a richer philosophical understanding of harm, promise to help clinicians and ethicists navigate the prevalent and difficult cases involving patient resuscitation and many other harm-based decisions in the clinical setting.

RPGRIP1L is required for stabilizing epidermal keratinocyte adhesion through regulating desmoglein endocytosis.

Cilia-related proteins are believed to be involved in a broad range of cellular processes. Retinitis pigmentosa GTPase regulator interacting protein 1-like (RPGRIP1L) is a ciliary protein required for ciliogenesis in many cell types, including epidermal keratinocytes. Here we report that RPGRIP1L is also involved in the maintenance of desmosomal junctions between keratinocytes. Genetically disrupting the Rpgrip1l gene in mice caused intraepidermal blistering, primarily between basal and suprabasal keratinocytes. This blistering phenotype was associated with aberrant expression patterns of desmosomal proteins, impaired desmosome ultrastructure, and compromised cell-cell adhesion in vivo and in vitro. We found that disrupting the RPGRIP1L gene in HaCaT cells, which do not form primary cilia, resulted in mislocalization of desmosomal proteins to the cytoplasm, suggesting a cilia-independent function of RPGRIP1L. Mechanistically, we found that RPGRIP1L regulates the endocytosis of desmogleins such that RPGRIP1L-knockdown not only induced spontaneous desmoglein endocytosis, as determined by AK23 labeling and biotinylation assays, but also exacerbated EGTA- or pemphigus vulgaris IgG-induced desmoglein endocytosis. Accordingly, inhibiting endocytosis with dynasore or sucrose rescued these desmosomal phenotypes. Biotinylation assays on cell surface proteins not only reinforced the role of RPGRIP1L in desmoglein endocytosis, but also suggested that RPGRIP1L may be more broadly involved in endocytosis. Thus, data obtained from this study advanced our understanding of the biological functions of RPGRIP1L by identifying its role in the cellular endocytic pathway.

CT-based patient-specific instrumentation for total knee arthroplasty in over 700 cases: single-use instruments are as accurate as standard instruments.

PURPOSE: Efforts in total knee arthroplasty are made to improve accuracy for a correct leg axis and reduce component malpositioning using patient-specific instruments. It was hypothesized that use of patient-specific instruments (vs. computer-navigated and conventional techniques) will reduce the number of outliers. Our second hypothesis was that single-use instrumentation will lead to the same accuracy compared to patient-specific instruments made of metal. METHODS: 708 primary total knee arthroplasties between 2014 and 2018 using computer tomography (CT)-based patient-specific cutting block technique and a preoperative planning protocol were retrospectively reviewed. Preoperative data [hip-knee-angle (HKA), lateral distal femoral angle (LDFA), medial proximal tibial angle (MPTA), tibial slope, femoral component flexion] was compared to postoperative performed standard radiological follow-up X-rays. Differences of > 3° between measurements were defined as outliers. RESULTS: Overall 500 prostheses using standard instrumentation and 208 prostheses using single-use instruments were implanted. Preoperative HKA axes (- 1.2°; p < 0.001), femoral component flexion (Δ 0.8°, p < 0.001), LDFA (Δ - 1.5°, p < 0.001), MPTA (Δ - 0.5°, p < 0.001) and tibial posterior slopes (Δ 0.5°, p < 0.001), respectively, were different from postoperative axes. More outliers occurred using standard (vs. single-use) instruments (p < 0.001) regarding postoperative HKA (ranges of standard- vs. single-use: instruments: HKA 178.0°-180.5° vs. 178.0°-180.5°, femoral component flexion 0.0°-6.0° vs. 0.0°-4.5°, LDFA 90.0°-91.0° vs. 90.0°-90.0°, MPTA 90.0°-90.0° vs. 90.0°-90.0°, tibial posterior slope - 10° to 10° vs. - 1° to 10°). No differences were seen for other angles measured. Comparing both systems, total number of outliers was higher using standard (8%) vs. single-use instruments (4.3%). CONCLUSION: This study shows a high accuracy of CT-based patient-specific instrumentation concerning postoperative achieved knee angles and mechanical leg axes. Single-use instruments showed a similar accuracy. LEVEL OF EVIDENCE: III.

A novel augmented reality-based surgical guidance system for total knee arthroplasty.

INTRODUCTION: Many of the functional complications that arise after total knee arthroplasty (TKA) are caused by a non-optimal balance of the knee after surgery. Over the past 20 years, technology has been used in the Operating Room (OR) to help improve precision and balance. The results of Computer-Assisted Surgery (CAS) and robotic systems show improved accuracy regarding implant positioning but a relatively small improvement in patient-reported outcomes and implant survival compared to conventional TKA. Recently, Augmented Reality (AR) has been proposed as a technology that could improve accuracy in orthopaedic surgery, providing a more efficient and cost-effective solution. MATERIALS AND METHODS: This article describes a novel AR-based surgical guidance system that measures intra-operatively the effect of prosthesis alignment and positioning on soft tissue balance. The system is integrated in a pair of smart glasses and two small sensors and displays surgical targets directly in the field of view of the surgeon. RESULTS: The system has been used in a limited number of cases. While the preliminary experience has been positive, clinical research is ongoing to confirm to confirm the performance of the system and the impact on clinical outcomes. CONCLUSION: Augmented Reality can be a valuable tool to improve accuracy in TKA. The use of smart glasses and integrated sensors improves the efficiency of the procedure, particularly when coupled with single-use instrumentation. A novel protocol for soft tissue assessment allows for a 3-dimensional evaluation of the ligaments and a better measurement of the effect of tibial rotation.

Duodenal-type and nodal follicular lymphomas differ by their immune microenvironment rather than their mutation profiles.

Duodenal-type follicular lymphoma (DTFL) is a rare and highly indolent follicular lymphoma (FL) variant. It is morphologically and immunophenotypically indistinguishable from typical FL, characterized by restricted involvement of intestinal mucosa, and lacks extraintestinal manifestations. The molecular determinants of this distinct clinical behavior are largely unknown. Thirty-eight diagnostic biopsies from patients with DTFL were evaluated. The 10-year overall survival rate was 100% in clinically evaluable patients (n = 19). We compared the targeted mutation profile of DTFL (n = 31), limited-stage typical FL (LSTFL; n = 17), and advanced-stage typical FL (ASTFL; n = 241). The mutation frequencies of recurrently mutated genes, including CREBBP, TNFRSF14/HVEM, and EZH2 were not significantly different. However, KMT2D was less commonly mutated in DTFL (52%) and LSTFL (24%) as compared with ASTFL (79%). In ASTFL, 41% of KMT2D-mutated cases harbored multiple mutations in KMT2D, as compared with only 12% in LSTFL (P = .019) and 0% in DTFL (P < .0001). Whole exome and targeted sequencing of DTFL revealed high mutation frequencies of EEF1A1 (35%) and HVCN1 (22%). We compared the immune microenvironment gene expression signatures of DTFL (n = 8) and LSTFL (n = 7). DTFL clearly separated from LSTFL by unsupervised, hierarchical clustering of 147 chemokines and cytokines and was enriched for a chronic inflammation signature. In conclusion, the mutational landscape of DTFL is highly related to typical FL. The lower frequency of multiple mutations in KMT2D in DTFL and LSTFL indicates an increasing selection pressure for complete KMT2D loss in ASTFL pathogenesis. The highly dissimilar immune microenvironment of DTFL suggests a central role in the biology of this disease.

Anterolateral Ligament Reconstruction and Modified Lemaire Lateral Extra-Articular Tenodesis Similarly Improve Knee Stability After Anterior Cruciate Ligament Reconstruction: A Biomechanical Study.

PURPOSE: To determine the stabilizing role of anterolateral ligament reconstruction (ALLR) and modified Lemaire lateral extra-articular tenodesis (LET) performed in combination with anterior cruciate ligament reconstruction (ACLR) and to determine whether either procedure was superior to the other. METHODS: Six nonpaired, human, fresh-frozen cadaveric knees were tested with a 6-df robotic system. Internal rotation and anterior translation of the knee were recorded from 0° to 90° of flexion after application of a 5-Nm internal rotation torque and a 134-N anterior load, respectively. A full kinematic assessment was performed in each of the following conditions: (1) intact knee, (2) after sectioning of the anterior cruciate ligament (ACL), (3) after sectioning of the ACL and anterolateral ligament, (4) after isolated ACLR, and (5) after combined ACLR and Lemaire LET and combined ACLR and ALLR. ALLR was performed using the gracilis tendon, whereas the modified Lemaire procedure was performed using the central strip of the iliotibial band. The different states were compared using a Tukey paired comparison test. RESULTS: In knees with combined deficiency of the ACL and anterolateral structures, anterior translation and internal rotation remained significantly increased after isolated ACLR compared with the intact knee (+2.33 ± 1.44 mm and +1.98° ± 1.06°, respectively; P < .01). On the other hand, the addition of ALLR or modified Lemaire LET to ACLR restored anterior translation and internal rotation to values similar to those in the intact knee. The 2 anterolateral procedures did not show statistically significantly different values for both tests. This difference was 0.67 ± 1.46 mm for anterior translation (P = .79) and 0.11° ± 1.11° for internal rotation (P = .99). CONCLUSIONS: In knees with ACL and anterolateral deficiency, combined ACLR and anterolateral reconstruction restored the native knee stability in anterior translation and internal rotation contrary to isolated ACLR. In addition, both types of extra-articular reconstruction-ALLR and modified Lemaire LET-were similar in terms of restoring knee kinematics, and neither overconstrained the knee. CLINICAL RELEVANCE: In knees with deficiency of the ACL and anterolateral structures, combined ACLR and anterolateral reconstruction increased knee stability at time zero after surgery. This biomechanical improvement could be responsible for the protective effect on ACL graft and meniscal repair reported in the literature after the combined procedure.

[Working conditions and health status of young physicians and nurses in German hospitals]. / Arbeitsbedingungen und Gesundheitszustand junger Ärzte und professionell Pflegender in deutschen Krankenhäusern.

BACKGROUND: Profound transformations in the German healthcare system lead to intense working conditions for young employees in inpatient care. Published data suggest associated health risks. OBJECTIVES: This investigation aims to assess current stress factors, their consequences, and subjective measures for improvement. METHODS: During September 2017, a cross-sectional survey was conducted among physicians and nurses ≤35 years of age and with work experience in inpatient care not exceeding six years. Field access was gained via seven scientific and professional societies. The electronic questionnaire consisted of mainly validated instruments. Regression models included confounders into the final data analysis. RESULTS: Included in the final data analysis were 1060 complete cases. The overall response rate was 13%. Different stress factors (e.g. time-related or psychosocial) were found at high levels. These stress factors were connected to reduced health and higher risk of burnout. Furthermore, they were associated with inferior perceived quality of care. Young physicians claimed less documentation requirements and less intense working conditions. Young nurses demanded fair salary and an appropriate nurse-patient allocation. CONCLUSION: Today's working conditions in inpatient care are a threat to the health status of young employees. General conditions, which ensure a sustainable healthy and effective working environment, need to be ensured.

[Unicompartmental knee arthroplasty - a solution?] / Teilprothesen am Kniegelenk ­ wann sinnvoll?

Unicompartmental knee arthroplasty - a solution? Abstract. Unicompartmental knee arthroplasty (UKA) has various advantages over total knee arthroplasty (TKA); however, national joint registries communicate a significantly higher revision rate. Nevertheless, good results with high patient satisfaction can be achieved by appropriate patient selection. The good functional outcome may be due to the philosophy of the procedure, since the unicompartmental joint replacement is a pure resurfacing replacement, which aims to restore the individual, variable native, pre-arthrotic alignment, joint line and knee laxity, thus respecting the kinematics of the native knee joint. In addition, important proprioceptive structures such as ligaments are preserved. The advantages of unicompartmental joint replacement (minimally invasive procedure, preserving ligaments, cartilage and bone stock, more physiological kinematics, faster rehabilitation and easier revision surgery) outweigh the disadvantages of this procedure (technically more demanding, higher revision rate in national registers).

We don't need unilateral DNRs: taking informed non-dissent one step further.

Although shared decision-making is a standard in medical care, unilateral decisions through process-based conflict resolution policies have been defended in certain cases. In patients who do not stand to receive proportional clinical benefits, the harms involved in interventions such as cardiopulmonary resuscitation seem to run contrary to the principle of non-maleficence, and provision of such interventions may cause clinicians significant moral distress. However, because the application of these policies involves taking choices out of the domain of shared decision-making, they face important ethical and legal problems, including a recent challenge to their constitutionality. In light of these concerns, we suggest a re-conceptualization of informed non-dissent as an alternative approach in cases where the application of process-based policies is being considered. This clinician-directed communication model still preserves what is valuable in such policies and salvages professional integrity, while minimising ethical and legal challenges.

Bone autografting in medial open wedge high tibial osteotomy results in improved osseous gap healing on computed tomography, but no functional advantage: a prospective, randomised, controlled trial.

PURPOSE: Medial open wedge high tibial osteotomy (owHTO) is a valuable surgical technique used to manage medial degeneration in varus knees. Iliac crest autograft is considered the gold standard gap-filler. It was hypothesised that iliac crest autograft promotes gap healing and improves functional outcome in owHTO. METHODS: Between 2005 and 2009, patients scheduled to undergo owHTO stabilised by a medial locking compression plate were randomised to undergo owHTO either with iliac crest autograft (group A) or without bone void filler (group B). Pre- and postoperative leg axes were recorded. At 3 and 12 months postoperatively, the healing of the osteotomy gap was measured as a percentage on CT images, and functional scores were recorded. RESULTS: There were 15 patients in group A, and 25 in group B. The groups were similar in age, sex ratio, knee varus deformity, body mass index, and smoking status. Group A and B had similar preoperative varus (6.9° vs. 7.6°) and postoperative valgus (2.2° vs. 3.0°). Compared with the control group, group A had a significantly greater degree of osseous gap healing after 3 months (40.1% vs. 10.8%, p = 0.045) and 12 months (91.5% vs. 59.1%, p ≤ 0.001). Multiple linear regression analysis found that bone grafting was an independent promoting factor for gap healing, while increased preoperative varus was an independent retardant factor at 3 months (p = 0.004 and p = 0.002, respectively) and 12 months (p ≤ 0.001 and p = 0.003, respectively). Younger age was a promoting factor for gap healing on CT at 3 months (p ≤ 0.001), but not at 12 months. No correlations were found between bone healing and functional outcome, body mass index, or smoking status. CONCLUSIONS: Iliac crest autograft significantly increases healing of the osteotomy gap after owHTO. Increased preoperative varus and older patient age are independent factors that delay early healing of the osteotomy. However, no functional advantage was found at 3 or 12 months postoperatively. Therefore, routine use of iliac crest autograft cannot be recommended. LEVEL OF EVIDENCE: II.

Prevalence and quantification of contamination of knitted cotton outer gloves during hip and knee arthroplasty surgery.

INTRODUCTION: Knitted cotton outer gloves offer protection against surgical glove perforation and provide improved grip on instruments. These gloves absorb blood and other fluids during surgery, and may therefore also accumulate contaminating bacteria. To date, there is no published data on microbial contamination of such gloves during surgery. METHODS: Knitted cotton outer gloves used in primary and revision hip and knee arthroplasty from two Swiss hospitals were analysed by quantitative bacteriology. Samples were subjected to sonication and vortexing, followed by membrane filtration of the sonicate. Membranes were incubated under aerobic and anaerobic culture conditions, respectively, for 21 days. Total microbial load for each pair of gloves was determined by colony-forming units (CFU) count. Strain identification was performed with MALDI-TOF. RESULTS: A total of 43 pairs of gloves were collected from continuous series of surgeries. Under aerobic culture conditions, total CFU counts ranged 0-1103, 25 (58%) samples remaining sterile, and 4 (9%) yielding > 100 CFU. Under anaerobic culture conditions, total CFU counts ranged 0-3579, 22 (51%) samples remaining sterile, 6 (14%) yielding > 100 CFU. The only covariate significantly associated with the level of contamination was the provider hospital (p < 0.0001 for aerobic and p = 0.007 for anaerobic cultures). Strain identification revealed only skin commensals, mainly coagulase-negative staphylococci and Propionibacterium spp. CONCLUSION: While contamination of surgical latex gloves is a well-known issue, no study has examined so far contamination of knitted cotton outer gloves. No or very low microbial contamination could be identified in the majority of the knitted cotton outer gloves assayed. However, a relevant proportion showed contamination far higher than estimated minimal thresholds for implant-associated infection. Clinical relevance of these findings remains to be established.

Interferometric detection of 3D motion using computational subapertures in optical coherence tomography.

Doppler optical coherence tomography (OCT) quantifies axial motion with high precision, whereas lateral motion cannot be detected by a mere evaluation of phase changes. This problem was solved by the introduction of three-beam Doppler OCT, which, however, entails a high experimental effort. Here, we present the numerical analogue to this experimental approach. Phase-stable complex-valued OCT datasets, recorded with full-field swept-source OCT, are filtered in the Fourier domain to limit imaging to different computational subapertures. These are used to calculate all three components of the motion vector with interferometric precision. As known from conventional Doppler OCT for axial motion only, the achievable accuracy exceeds the actual imaging resolution by orders of magnitude in all three dimensions. The feasibility of this method is first demonstrated by quantifying micro-rotation of a scattering sample. Subsequently, a potential application is explored by recording the 3D motion vector field of tissue during laser photocoagulation in ex-vivo porcine retina.

Simple approach for aberration-corrected OCT imaging of the human retina.

Aberration-corrected imaging of human photoreceptor cells, whether hardware or software based, presently requires a complex and expensive setup. Here we use a simple and inexpensive off-axis full-field time-domain optical coherence tomography (OCT) approach to acquire volumetric data of an in vivo human retina. Full volumetric data are recorded in 1.3 s. After computationally correcting for aberrations, single photoreceptor cells were visualized. In addition, the numerical correction of ametropia is demonstrated. Our implementation of full-field optical coherence tomography combines a low technical complexity with the possibility for computational image correction.

Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease.

BACKGROUND AND AIMS: In patients with inflammatory bowel disease (IBD), restless legs syndrome (RLS) may occur as an extraintestinal disease manifestation. Iron deficiency (ID) or folate deficiency/vitamin B12 deficiency (FD/VB12D) has previously been described to cause RLS. Here, we determined the prevalence and severity of RLS in IBD patients and evaluated the effect of iron and/or folic acid/vitamin B12 supplementation. METHODS: Patients were screened for ID and RLS by a gastroenterologist. If RLS was suspected, a neurologist was consulted for definitive diagnosis and severity. Patients with RLS and ID, FD, or VB12D received supplementation and were followed-up at weeks 4 and 11 after starting supplementation. RESULTS: A total of 353 IBD patients were included. Prevalence for RLS was 9.4% in Crohn's disease (CD) and 8% in ulcerative colitis (UC). Prevalence for the subgroup of clinically relevant RLS (symptoms ≥ twice/week with at least moderate distress) was 7.1% (n = 16) for CD and 4.8% (n = 6) for UC. 38.7% of RLS patients presented with ID, FD, and/or VB12D. Most frequently ID was seen (25.8%; n = 8). Iron supplementation resulted in RLS improvement (p = 0.029) at week 4 in seven out of eight patients. CONCLUSION: Although the overall prevalence of RLS in IBD did not differ to the general population, clinically relevant RLS was more frequent in IBD patients and, therefore, it is important for clinicians to be aware of RLS symptoms. Though for definite diagnosis and proper treatment of RLS, a neurologist must be consulted. Additionally, iron supplementation of IBD patients with ID can improve RLS symptoms. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03457571.

Impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, and quality of life.

PURPOSE: Inflammatory bowel disease has been associated with neurological symptoms including restless legs syndrome. Here, we investigated the impact of restless legs syndrome in patients with inflammatory bowel disease on sleep, fatigue, mood, cognition, and quality of life. METHODS: Two groups of inflammatory bowel disease patients, with and without restless legs syndrome, were prospectively evaluated for sleep disorders, fatigue, daytime sleepiness, depression, anxiety, and health-related quality of life. Furthermore, global cognitive function, executive function, attention, and concentration were assessed in both groups. Disease activity and duration of inflammatory bowel disease as well as current medication were assessed by interview. Inflammatory bowel disease patients with and without restless legs syndrome were matched for age, education, severity, and duration of their inflammatory bowel disease. RESULTS: Patients with inflammatory bowel disease and clinically relevant restless leg syndrome suffered significantly more frequent from sleep disturbances including sleep latency and duration, more fatigue, and worse health-related quality of life as compared to inflammatory bowel disease patients without restless legs syndrome. Affect and cognitive function including cognitive flexibility, attention, and concentration showed no significant differences among groups, indicating to be not related to restless legs syndrome. CONCLUSIONS: Sleep disorders including longer sleep latency, shorter sleep duration, and fatigue are characteristic symptoms of restless legs syndrome in inflammatory bowel disease patients, resulting in worse health-related quality of life. Therefore, clinicians treating patients with inflammatory bowel disease should be alert for restless legs syndrome.