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Abstract Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Abstract Background Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer’s disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay. Methods We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer’s-like pathology, synaptic transmission, and behavior. Results The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI. Conclusion In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

Abstract Breakdown of synthesis, excretion and detoxification defines liver failure. Post-hepatectomy liver failure (PHLF) is specific for liver resection and a rightfully feared complication due to high lethality and limited therapeutic success. Individual cytokine and growth factor profiles may represent potent predictive markers for recovery of liver function. We aimed to investigate these profiles in post-hepatectomy regeneration. This study combined a time-dependent cytokine and growth factor profiling dataset of a training (30 patients) and a validation (14 patients) cohorts undergoing major liver resection with statistical and predictive models identifying individual pathway signatures. 2319 associations were tested. Primary hepatocytes isolated from patient tissue samples were stimulated and their proliferation was analysed through DNA content assay. Common expression trajectories of cytokines and growth factors with strong correlation to PHLF, morbidity and mortality were identified despite highly individual perioperative dynamics. Especially, dynamics of EGF, HGF, and PLGF were associated with mortality. PLGF was additionally associated with PHLF and complications. A global association-network was calculated and validated to investigate interdependence of cytokines and growth factors with clinical attributes. Preoperative cytokine and growth factor signatures were identified allowing prediction of mortality following major liver resection by regression modelling. Proliferation analysis of corresponding primary human hepatocytes showed associations of individual regenerative potential with clinical outcome. Prediction of PHLF was possible on as early as first postoperative day (POD1) with AUC above 0.75. Prediction of PHLF and mortality is possible on POD1 with liquid-biopsy based risk profiling. Further utilization of these models would allow tailoring of interventional strategies according to individual profiles.

Abstract Background Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present. Main text A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto. Conclusion Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

Abstract Background The impact of hepatic resection for liver metastases (LM) on the survival of pediatric patients with Wilms’ tumor (WT) is unclear. So far, there is a lack of studies investigating the best suited treatment for patients with WTLM, and the role of liver resection has rarely been investigated. Thus, the development of evidence-based guidelines concerning indications of liver resection for WTLM remains difficult. Aim To investigate the role of surgery in the therapy of WTLM. All available data on liver resections and subgroup outcomes of patients with WTLM are analyzed. Main research question is whether liver resection improves survival rates of patients with WTLM compared to non-surgical treatment. Methods A systematic literature search of MEDLINE, Web of Science, and Central provided the basis for this PRISMA-compliant systematic review. For the main analysis (I), all studies reporting on surgical treatment of pediatric WTLM were included. To provide a representative overview of the general outcome of WTLM patients, in analysis II all studies with cohorts of at least five WTLM patients, regardless of the kind of treatment, were reviewed and analyzed. A Multiple meta-regression model was applied to investigate the impact liver resection on overall survival. Results 14 studies with reports of liver resection for WTLM were found (Analysis I). They included a total of 212 patients with WTLM, of which 93 underwent a liver resection. Most studies had a high risk of bias, and the quality was heterogenous. For the analysis II, eight studies with subgroups of at least five WTLM patients were found. The weighted mean overall survival (OS) of WTLM patients across the studies was 55% (SD 29). A higher rate of liver resection was a significant predictor of better OS in a multiple meta-regression model with 4 covariates (I2 29.43, coefficient 0.819, p = 0.038). Conclusions This is the first systematic review on WTLM. Given a lack of suited studies that specifically investigated WTLM, ecological bias was high in our analyses. Generating evidence is complicated in rare pediatric conditions and this study must be viewed in this context. Meta-regression analyses suggest that liver resection may improve survival of patients with WTLM compared to non-surgical treatment. Especially patients with persisting disease after neoadjuvant chemotherapy but also patients with metachronous LM seem to benefit from resection. Complete resection of LM is vital to achieve higher OS. Studies that prospectively investigate the impact of surgery on survival compared to non-surgical treatment for WTLM are highly needed to further close the current evidence gap. Study Registration PROSPERO 2021 CRD42021249763 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249763 .

Abstract Background Metabolic syndrome (MetS) is a risk factor in surgery. MetS can progress to metabolic (dysfunction)-associated fatty liver disease (MAFLD), a vast-growing etiology of primary liver tumors which are major indications for liver surgery. The aim of this meta-analysis was to investigate the impact of MetS on complications and long-term outcomes after hepatectomy. Methods The protocol for this meta-analysis was registered at PROSPERO prior to data extraction. MEDLINE, Web of Science, and Cochrane Library were searched for publications on liver resections and MetS. Comparative studies were included. Outcomes encompassed postoperative complications, mortality, and long-term oncologic status. Data were pooled as odds ratio (OR) with a random-effects model. Risk of bias was assessed using the Quality in Prognostic Studies tool (QUIPS), and the certainty of the evidence was evaluated with GRADE. Subgroup analyses for patients with histopathologically confirmed non-alcoholic fatty liver disease (NAFLD) versus controls were performed. Results The meta-analyses included fifteen comparative studies. Patients with MetS suffered significantly more overall complications (OR 1.55; 95% CI [1.05; 2.29]; p=0.03), major complications (OR 1.97 95% CI [1.13; 3.43]; p=0.02; I 2=62%), postoperative hemorrhages (OR 1.76; 95% CI [1.23; 2.50]; p=0.01) and infections (OR 1.63; 95% CI [1.03; 2.57]; p=0.04). There were no significant differences in mortality, recurrence, 1- or 5-year overall or recurrence-free survivals. Patients with histologically confirmed NAFLD did not have significantly more overall complications; however, PHLF rates were increased (OR 4.87; 95% CI [1.22; 19.47]; p=0.04). Recurrence and survival outcomes did not differ significantly. The certainty of the evidence for each outcome ranged from low to very low. Conclusion Patients with MetS that undergo liver surgery suffer more complications, such as postoperative hemorrhage and infection but not liver-specific complications—PHLF and biliary leakage. Histologically confirmed NAFLD is associated with significantly higher PHLF rates, yet, survivals of these patients are similar to patients without the MetS. Further studies should focus on identifying the tipping point for increased risk in patients with MetS-associated liver disease, as well as reliable markers of MAFLD stages and early markers of PHLF. Trial registration PROSPERO Nr: CRD42021253768

Understanding how different Black and other racially minoritised communities thrive is an emerging priority area in mental health promotion. Literature demonstrates health benefits of social capital (social resources embedded within social networks). However, its effects are not always positive, particularly for certain subpopulations who are already disadvantaged.The CONtributions of social NEtworks to Community Thriving (CONNECT) study will use Participatory Action Research (PAR) to investigate social capital as a resource that benefits (or hinders) racially minoritised communities and their mental health. The CONNECT study was designed within a partnership with community organisations and responds to local policy in two South-East London Boroughs, thereby providing potential channels for the action component of PAR. Taking an anti-racism lens, we acknowledge the underpinning role of racism in creating health inequities. We apply an intersectional framework to be considerate of overlapping forms of oppression such as age, gender, socioeconomic status, and sexual orientation as an essential part of developing effective strategies to tackle health inequities. Key components of this mixed methods PAR study include (1) involving racialised minority community members as peer researchers in the team (2) collecting and analysing primary qualitative data via interviews, photovoice, and community mapping workshops, (3) developing relevant research questions guided by peer researchers and collaborating organisations and analysing secondary quantitative data accordingly, (4) integrating qualitative and quantitative phases, and (5) working closely with community and policy partners to act on our findings and use our research for social change.The PAR approach will allow us to engage community (voluntary sector and government) and academic partners in decision making and help address imbalances in power and resource allocation. Knowledge generated through this collaborative approach will contribute to existing community initiatives, policies, and council strategies. This will ensure the views and experiences of racially minoritised communities drive the changes we are collaboratively committed to achieving.

Objectives:. To compare the outcomes of modified-Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) techniques with those of conventional-ALPPS. Background:. ALPPS is an established technique for treating advanced liver tumors. Methods:. PubMed, Web of Science, and Cochrane databases were searched. The outcomes were assessed by single-arm and 2-arm analyses. Results:. Seventeen studies containing 335 modified-ALPPS patients were included in single-arm meta-analysis. The estimated blood loss was 267 ± 29 mL (95% confidence interval [CI], 210–324 mL) during the first and 662 ± 51 mL (95% CI, 562–762 mL) during the second stage. The operation time was 166 ± 18 minutes (95% CI, 131–202 minutes) during the first and 225 ± 19 minutes (95% CI, 188–263 minutes) during the second stage. The major morbidity rate was 14% (95% CI, 9%–22%) after the first stage. The future liver remnant hypertrophy rate was 65.2% ± 5% (95% CI, 55%–75%) and the interstage interval was 16 ± 1 days (95% CI, 14–17 days). The dropout rate was 9% (95% CI, 5%–15%). The overall complication rate was 46% (95% CI, 37%–56%) and the major complication rate was 20% (95% CI, 14%–26%). The postoperative mortality rate was 7% (95% CI, 4%–11%). Seven studies containing 215 patients were included in comparative analysis. The hypertrophy rate was not different between 2 methods (mean difference [MD], –5.01; 95% CI, –19.16 to 9.14; P = 0.49). The interstage interval was shorter for partial-ALPPS (MD, 9.43; 95% CI, 3.29–15.58; P = 0.003). The overall complication rate (odds ratio [OR], 10.10; 95% CI, 2.11–48.35; P = 0.004) and mortality rate (OR, 3.74; 95% CI, 1.36–10.26; P = 0.01) were higher in the conventional-ALPPS. Conclusions:. The hypertrophy rate in partial-ALPPS was similar to conventional-ALPPS. This shows that minimizing the first stage of the operation does not affect hypertrophy. Moreover, the postoperative overall morbidity and mortality rates were lower following partial-ALPPS.

Abstract The pathophysiology of post-hepatectomy liver failure is not entirely understood but is rooted in the disruption of normal hepatocyte regeneration and homeostasis. Current investigations of post-hepatectomy liver failure and regeneration are focused on evaluation of circulating hepatic function parameters (transaminases, cholestasis, and coagulation parameters), volumetry and hepatic hemodynamics. However, identification of biochemical factors associated with regeneration and post hepatectomy liver failure is crucial for understanding the pathophysiology and identification of patients at risk. The objective of the present systematic review was to identify circulating factors associated with liver regeneration and post hepatectomy liver failure in patients undergoing hepatectomy. The quantitative analysis was intended if studies provided sufficient data. Electronic databases (MEDLINE via PubMed, Web of Knowledge, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on cell signaling factors in liver regeneration and post-hepatectomy liver failure following liver resection in clinical setting. No date restriction was given. No language restriction was used. Studies were assessed using MINORS. This study was registered at PROSPERO (CRD42020165384) prior to data extraction. In total 1953 publications were evaluated for titles and abstracts after exclusion of duplicates. Full texts of 167 studies were further evaluated for inclusion. 26 articles were included in the review and 6 publications were included in the meta-analyses. High levels of serum hyaluronic acid even preoperatively are associated with PHLF but especially increased levels early after resection are predictive of PHLF with high sensitivity and specificity. Postoperative elevation of HA to levels between 100 and 500 ng/ml is increased the risk for PHLF ([OR] = 246.28, 95% [CI]: 11.82 to 5131.83; p = 0.0004) Inteleukin-6 levels show contradicting result in association with organ dysfunction. HGF positively correlates with liver regeneration. Overall, due to heterogeneity, scarcity, observational study design and largely retrospective analysis, the certainty of evidence, assessed with GRADE, is very low. High levels of serum hyaluronic acid show a strong association with PHLF and increased levels after resection are predictive of PHLF with high sensitivity and specificity, even on POD1. Interleukin-6 levels need to be studied further due to contradictive results in association with organ dysfunction. For HGF, no quantitative analysis could be made. Yet, most studies find positive correlation between high HGF levels and regeneration. Prospective studies investigating HGF and other growth factors, hyaluronic acid and interleukins 1 and 6 in correlation with liver regeneration measured sequentially through e.g. volumetry, and liver function parameters, preferably expanding the analysis to include dynamic liver function tests, are needed to sufficiently illustrate the connection between biomolecule levels and clinical outcomes.

Introduction Surgical site infections (SSIs) are among the most common complications after abdominal surgery and develop in approximately 20% of patients. These patients suffer a 12% increase in mortality, underlying the need for strategies reducing SSI. Perioperative antibiotic prophylaxis is paramount for SSI prevention in major abdominal surgery. Yet, intraoperative redosing criteria are subjective and whether patients benefit from it remains unclear.Methods and analysis The REpeat versus SIngle ShoT Antibiotic prophylaxis in major Abdominal Surgery (RESISTAAS I) study is a single-centre, prospective, observational study investigating redosing of antibiotic prophylaxis in 300 patients undergoing major abdominal surgery. Adult patients scheduled for major abdominal surgery will be included. Current practice of redosing regarding number and time period will be recorded. Postoperative SSIs, nosocomial infections, clinically relevant infection-associated bacteria, postoperative antibiotic treatment, in addition to other clinical, pharmacological and economical outcomes will be evaluated. Differences between groups will be analysed with analysis of covariance.Ethics and dissemination RESISTAAS I will be conducted in accordance with the Declaration of Helsinki and internal, national and international standards of GCP. The Medical Ethics Review Board of Heidelberg University has approved the study prior to initiation (S-404/2021). The study has been registered on 7 February 2022 at German Clinical Trials Register, with identifier DRKS00027892. We plan to disseminate the results of the study in a peer-reviewed journal.Trial registration German Clinical Trials Register (DRKS): DRKS00027892.

Abstract Prophylactic drainage after major liver resection remains controversial. This systematic review and meta-analysis evaluate the value of prophylactic drainage after major liver resection. PubMed, Web of Science, and Cochrane Central were searched. Postoperative bile leak, bleeding, interventional drainage, wound infection, total complications, and length of hospital stay were the outcomes of interest. Dichotomous outcomes were presented as odds ratios (OR) and for continuous outcomes, weighted mean differences (MDs) were computed by the inverse variance method. Summary effect measures are presented together with their corresponding 95% confidence intervals (CI). The certainty of evidence was evaluated using the Grades of Research, Assessment, Development and Evaluation (GRADE) approach, which was mostly moderate for evaluated outcomes. Three randomized controlled trials and five non-randomized trials including 5,050 patients were included. Bile leakage rate was higher in the drain group (OR: 2.32; 95% CI 1.18–4.55; p = 0.01) and interventional drains were inserted more frequently in this group (OR: 1.53; 95% CI 1.11–2.10; p = 0.009). Total complications were higher (OR: 1.71; 95% CI 1.45–2.03; p

BackgroundTechniques to increase the future liver remnant (FLR) have fundamentally changed the indications and criteria of resectability in adult liver surgery. In pediatric patients however, these procedures have rarely been applied and the potential benefit or harm as well as suited indications are unclear.MethodsA systematic literature search of MEDLINE, Web of Science, and CENTRAL was conducted. Based on a PRISMA-compliant, predefined methodology, all studies reporting pediatric patients (< 18y) undergoing liver resection with either associating liver partition and portal vein ligation for stages hepatectomy (ALPPS) or preoperative portal vein embolization or ligation (PVE/PVL) were included. Baseline data, periinterventional morbidity, increase of FLR and outcomes were analyzed.Results15 studies reporting on 21 pediatric patients with a mean age of 4 years and 7 months (range 1.8 months – 17 years) were included. 12 ALPPS procedures, 8 PVE and 1 PVL were performed. The applied criteria for performing ALPPS or PVE were heterogenous and thresholds for minimally acceptable FLR varied. Mean FLR [% of total liver volume] before the intervention was 23.6% (range 15.0 – 39.3%) in the ALPPS group and 31.4% (range 21.5 – 56.0%) in the PVE group. Mean increase of FLR before stage 2 resection was 69.4% (range 19.0 – 103.8%) for ALPPS and 62.8% (range 25.0 – 108.0%) after PVE. No postoperative death occurred, one early intrahepatic recurrence after an ALPPS procedure was reported. Overall postoperative morbidity was 23.8%.ConclusionValidated criteria for minimal FLR in pediatric liver resection are lacking and so are clear indications for ALPPS or PVE. In special cases, ALPPS and PVE can be valuable techniques to achieve complete resection of pediatric liver tumors. However, more data are needed, and future studies should focus on a definition and validation of posthepatectomy liver failure as well as the minimally needed FLR in pediatric patients undergoing extended hepatectomy.Systematic Review Registration[www.clinicaltrials.gov], identifier [PROSPERO 2021 CRD42021274848].

Abstract Background Patient-related risk factors such as diabetes mellitus and obesity are increasing in western countries. At the same time the indications for liver resection in both benign and malignant diseases have been significantly extended in recent years. Major liver resection is performed more frequently in a patient population of old age, comorbidity and high rates of neoadjuvant chemotherapy. The aim of this study was to evaluate whether diabetes mellitus, obesity and overweight are risk factors for the short-term post-operative outcome after major liver resection. Methods Four hundred seventeen major liver resections (≥ 3 segments) were selected from a prospective database. Exclusion criteria were prior liver resection in patient’s history and synchronous major intra-abdominal procedures. Overweight was defined as BMI ≥ 25 kg/m2 and

Abstract Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNα signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model‐based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNα dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNα leads to a dose‐dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient‐specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient‐specific pathway desensitization, while the abundance of STAT2 predicts the patient‐specific IFNα signal response.

Abstract Background Clinicopathological features and surgical outcomes of patients with fibrolamellar hepatocellular carcinoma (FL-HCC) are underreported. The aim of this study is to describe clinical characteristics and surgical outcomes for patients with this rare tumor to raise awareness among clinicians and surgeons. Methods Retrospective review of records of a tertiary referral center and specialized liver unit was performed. Out of 3623 patients who underwent liver resection, 366 patients received surgical treatment for HCC; of them, eight (2.2%) had FL-HCC and were resected between October 2001 and December 2018. Results Eight patients (3 males and 5 females) with FL-HCC (median age 26 years) underwent primary surgical treatment. All patients presented with unspecific symptoms or were diagnosed as incidental finding. No patient had cirrhosis or other underlying liver diseases. Coincidentally, three patients (37.5%) had a thromboembolic event prior to admission. The majority of patients had BCLC stage C and UICC stage IIIB/IVA; four patients (50%) presented with lymph node metastases. The median follow-up period was 33.5 months. The 1-year survival was 71.4%, and 3-year survival was 57.1%. Median survival was at 36.4 months. Five patients (62.5%) developed recurrent disease after a median disease-free survival of 9 months. Two patients (25.0%) received re-resection. Conclusion FL-HCC is a rare differential diagnosis of liver masses in young patients. Since the prognosis is limited, patients with incidental liver tumors or lesions with suspicious features in an otherwise healthy liver should be presented at a specialized hepatobiliary unit. Thromboembolism might be an early paraneoplastic symptom and needs to be elucidated further in the context of FL-HCC.

Abstract Background Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. Methods MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. Results Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. Conclusion High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual’s regenerative potential in the future.

Abstract Background Indications for liver surgery are expanding fast and complexity of procedures increases. Preoperative mortality risk assessment by scoring systems is debatable. A previously published externally validated Mortality Risk Score allowed easy applicable and precise prediction of postoperative mortality. Aim of the study was to compare the performance of the Mortality Risk Score with the standard scores MELD and P-POSSUM. Methods Data of 529 patients undergoing liver resection were analysed. Mortality Risk Score, the labMELD Score and the P-POSSUM Scores (PS, OS, P-POSSUM mortality %) were calculated. The ROC curves of the three scoring systems were computed and the areas under the curve (C-index) were calculated using logistic regression models. Comparisons between the ROC curves were performed using the corresponding Wald tests. Results Internal validation confirmed that the risk model was predictive for a 90-day mortality rate with a C-index of 0.8421. The labMELD Score had a C-index of 0.7352 and the P-POSSUM system 0.6795 (PS 0.6953, OS 0.5413). The 90-day mortality rate increased with increasing labMELD values (p

Exergames have the potential to be used as motivating physical training tools. Numerous studies are currently available that investigate the effects of physical training with Exergames. However, most studies focus on specific training effects or specific target groups. A comprehensive summary of conditioning, coordinative and sports skill related training effects with Exergames in healthy adults is still missing. This contribution presents the protocol for a systematic review that aims to: a) summarize absolute and relative effects of training with Exergames on physical indicators and motivation compared to no or conventional training; b) identify possible mediators and moderators for varying training responses; c) identify gaps in the current evidence related to Exergame-based training.

Background: Choice of the fraction of inspiratory oxygen (FiO2) is controversial. The objective of this analysis was to evaluate whether intraoperative FiO2 was associated with recurrence-free survival after elective cancer surgery.Methods and Analysis: In this single-center, retrospective study, we analyzed 1,084 patients undergoing elective resection of pancreatic (n = 652), colorectal (n = 405), or hepatic cancer (n = 27) at Heidelberg University Hospital between 2009 and 2016. Intraoperative mean FiO2 values were calculated. For unstratified analyses, the study cohort was equally divided into a low- and a high-FiO2 group. For cancer-stratified analyses, this division was done within cancer-strata. The primary outcome measure was recurrence-free survival until the last known follow-up. Groups were compared using Kaplan–Meier analysis. A stratified log rank test was used to control for different FiO2 levels and survival times between the cancer strata. Cox-regression analyses were used to control for covariates. Sepsis, reoperations, surgical-site infections, and cardiovascular events during hospital stay and overall survival were secondary outcomes.Results: Median FiO2 was 40.9% (Q1–Q3, 38.3–42.9) in the low vs. 50.4% (Q1–Q3, 47.4–54.7) in the high-FiO2 group. Median follow-up was 3.28 (Q1–Q3, 1.68–4.97) years. Recurrence-free survival was considerable higher in the high-FiO2 group (p < 0.001). This effect was also confirmed when stratified for the different tumor entities (p = 0.007). In colorectal cancer surgery, increased FiO2 was independently associated with increased recurrence-free survival. The hazard for the primary outcome decreased by 3.5% with every 1% increase in FiO2. The effect was not seen in pancreatic cancer surgery and we did not find differences in any of the secondary endpoints.Conclusions: Until definite evidence from large-scale trials is available and in the absence of relevant clinical conditions warranting specific FiO2 values, perioperative care givers should aim for an intraoperative FiO2 of 50% in abdominal cancer surgery as this might benefit oncological outcomes.

BackgroundThe biliary tree is a rare location of pediatric rhabdomyosarcoma. Due to the low incidence, there is a lack of evidence concerning therapeutic guidelines for this tumor location. In particular, the impact of surgery is discussed controversially.PurposeObjective is to generate evidence-based treatment guidelines for pediatric biliary rhabdomyosarcoma (BRMS). All available published data on therapeutic regimens and important prognostic factors are investigated with a focus on the role of surgery.MethodsA systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed. Patient data were entered individually. Data was pooled and qualitative and quantitative analyses of demographic data, therapy, postoperative/interventional outcomes, relapse, and survival were conducted. In an individual patient data analysis, cox regression was applied to identify key factors predicting the outcome of patients with BRMS.Results65 studies met the inclusion criteria, providing data on 176 patients with BRMS. Individual patient data analysis showed a 5-year overall survival and progression-free survival of 51% and 50% for the total study population. For patients treated after 2000, 5-year OS and PFS was 65% and 59%, respectively. Absence of surgical tumor resection was an independent risk factor for death (Hazard ratio 8.9, 95%-CI 1.8-43.6, p = 0.007) and significantly associated with recurrent disease and disease-related death.ConclusionThis analysis provides comprehensive information on the largest number of patients hitherto reported in the literature. BRMS is still associated with high morbidity and mortality. Surgical tumor resection is essential for appropriate oncological treatment of BRMS. International cooperation studies are needed to enhance evidence and improve the outcome of this orphan disease.Protocol RegistrationPROSPERO (CRD42021228911) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228911.

Purpose: To establish comparable reporting of surgical results in pediatric liver surgery, the recently introduced composite outcome measures Textbook Outcome (TO) and Comprehensive Complication Index (CCI) are applied and validated in a pediatric surgery context for the first time. In a representative cohort of pediatric patients undergoing liver resection, predictive factors for TO and CCI are investigated, and outcomes are compared to available literature on surgical outcomes of pediatric liver resection.Methods: All liver resections for patients under 21 years of age performed at the Department of General, Visceral, Transplantation and Pediatric Surgery of the University of Heidelberg between 2009 and 2020 were included in the analysis. Criteria for TO were defined prior to the analysis. Univariate and Multivariate regression was applied to identify factors associated with TO and CCI.Results: Fifty-three pediatric patients underwent liver resections during the observation period. No 30- or 90-day mortality occurred. Twenty-three patients (43.4%) had a TO. CCI and TO showed highly significant correlation (b = −30.33, 95% CI [−37.44; −23.22], p < 0.001). Multivariate analyses revealed significant association between intraoperative blood loss (adjusted for circulating blood volume) and CCI (b = 0.70, 95%CI [0.22; 1.32], p = 0.008) and failure to achieve TO (OR = 0.85, 95%CI [0.69; 0.97], p = 0.048).Conclusion: TO and CCI are suited outcome measures in pediatric surgical studies and offer objective comparability of results. Their application in clinical studies will be a major step forward to establish evidence-based therapies in pediatric surgery. Systematic utilization of TO and CCI can aid in generating comparable studies on surgical techniques and outcomes in pediatric liver resection.

Abstract Background Hepatoblastoma is a rare disease that nevertheless accounts for the majority of liver malignancies in children. Due to limited epidemiological data, therapy for hepatoblastoma tends to be individualized. This study aimed to evaluate incidence trends of hepatoblastoma and to develop a nomogram to predict the survival of children with newly diagnosed hepatoblastoma on a population-based level. Methods Individuals up to 18 years of age with hepatoblastoma recorded in 18 registries of the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2015 were examined. Joinpoint regression analyses were applied to assess incidence trends in annual percentage change (APC). Multivariable Cox regression was used to identify factors associated with overall survival (OS). A nomogram was constructed to predict OS in individual cases based on independent predictors. Concordance index (C-index) and calibration curves were used to evaluate predictive performance. Results Between 2004 and 2015, hepatoblastoma incidence increased significantly (APC, 2.2%; 95% confidence interval [CI] 0.5% to 3.8%, P

ObjectiveThe utilization of fluorescein-guided biopsies and resection has been recently discussed as a suitable strategy to improve and expedite operative techniques for the resection of central nervous system (CNS) tumors. However, little is known about the optical properties of sodium fluorescein (NaFl) in human tumor tissue and their potential impact on ex vivo analyses involving fluorescence-based methods.MethodsTumor tissue was obtained from a study cohort of an observational study on the utilization of fluorescein-guided biopsy and resection (n=5). The optical properties of fluorescein-stained tissue were compared to the optical features of the dye in vitro and in control samples consisting of tumor tissue of high-grade glioma patients (n=3) without intravenous (i.v.) application of NaFl. The dye-exposed tumor tissues were used for optical measurements to confirm the detectability of NaFl emission ex vivo. The tissue samples were fixed in 4%PFA, immersed in 30% sucrose, embedded in Tissue-Tek OCT compound, and cut to 10 μm cryosections. Spatially resolved emission spectra from tumor samples were recorded on representative slides with a Confocal Laser Scanning Microscope FV1000 (Olympus GmbH, Hamburg, Germany) upon excitation with λexc = 488 nm.ResultsOptical measurements of fluorescein in 0.9% sodium chloride (NaCl) under in vitro conditions showed an absorption maximum of λmax abs = 479 nm as detected with spectrophotometer Specord 200 and an emission peak at λmax em = 538 nm recorded with the emCCD detection system of a custom-made microscope-based single particle setup using a 500 nm long-pass filter. Further measurements revealed pH- and concentration-dependent emission spectra of NaFl. Under ex vivo conditions, confocal laser scanning microscopy of fluorescein tumor samples revealed a slight bathochromic shift and a broadening of the emission band.ConclusionTumor uptake of NaFl leads to changes in the optical properties – a bathochromic shift and broadening of the emission band – possibly caused by the dye’s high pH sensitivity and concentration-dependent reabsorption acting as an inner filter of the dye’s emission, particularly in the short wavelength region of the emission spectrum where absorption and fluorescence overlap. Understanding the ex vivo optical properties of fluorescein is crucial for testing and validating its further applicability as an optical probe for intravital microscopy, immunofluorescence localization studies, and flow cytometry analysis.

BackgroundIn patients with hepatic cystic echinococcosis (CE), treatment effectiveness, outcomes, complications, and recurrence rate are controversial. Endocystectomy is a conservative surgical approach that adequately removes cyst contents without loss of parenchyma. This conservative procedure has been modified in several ways to prevent complications and to improve surgical outcomes. This systematic review aimed to evaluate the intraoperative and postoperative complications of endocysectomy for hepatic CE as well as the hepatic CE recurrence rate following endocystectomy.MethodsA systematic search was made for all studies reporting endocystectomy to manage hepatic CE in PubMed, Web of Science, and Cochrane CENTRAL databases. Study quality was assessed using the methodological index for non-randomized studies (MINORS) criteria and the Cochrane revised tool to assess risk of bias in randomized trials (RoB2). The random-effects model was used for meta-analysis and the arscine-transformed proportions were used to determine complication-, mortality-, and recurrence rates. This study is registered with PROSPERO (number CRD42020181732).ResultsOf 3,930 retrieved articles, 54 studies reporting on 4,058 patients were included. Among studies reporting preoperative anthelmintic treatment (31 studies), albendazole was administered in all of them. Complications were reported in 19.4% (95% CI: 15.9-23.2; I2 = 84%; p-value ConclusionEndocystectomy is a conservative and feasible surgical approach. Despite previous disencouraging experiences, our results suggest that endocystectomy is associated with low mortality and recurrence.

Background: Tamoxifen-adapted MCF-7-Tam cells represent an in-vitro model for acquired tamoxifen resistance, which is still a problem in clinics. We here investigated the correlation of microRNA-, mRNA- and eukaryotic initiation factors (eIFs) expression in this model. Methods: MicroRNA- and gene expression were analyzed by nCounter and qRT-PCR technology; eIFs by Western blotting. Protein translation mode was determined using a reporter gene assay. Cells were transfected with a miR-1972-mimic. Results: miR-181b-5p,-3p and miR-455-5p were up-, miR-375, and miR-1972 down-regulated and are significant in survival analysis. About 5% of the predicted target genes were significantly altered. Pathway enrichment analysis suggested a contribution of the FoxO1 pathway. The ratio of polio-IRES driven to cap-dependent protein translation shifted towards cap-dependent initiation. Protein expression of eIF2A, -4G, -4H and -6 decreased, whereas eIF3H was higher in MCF-7-Tam. Significant correlations between tamoxifen-regulated miRNAs and eIFs were found in representative breast cancer cell lines. Transfection with a miR-1972-mimic reverses tamoxifen-induced expression for a subset of genes and increased proliferation in MCF-7, but reduced proliferation in MCF-7-Tam, especially in the presence of 4OH-tamoxifen. Migration was inhibited in MCF-7-Tam cells. Translation mode remained unaffected. Conclusions: miR-1972 contributes to the orchestration of gene-expression and physiological consequences of tamoxifen adaption.

Background: Prophylactic antibiotics are frequently administered after major abdominal surgery including hepatectomies aiming to prevent infective complications. Yet, excessive use of antibiotics increases resistance in bacteria. The aim of this systematic review and meta-analysis is to assess the efficacy of prophylactic antibiotics after hepatectomy (postoperative antibiotic prophylaxis, POA). Method: This systematic review and meta-analysis were completed according to the current PRISMA guidelines. The protocol has been registered prior to data extraction (PROSPERO registration Nr: CRD42021288510). MEDLINE, Web of Science and CENTRAL were searched for clinical reports on POA in hepatectomy restrictions. A random-effects model was used for synthesis. Methodological quality was assessed with RoB2 and ROBINS-I. GRADE was used for the quality of evidence assessment. Results: Nine comparative studies comprising 2987 patients were identified: six randomized controlled trials (RCTs) and three retrospectives. POA did not lead to a reduction in postoperative infective complications or have an effect on liver-specific complications—post-hepatectomy liver failure and biliary leaks. POA over four or more days was associated with increased rates of deep surgical site infections compared to short-term administration for up to two days (OR 1.54; 95% CI [1.17;2.03]; p = 0.03). Routine POA led to significantly higher MRSA incidence as a pathogen (p = 0.0073). Overall, the risk of bias in the studies was low and the quality of evidence moderate. Conclusion: Routine POA cannot be recommended after hepatectomy since it does not reduce postoperative infection or liver-specific complications but contributes to resistance in bacteria. Studies into individualized risk-adapted antibiotic prophylaxis strategies are needed to further optimize perioperative treatment in liver surgery.

Abstract Background Delirium affects 25% of older inpatients and is associated with long-term cognitive impairment and future dementia. However, no population studies have systematically ascertained cognitive function before, cognitive deficits during, and cognitive impairment after delirium. Therefore, there is a need to address the following question: does delirium, and its features (including severity, duration, and presumed aetiologies), predict long-term cognitive impairment, independent of cognitive impairment at baseline? Methods The Delirium and Population Health Informatics Cohort (DELPHIC) study is an observational population-based cohort study based in the London Borough of Camden. It is recruiting 2000 individuals aged ≥70 years and prospectively following them for two years, including daily ascertainment of all inpatient episodes for delirium. Daily inpatient assessments include the Memorial Delirium Assessment Scale, the Observational Scale for Level of Arousal, and the Hierarchical Assessment of Balance and Mobility. Data on delirium aetiology is also collected. The primary outcome is the change in the modified Telephone Interview for Cognitive Status at two years. Discussion DELPHIC is the first population sample to assess older persons before, during and after hospitalisation. The cumulative incidence of delirium in the general population aged ≥70 will be described. DELPHIC offers the opportunity to quantify the impact of delirium on cognitive and functional outcomes. Overall, DELPHIC will provide a real-time public health observatory whereby information from primary, secondary, intermediate and social care can be integrated to understand how acute illness is linked to health and social care outcomes.

Cleavage of double-stranded RNA is described as an evolutionary conserved host defense mechanism against viral infection. Small RNAs are the product and triggers of post transcriptional gene silencing events. Up until now, the relevance of this mechanism for SARS-CoV-2-directed immune responses remains elusive. Herein, we used high throughput sequencing to profile the plasma of active and convalescent COVID-19 patients for the presence of small circulating RNAs. The existence of SARS-CoV-2 derived small RNAs in plasma samples of mild and severe COVID-19 cases is described. Clusters of high siRNA abundance were discovered, homologous to the nsp2 3′-end and nsp4 virus sequence. Four virus-derived small RNA sequences have the size of human miRNAs, and a target search revealed candidate genes associated with ageusia and long COVID symptoms. These virus-derived small RNAs were detectable also after recovery from the disease. The additional analysis of circulating human miRNAs revealed differentially abundant miRNAs, discriminating mild from severe cases. A total of 29 miRNAs were reduced or absent in severe cases. Several of these are associated with JAK-STAT response and cytokine storm.

Introduction Liver resection is the only curative treatment for primary and secondary hepatic tumours. Improvements in perioperative preparation of patients and new surgical developments have made complex liver resections possible. However, small for size and flow syndrome (SFSF) is still a challenging issue, rendering patients inoperable and causing postoperative morbidity and mortality. Although the role of transhepatic flow in the postoperative outcome has been shown in small partial liver transplantation and experimental studies of SFSF, this has never been studied in the clinical setting following liver resection. The aim of this study is to systematically evaluate transhepatic flow changes following major liver resection and its correlation with postoperative outcomes.Methods and analysis The TransHEpatic FLOW (THEFLOW) study is a single-centre, non-interventional cohort study, and aims to enrol 50 patients undergoing major hepatectomy (defined as hemihepatectomy or extended hepatectomy based on the Brisbane classification) with or without prior chemotherapy. The portal venous flow, hepatic artery flow and portal venous pressure are measured before and after each resection. All patients are followed-up for 3 months after the operation. During each evaluation, standard clinical data, posthepatectomy liver failure and overall morbidity and mortality will be recorded. THEFLOW study was initiated on 25 March 2018 and is expected to progress for 2 years.Ethics and dissemination This protocol study received approval from the Ethics Committee of the University of Heidelberg (registration number: S576/2017). The results of this study will be published in a peer-reviewed journal, and will also be presented at medical meetings.Trial registration number NCT03762876.

BackgroundTwo surgical options are available for cystic echinococcosis (CE). The two principal approaches are radical (resection of the cyst) and conservative (evacuation of the cyst content and partial removal of the cyst capsule). Here, we describe a standardized endocystectomy technique for hepatic echinococcosis.Subjects and methodsTwenty-one patients (male/female: 4/3; median age: 28 years) with uncomplicated, isolated hepatic CE (cyst stages WHO CE1, 2, 3a, and 3b) that were treated with the standardized endocystectomy described in this paper. Before the operation and during the follow-up period (mean: 33.8 months, median: 24 months), patients underwent clinical and sonographical and/or magnetic resonance imaging assessment during regular visits managed by an interdisciplinary team.ResultsForty-seven cysts were treated with the standardized endocystectomy technique. The median number of cysts per patient was two (range: 1-8). Nine patients (43%) had a single cystic lesion. The median operation time was 165 minutes and the median intraoperative bleeding volume was 200 mL. The median hospital stay was nine days (range: 6-28 days). Morbidity (Clavien-Dindo III) occurred in four patients (19%). No mortality and no recurrence were found during the median follow-up time of 24 months.ConclusionsThe standardized endocystectomy technique presented is a safe procedure with acceptable morbidity, no mortality, and without recurrences in our patient series. Important components of our CE management are interdisciplinary patient care, adequate diagnostic work-ups, and regular pre- and postoperative visits, including long-term follow-up for early and reliable capture of recurrences.

Nucleoporins build the nuclear pore complex (NPC), which, as sole gate for nuclear-cytoplasmic exchange, is of outmost importance for normal cell function. Defects in the process of nucleocytoplasmic transport or in its machinery have been frequently described in human diseases, such as cancer and neurodegenerative disorders, but only in a few cases of developmental disorders. Here we report biallelic mutations in the nucleoporin NUP88 as a novel cause of lethal fetal akinesia deformation sequence (FADS) in two families. FADS comprises a spectrum of clinically and genetically heterogeneous disorders with congenital malformations related to impaired fetal movement. We show that genetic disruption of nup88 in zebrafish results in pleiotropic developmental defects reminiscent of those seen in affected human fetuses, including locomotor defects as well as defects at neuromuscular junctions. Phenotypic alterations become visible at distinct developmental stages, both in affected human fetuses and in zebrafish, whereas early stages of development are apparently normal. The zebrafish phenotypes caused by nup88 deficiency are rescued by expressing wild-type Nup88 but not the disease-linked mutant forms of Nup88. Furthermore, using human and mouse cell lines as well as immunohistochemistry on fetal muscle tissue, we demonstrate that NUP88 depletion affects rapsyn, a key regulator of the muscle nicotinic acetylcholine receptor at the neuromuscular junction. Together, our studies provide the first characterization of NUP88 in vertebrate development, expand our understanding of the molecular events causing FADS, and suggest that variants in NUP88 should be investigated in cases of FADS.

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs∗28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from Escherichia coli to Homo sapiens by glutamine. Protein modeling based on the known crystal structure of ASNS of E. coli predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs∗28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in ASNS.

The use of wearable devices or “wearables” in the physical activity domain has been increasing in the last years. These devices are used as training tools providing the user with detailed information about individual physiological responses and feedback to the physical training process. Advantages in sensor technology, miniaturization, energy consumption and processing power increased the usability of these wearables. Furthermore, available sensor technologies must be reliable, valid, and usable. Considering the variety of the existing sensors not all of them are suitable to be integrated in wearables. The application and development of wearables has to consider the characteristics of the physical training process to improve the effectiveness and efficiency as training tools. During physical training, it is essential to elicit individual optimal strain to evoke the desired adjustments to training. One important goal is to neither overstrain nor under challenge the user. Many wearables use heart rate as indicator for this individual strain. However, due to a variety of internal and external influencing factors, heart rate kinetics are highly variable making it difficult to control the stress eliciting individually optimal strain. For optimal training control it is essential to model and predict individual responses and adapt the external stress if necessary. Basis for this modeling is the valid and reliable recording of these individual responses. Depending on the heart rate kinetics and the obtained physiological data, different models and techniques are available that can be used for strain or training control. Aim of this review is to give an overview of measurement, prediction, and control of individual heart rate responses. Therefore, available sensor technologies measuring the individual heart rate responses are analyzed and approaches to model and predict these individual responses discussed. Additionally, the feasibility for wearables is analyzed.

Background. It is a novel idea that platelet counts may be associated with postoperative outcome following liver surgery. This may help in planning an extended hepatectomy (EH), which is a surgical procedure with high morbidity and mortality. Aim. The aim of this study was to evaluate the predictive potential of platelet counts on the outcome of EH in patients without portal hypertension, splenomegaly, or cirrhosis. Methods. A series of 213 consecutive patients underwent EH (resection of ≥ five liver segments) between 2001 and 2016. The association of preoperative platelet counts with posthepatectomy liver failure (PHLF), morbidity (based on Clavien-Dindo classification), and 30-day mortality was evaluated using multivariate analysis. Results. PHLF was detected in 26.3% of patients, major complications in 26.8%, and 30-day mortality in 11.3% of patients. Multivariate analysis revealed that the preoperative platelet count is an independent predictor of PHLF (odds ratio [OR] 4.4, 95% confidence interval [CI] 1.3–15.0, p=0.020) and 30-day mortality (OR 4.4, 95% CI 1.1–18.8, p=0.043). Conclusions. Preoperative platelet count is associated with PHLF and mortality following extended liver resection. This association was independent of other related parameters. Prospective studies are needed to evaluate the predictive role and to determine the impact of preoperative correction of platelet count on postoperative outcomes after EH.

Durante la Primera Guerra Mundial, la prensa europea fue un instrumento eficaz de propaganda. Más allá de manipular o desmentir noticias, de alentar a la población civil o de atemorizar al enemigo, por primera vez se trató de una prensa que fortaleció sistemáticamente la identificación nacional demonizando al enemigo. De este modo, formó parte de la maquinaria de propaganda moderna en la cual Jeismann constató una doble dinámica. En primer lugar, en el centro bélico, la prensa se caracterizó por su extremada hostilidad contra los valores universales de la historia europea. Al mismo tiempo, exportaba la guerra hacia otros continentes de tal manera que vinculaba y manipulaba los conflictos y aspiraciones de otras regiones y pueblos de modo tal que favorecieran al propio país. Así, los propagandistas de la guerra trataban de controlar y determinar la duración y la intensidad de la misma a través de la globalización del conflicto bélico (Jeismann 2004: 198-200). En este trabajo nos centraremos en la prensa germanoparlante en Buenos Aires durante la Primera Guerra Mundial.

The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.

The ability of cell penetrating peptides (CPPs) to deliver biologically relevant cargos into cells is becoming more important as targets in the intracellular space continue to be explored. We have developed two assays based on CPP-dependent, intracellular delivery of TEM-1 β-lactamase enzyme, a functional biological molecule comparable in size to many protein therapeutics. The first assay focuses on the delivery of full-length β-lactamase to evaluate the internalization potential of a CPP sequence. The second assay uses a split-protein system where one component of β-lactamase is constitutively expressed in the cytoplasm of a stable cell line and the other component is delivered by a CPP. The delivery of a split β-lactamase component evaluates the cytosolic delivery capacity of a CPP. We demonstrate that these assays are rapid, flexible and have potential for use with any cell type and CPP sequence. Both assays are validated using canonical and novel CPPs, with limits of detection from

The Tsw gene conferring dominant resistance to the Tospo-virus Tomato spotted wilt virus (TSWV) in Capsicum spp. has been tagged with a random amplified polymorphic DNA marker and mapped to the distal portion of chromosome 10. No mapped homologues of Sw-5, a phenotypically similar dominant TSWV resistance gene in tomato, map to this region in C. annuum, although a number of Sw-5 homologues are found at corresponding positions in pepper and tomato. The relationship between Tsw and Sw-5 was also examined through genetic studies of TSWV. The capacity of TSWV-A to overcome the Tsw gene in pepper and the Sw-5 gene in tomato maps to different TSWV genome segments. Therefore, despite phenotypic and genetic similarities of resistance in tomato and pepper, we infer that distinct viral gene products control the outcome of infection in plants carrying Sw-5 and Tsw, and that these loci do not appear to share a recent common evolutionary ancestor.

We describe a consanguineous Iraqi family in which affected siblings had mild mental retardation and congenital ataxia characterized by quadrupedal gait. Genome-wide linkage analysis identified a 5.8 Mb interval on chromosome 8q with shared homozygosity among the affected persons. Sequencing of genes contained in the interval revealed a homozygous mutation, S100P, in carbonic anhydrase related protein 8 (CA8), which is highly expressed in cerebellar Purkinje cells and influences inositol triphosphate (ITP) binding to its receptor ITPR1 on the endoplasmatic reticulum and thereby modulates calcium signaling. We demonstrate that the mutation S100P is associated with proteasome-mediated degradation, and thus presumably represents a null mutation comparable to the Ca8 mutation underlying the previously described waddles mouse, which exhibits ataxia and appendicular dystonia. CA8 thus represents the third locus that has been associated with quadrupedal gait in humans, in addition to the VLDLR locus and a locus at chromosome 17p. Our findings underline the importance of ITP-mediated signaling in cerebellar function and provide suggestive evidence that congenital ataxia paired with cerebral dysfunction may, together with unknown contextual factors during development, predispose to quadrupedal gait in humans.