Dengue Virus and Zika Virus Seroprevalence in the South Pacific Populations of the Cook Islands and Vanuatu.

Arboviral diseases are serious threats to global health with increasing prevalence and potentially severe complications. Significant arthropod-borne viruses are the dengue viruses (DENV 1-4), the Zika virus (ZIKV), and the chikungunya virus (CHIKV). Among the areas most affected is the South Pacific Region (SPR). Here, arboviruses not only cause a high local burden of disease, but the region has also proven to contribute to their global spread. Outpatient serum samples collected between 08/2016 and 04/2017 on three islands of the island states of Vanuatu and the Cook Islands were tested for anti-DENV- and anti-ZIKV-specific antibodies (IgG) using enzyme-linked immunosorbent assays (ELISA). ELISA test results showed 89% of all test sera from the Cook Islands and 85% of the Vanuatu samples to be positive for anti-DENV-specific antibodies. Anti-ZIKV antibodies were identified in 66% and 52%, respectively, of the test populations. Statistically significant differences in standardized immunity levels were found only at the intranational level. Our results show that in both the Cook Islands and Vanuatu, residents were exposed to significant Flavivirus transmission. Compared to other seroprevalence studies, the marked difference between ZIKV immunity levels and previously published CHIKV seroprevalence rates in our study populations is surprising. We propose the timing of ZIKV and CHIKV emergence in relation to recurrent DENV outbreaks and the impact of seasonality as explanatory external factors for this observation. Our data add to the knowledge of arboviral epidemics in the SPR and contribute to a better understanding of virus spread, including external conditions with potential influence on outbreak dynamics. These data may support preventive and rapid response measures in the affected areas, travel-related risk assessment, and infection identification in locals and returning travelers.

Confidence interval comparison: Precision of maximum likelihood estimates in LLOQ affected data.

When data is derived under a single or multiple lower limits of quantification (LLOQ), estimation of distribution parameters as well as precision of these estimates appear to be challenging, as the way to account for unquantifiable observations due to LLOQs needs particular attention. The aim of this investigation is to characterize the precision of censored sample maximum likelihood estimates of the mean for normal, exponential and Poisson distribution affected by one or two LLOQs using confidence intervals (CI). In a simulation study, asymptotic and bias-corrected accelerated bootstrap CIs for the location parameter mean are compared with respect to coverage proportion and interval width. To enable this examination, we derived analytical expressions of the maximum likelihood location parameter estimate for the assumption of exponentially and Poisson distributed data, where the censored sample method and simple imputation method are used to account for LLOQs. Additionally, we vary the proportion of observations below the LLOQs. When based on the censored sample estimate, the bootstrap CI led to higher coverage proportions and narrower interval width than the asymptotic CI. The results differed by underlying distribution. Under the assumption of normality, the CI's coverage proportion and width suffered most from high proportions of unquantifiable observations. For exponentially and Poisson distributed data, both CI approaches delivered similar results. To derive the CIs, the point estimates from the censored sample method are preferable, because the point estimate of the simple imputation method leads to higher bias for all investigated distributions. This biased simple imputation estimate impairs the coverage proportion of the respective CI. The bootstrap CI surpassed the asymptotic CIs with respect to coverage proportion for the investigated choice of distributional assumptions. The variety of distributions for which the methods are suitable gives the applicant a widely usable tool to handle LLOQ affected data with appropriate approaches.

Facial thermal response to non-painful stressor in premature and term neonates.

BACKGROUND: This study is a preliminary clinical investigation with the objective to evaluate the facial thermal response of premature and term neonates to a non-painful stressor (hunger) using infrared thermography (IRT). The development of objective and reliable parameters to monitor pain and stress is of relevance for optimal neonatal outcome and achieving a better management of patient comfort. METHODS: We enrolled 12 neonates ranging from 27 to 39 weeks gestation (median: 34) and aged 3-79 days (median: 13). Recordings were performed before and after feeding, with and without hunger. Six regions of interest were chosen for evaluation (nose tip, periorbital and corrugator region, forehead, perioral and chin region). RESULTS: There was an increase in the facial temperature in infants immediately prior to their next feed relative to infants who were not hungry, with the nasal tip being the facial evaluation site with the greatest temperature change. CONCLUSIONS: The IRT appears to be a feasible and suitable method to detect changes in the neonatal patient. The thermal variations observed seem to reflect an arousal mediated by the parasympathetic nervous system, which has been described in existing infant stress research. IMPACT: This is the first study to examine the use of infrared thermography (IRT) in monitoring the facial thermal response to a mild stressor (hunger) in premature and term neonates. Hunger as a mild, non-pain-associated stressor showed a significant effect on the facial temperature. The thermal signature of the regions of interest chosen showed hunger-related thermal variations. Results suggest the feasibility and suitability of IRT as an objective diagnostic tool to approach stress and changes in the condition of the neonatal patient.

Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights. METHODS: PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology. RESULTS: Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62-1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27-1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability. CONCLUSION: Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD. Registration number in Prospero: CRD42022311166.

Cardiovascular Risk Profiles and Pre-Existing Health Conditions of Trekkers in the Solu-Khumbu Region, Nepal.

BACKGROUND: High-altitude tourist trekking continues to grow in popularity on the Everest Trek in Nepal. We examined which pre-existing cardiovascular and health conditions these global trekkers had and what health issues they encountered during the trek, be it exacerbations of pre-existing conditions, or new acute ones. METHOD: Trekkers (n = 350) were recruited from guesthouses along the Everest Trek, mostly at Tengboche (3860 m). After completing a questionnaire on their health and travel preparation, they underwent a basic physical examination with an interview. RESULTS: Almost half (45%) had pre-existing conditions, mostly orthopaedic and cardiovascular diseases. The average age was 42.7 years (range 18-76). The average BMI was 23.4 kg/m2, but 21% were overweight. A third were smokers (30%), and 86% had at least one major cardiovascular risk factor. A quarter (25%) were suffering from manifest acute mountain sickness (AMS), and 72% had at least one symptom of AMS. Adequate pre-travel examination, consultation, and sufficient personal preparation were rarely found. In some cases, a distinct cardiovascular risk profile was assessed. Hypertensive patients showed moderately elevated blood pressure, and cholesterol levels were favourable in most cases. No cardiovascular emergencies were found, which was fortunate as timely, sufficient care was not available during the trek. CONCLUSION: The results of earlier studies in the Annapurna region should be revalidated. Every trekker to the Himalayas should consult a physician prior to departure, ideally a travel medicine specialist. Preventative measures and education on AMS warrant special attention. Travellers with heart disease or with a pronounced cardiovascular risk profile should be presented to an internal medicine professional. Travel plans must be adjusted individually, especially with respect to adequate acclimatisation time and no physical overloading. With these and other precautions, trekking at high altitudes is generally safe and possible, even with significant pre-existing health conditions. Trekking can lead to invaluable personal experiences. Since organized groups are limited in their flexibility to change their itinerary, individual trekking or guided tours in small groups should be preferred.

Chikungunya virus (CHIKV) seroprevalence in the South Pacific populations of the Cook Islands and Vanuatu with associated environmental and social factors.

BACKGROUND: Arthropod-borne diseases pose a significant and increasing risk to global health. Given its rapid dissemination, causing large-scale outbreaks with severe human infections and economic loss, the Chikungunya virus (CHIKV) is one of the most important arboviruses worldwide. Despite its significance, the real global impact of CHIKV remains underestimated as outbreak data are often incomplete and based solely on syndromic surveillance. During 2011-2016, the South Pacific Region was severely affected by several CHIKV-epidemics, yet the area is still underrepresented in arboviral research. METHODS: 465 outpatient serum samples collected between 08/2016 and 04/2017 on three islands of the island states Vanuatu (Espiritu Santo) and the Cook Islands (Rarotonga, Aitutaki) were tested for anti-CHIKV specific antibodies using Enzyme-linked immunosorbent Assays. RESULTS: A total of 30% (Cook Islands) and 8% (Vanuatu) of specimens were found positive for anti-CHIKV specific antibodies with major variations in national and intranational immunity levels. Seroprevalence throughout all age groups was relatively constant. Four potential outbreak-protective factors were identified by comparing the different study settings: presence of Ae. albopictus (in absence of ECSA E1-A226V-mutation CHIKV), as well as low levels of human population densities, residents' travel activity and tourism. CONCLUSION: This is the first seroprevalence study focussing on an arboviral disease in the Cook Islands and Vanuatu. It highlights the impact of the 2014/2015 CHIKV epidemic on the Cook Islands population and shows that a notable part of the Vanuatu test population was exposed to CHIKV although no outbreaks were reported. Our findings supplement the knowledge concerning CHIKV epidemics in the South Pacific Region and contribute to a better understanding of virus dissemination, including outbreak modifying factors. This study may support preventive and rapid response measures in affected areas, travel-related risk assessment and infection identification in returning travellers. TRIAL REGISTRATION: ClinicalTrials.gov Aachen: 051/16_09/05/2016 Cook Islands Ref.: #16-16 Vanuatu Ref.: MOH/DG 10/1/1-GKT/lr.

Equine-Assisted Therapies for Children With Cerebral Palsy: A Meta-analysis.

CONTEXT: Equine-assisted therapy in different facets aims to improve the clinical condition of children with cerebral palsy. A more comprehensive overview on the overall effects and on the differences between different treatment modalities seems desirable. OBJECTIVE: We compared the effectiveness of various equine-assisted treatments on motor capabilities and quality of life of children with cerebral palsy. DATA SOURCES: We conducted systematic searches of PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. STUDY SELECTION: Randomized and nonrandomized controlled parallel-group or crossover studies on equine-assisted therapies in comparison with standard of care were included. DATA EXTRACTION: Data on motor function assessed by different instruments were considered as the primary outcome. Secondary outcomes included global, social, physical, and emotional scores of quality of life. RESULTS: Strong evidence for a positive effect of equine-assisted therapies, particularly hippotherapy, on global gross motor function and motor capabilities during walking in children with cerebral palsy was identified (SMD 0.24, 95% CI 0.05 to 0.43, P = .01, t2 = 0.00, I2 = 15%; SMD 2.68, 95% CI 1.02 to 4.34, P = .002, t2 = 0.0, I2 = 0%). No evidence for the improvement in quality of life could be shown in the global assessment, nor in any subscore. CONCLUSIONS: Equine-assisted therapy, particularly hippotherapy, can be a therapeutic tool for children who are learning to walk. LIMITATION: The heterogeneity of tools used in different studies and the low number of studies addressing quality of life issues limited the number of studies available for distinct analyses.

Multimodal Treatment of Nasopharyngeal Carcinoma in Children, Adolescents and Young Adults-Extended Follow-Up of the NPC-2003-GPOH Study Cohort and Patients of the Interim Cohort.

Nasopharyngeal carcinoma (NPC) in children and young adults has been treated within two consecutive prospective trials in Germany, the NPC-91 and the NPC-2003 study of the German Society of Pediatric Oncology and Hematology (GPOH). In these studies, multimodal treatment with induction chemotherapy, followed by radio (chemo)therapy and interferon-beta maintenance, yielded promising survival rates even after adapting total radiation doses to tumor response. The outcome of 45 patients in the NPC-2003 study was reassessed after a median follow-up of 85 months. In addition, we analyzed 21 further patients after closure of the NPC-2003 study, recruited between 2011 and 2017, and treated as per the NPC-2003 study protocol. The EFS and OS of 66 patients with locoregionally advanced NPC were 93.6% and 96.7%, respectively, after a median follow-up of 73 months. Seven patients with CR after induction therapy received a reduced radiation dose of 54 Gy; none relapsed. In young patients with advanced locoregional NPC, excellent long-term survival rates can be achieved by multimodal treatment, including interferon-beta. Radiation doses may be reduced in patients with complete remission after induction chemotherapy and may limit radiogenic late effects.

mTICCS and its inter-rater reliability to predict the need for massive transfusion in severely injured patients.

PURPOSE: The modified Trauma-Induced Coagulopathy Clinical Score (mTICCS) presents a new scoring system for the early detection of the need for a massive transfusion (MT). This easily applicable score was validated in a large trauma cohort and proven comparable to more established complex scoring systems. However, the inter-rater reliability of the mTICCS has not yet been investigated. METHODS: Therefore, a dataset of 15 randomly selected and severely injured patients (ISS ≥ 16) derived from the database of a level I trauma centre (2010-2015) was used. Moreover, 15 severely injured subjects that received MT were chosen from the same databank. A web-based survey was sent to medical professionals working in the field of trauma care asking them to evaluate each patient using the mTICCS. RESULTS: In total, 16 raters (9 residents and 7 specialists) completed the survey. Ratings from 15 medical professionals could be evaluated and led to an ICC of 0.7587 (95% Bootstrap confidence interval (BCI) 0.7149-0.8283). A comparison of working experience specific ICC (n = 7 specialists, ICC: 0.7558, BCI: 0.7076-0.8270; n = 8 residents, ICC: 0.7634, BCI: 0.7183-0.8335) showed no significant difference between the two groups (p = 0.67). CONCLUSION: In summary, reliability values need to be considered when making clinical decisions based on scoring systems. Due to its easy applicability and its almost perfect inter-rater reliability, even with non-specialists, the mTICCS might therefore be a useful tool to predict the early need for MT in multiple trauma.

Influence of Clinical Expertise Between Clinician-Instructors Versus Student-Instructors on the Effectiveness of Ultrasound Courses.

PURPOSE: To investigate how the extent of an ultrasound instructor's clinical expertise influences the level of hands-on ultrasound competency achieved by clinicians after three-day ultrasound courses in abdominal and emergency ultrasound. The second goal was to determine how physicians in residency rate the sonographic and didactic skills of student instructors compared to medical staff instructors. METHOD: A total of N = 100 residents participating in a 3-day ultrasound workshop were randomly trained either by 15 student instructors or by clinical staff physicians, both with > 2 years of teaching experience. Both instructor groups had previously completed 120 hours of didactic instructor training. Ultrasound competencies were assessed by a standardized objective structured clinical examination (OSCE) of healthy individuals. The sonographic and didactic skills of both instructor groups were rated by questionnaires with six-step Likert items (1 = excellent, 6 = poor). RESULTS: The cohort, trained by student instructors, achieved the same scoring level as the second cohort, trained by physician instructors (mean score 76.4, versus 73.7 of max. 100 points, p = 0.28) in the final OSCE. The sonographic qualification was rated for student educators as 1.44 (mean) [1.1-1.62], versus residents 1.46 [1.26-1.61], versus attendings 1.29 [1.05-1.61]. Didactic skill levels were rated without significant differences with means of 1.53, 1.57 and 1.53, respectively. DISCUSSION & CONCLUSION: The didactic competence of student instructors does not differ statistically from the competency levels of experienced physicians. In terms of the acquired ultrasound skills of trainees, our data indicate that student instructors can be as efficient as staff instructors. Therefore, student instructors can be employed as resource-saving ultrasound educators without decreasing the skills level achieved by course participants, provided that they previously underwent a comprehensive didactic and sonographic training program.

Detection of acute ventilatory problems via magnetic induction in a newborn animal model.

BACKGROUND: Magnetic induction measurement (MIM) is a noninvasive method for the contactless registration of respiration in newborn piglets by using measurement coils positioned at the bottom of an incubator. Acute pulmonary problems may be determinants of poor neurological and psychomotor outcomes in preterm infants. The current study tested the detection of pulmonary ventilation disorders via MIM in 11 newborn piglets. METHODS: Six measurement coils determined changes in magnetic induction, depending on the ventilation of the lung, in comparison with flow resistance. Contactless registration of induced acute pulmonary ventilation disorders (apnea, atelectasis, pneumothorax, and aspiration) was detected by MIM. RESULTS: All pathologies except aspiration were detected by MIM. Significant changes occurred after induction of apnea (three coils), malposition of the tube (one coil), and pneumothorax (three coils) (p ≤ 0.05). No significant changes occurred after induction of aspiration (p = 0.12). CONCLUSIONS: MIM seems to have some potential to detect acute ventilation disorders in newborn piglets. The location of the measurement coil related to the animal's position plays a critical role in this process. In addition to an early detection of acute pulmonary problems, potential information pointing to a therapeutic intervention, for example, inhalations or medical respiratory analepsis, may be conceivable with MIM in the future. IMPACT: MIM seems to be a method in which noncontact ventilation disorders of premature and mature infants can be detected. This study is an extension of the experimental setup to obtain preliminary evidence for detection of respiratory activity in neonatal piglets. For the first time, MIM is used to register acute ventilation problems of neonates. The possibility of an early detection of acute ventilation problems via MIM may provide an opportunity to receive patient-side information for therapeutical interventions like inhalations or medical respiratory analepsis.

A roadmap to using randomization in clinical trials.

BACKGROUND: Randomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial. METHODS: We survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice. RESULTS: Restricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size. CONCLUSIONS: The choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.

Evaluation of the optimal cooling temperature for the face measured by the tissue perfusion during hilotherapy using laser Doppler spectrophotometry.

After craniofacial trauma, symptoms like swelling and pain occur. Cooling reduces these symptoms but the optimal cooling temperature for a maximum benefit without adverse effects is unclear. 30 participants were cooled at 10 °C, 15 °C, 20 °C, 25 °C and 30 °C for 30 min. Before cooling and at 15, 30, 45 and 60 min after cooling, the skin blood flow, oxygen saturation (SO) and haemoglobin concentration (Hb) were measured by laser Doppler spectrophotometry at 2 mm and 8 mm depth. The skin temperature was measured, and the participant's satisfaction was marked on a visual analogue scale. There were significant differences between males and females in the blood flow, SO and Hb (p < 0.0001). After cooling, the blood flow, SO and Hb was reduced. The measured values rose slightly above the initial values 60 min after cooling. Depending on the cooling temperature the decrease in blood flow, SO and Hb was significantly different. Both sexes were most comfortable with a 25 °C cooling temperature and satisfaction decreased with lower temperatures. Significant differences for the satisfaction between both sexes were measured (10 °C: p < 0.0001, 15 °C: p < 0.0001, 20 °C: p = 0.0168, 25 °C: p = 0.0293). After 60 min, the males and females exhibited mild skin hyperthermia. The optimal cooling temperatures their physiological effects and their perception for females and males were different. For females, around 20 °C is an optimal cooling temperature. For males, it is around 15-20 °C.

Nerve Fibers in the Tumor Microenvironment Are Co-Localized with Lymphoid Aggregates in Pancreatic Cancer.

B cells and tertiary lymphoid structures (TLS) are reported to be important in survival in cancer. Pancreatic Cancer (PDAC) is one of the most lethal cancer types, and currently, it is the seventh leading cause of cancer-related death worldwide. A better understanding of tumor biology is pivotal to improve clinical outcome. The desmoplastic stroma is a complex system in which crosstalk takes place between cancer-associated fibroblasts, immune cells and cancer cells. Indirect and direct cellular interactions within the tumor microenvironment (TME) drive key processes such as tumor progression, metastasis formation and treatment resistance. In order to understand the aggressiveness of PDAC and its resistance to therapeutics, the TME needs to be further unraveled. There are some limited data about the influence of nerve fibers on cancer progression. Here we show that small nerve fibers are located at lymphoid aggregates in PDAC. This unravels future pathways and has potential to improve clinical outcome by a rational development of new therapeutic strategies.

Gut microbiota and brain alterations in a translational anorexia nervosa rat model.

Anorexia nervosa (AN) is an eating disorder that leads to brain volume reduction and is difficult to treat since the underlying pathophysiology is poorly understood. The human gut microbiota is known to be involved in host metabolism, appetite- and bodyweight regulation, gut permeability, inflammation and gut-brain interactions. In this study, we used a translational activity-based anorexia (ABA) rat model including groups with food restriction, running-wheel access and a combination to disentangle the influences on the gut microbiota and associated changes in brain volume parameters. Our data demonstrated that chronic food restriction but not running-wheel activity had a major influence on the gut microbiota diversity and composition and reduced brain volume. Negative correlations were found between global brain weight and α-diversity, and astrocyte markers and relative abundances of the genera Odoribacter and Bifidobacterium. In contrast, the presence of lactobacilli was positively associated with white and grey brain matter volume. ABA and food-restricted rats are an interesting pre-clinical model to assess the causal influence of starvation on the gut microbiome and gut-brain interactions and can help to dissect the underlying pathophysiologic mechanisms relevant to AN.

Risk of postprocedural intracerebral hemorrhage in patients with ruptured cerebral aneurysms after treatment with antiplatelet agents.

OBJECTIVE: Endovascular treatment of ruptured cerebral aneurysms frequently requires antiplatelet medication to prevent thromboembolism. This might raise concern regarding the risk of postprocedural hemorrhage (pH), e.g. from placement of intracranial probes. We explored the risk of PH associated with standard antiplatelet therapy (sAP: acetylsalicylic acid, and/or clopidogrel) in the context of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We retrospectively reviewed a total of 146 consecutive cases with cerebral aneurysms treated between 1/2011-12/2015, and distinguished between minor (0.5 cm3) - 4 cm3) or major (> 4 cm3) PH occurring within four weeks after intervention. A separate analysis included hemorrhages related to placement of intracranial probes and drainages in the subgroup of 99 cases with such surgical interventions (pPH). Clinical outcome was assessed via Glasgow Outcome Scale (GOS) twelve months after aSAH. RESULTS: A total of 49 cases (33.6%) in the overall sample sustained PH, there were 19 cases of pPH. Multifactorial analyses yielded sAP as an independent predictor for minor, but not major PH (p < 0.001 vs. p = 0.829), with comparable results for pPH (p = 0.001 vs. p = 0.184). sAP did not influence the clinical outcome in either group. CONCLUSIONS: sAP was associated with a higher rate of minor PH and, more specifically, of minor pPH. However, it was neither accompanied by the occurrence of major hemorrhages nor by unfavorable clinical outcome. Future prospective studies should confirm these observations and hemorrhage risks associated with extended anticoagulation regimes after complex interventions and intra-arterial vasospasm therapy should be explored in order to facilitate interdisciplinary decision-making in aSAH.

Towards biomarkers for outcomes after pancreatic ductal adenocarcinoma and ischaemic stroke, with focus on (co)-morbidity and ageing/cellular senescence (SASKit): protocol for a prospective cohort study.

INTRODUCTION: Ageing-related processes such as cellular senescence are believed to underlie the accumulation of diseases in time, causing (co)morbidity, including cancer, thromboembolism and stroke. Interfering with these processes may delay, stop or reverse morbidity. The aim of this study is to investigate the link between (co)morbidity and ageing by exploring biomarkers and molecular mechanisms of disease-triggered deterioration in patients with pancreatic ductal adenocarcinoma (PDAC) and (thromboembolic) ischaemic stroke (IS). METHODS AND ANALYSIS: We will recruit 50 patients with PDAC, 50 patients with (thromboembolic) IS and 50 controls at Rostock University Medical Center, Germany. We will gather routine blood data, clinical performance measurements and patient-reported outcomes at up to seven points in time, alongside in-depth transcriptomics and proteomics at two of the early time points. Aiming for clinically relevant biomarkers, the primary outcome is a composite of probable sarcopenia, clinical performance (described by ECOG Performance Status for patients with PDAC and the Modified Rankin Scale for patients with stroke) and quality of life. Further outcomes cover other aspects of morbidity such as cognitive decline and of comorbidity such as vascular or cancerous events. The data analysis is comprehensive in that it includes biostatistics and machine learning, both following standard role models and additional explorative approaches. Prognostic and predictive biomarkers for interventions addressing senescence may become available if the biomarkers that we find are specifically related to ageing/cellular senescence. Similarly, diagnostic biomarkers will be explored. Our findings will require validation in independent studies, and our dataset shall be useful to validate the findings of other studies. In some of the explorative analyses, we shall include insights from systems biology modelling as well as insights from preclinical animal models. We anticipate that our detailed study protocol and data analysis plan may also guide other biomarker exploration trials. ETHICS AND DISSEMINATION: The study was approved by the local ethics committee (Ethikkommission an der Medizinischen Fakultät der Universität Rostock, A2019-0174), registered at the German Clinical Trials Register (DRKS00021184), and results will be published following standard guidelines.

Ivabradine as adjuvant treatment for chronic heart failure.

BACKGROUND: Chronic heart failure is one of the most common medical conditions, affecting more than 23 million people worldwide. Despite established guideline-based, multidrug pharmacotherapy, chronic heart failure is still the cause of frequent hospitalisation, and about 50% die within five years of diagnosis. OBJECTIVES: To assess the effectiveness and safety of ivabradine in individuals with chronic heart failure. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and CPCI-S Web of Science in March 2020. We also searched ClinicalTrials.gov and the WHO ICTRP. We checked reference lists of included studies. We did not apply any time or language restrictions. SELECTION CRITERIA: We included randomised controlled trials in which adult participants diagnosed with chronic heart failure were randomly assigned to receive either ivabradine or placebo/usual care/no treatment. We distinguished between type of heart failure (heart failure with a reduced ejection fraction or heart failure with a preserved ejection fraction) as well as between duration of ivabradine treatment (short term (< 6 months) or long term (≥ 6 months)). DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, extracted data, and checked data for accuracy. We calculated risk ratios (RR) using a random-effects model. We completed a comprehensive 'Risk of bias' assessment for all studies. We contacted authors for missing data. Our primary endpoints were: mortality from cardiovascular causes; quality of life; time to first hospitalisation for heart failure during follow-up; and number of days spent in hospital due to heart failure during follow-up. Our secondary endpoints were: rate of serious adverse events; exercise capacity; and economic costs (narrative report). We assessed the certainty of the evidence applying the GRADE methodology. MAIN RESULTS: We included 19 studies (76 reports) involving a total of 19,628 participants (mean age 60.76 years, 69% male). However, few studies contributed data to meta-analyses due to inconsistency in trial design (type of heart failure) and outcome reporting and measurement. In general, risk of bias varied from low to high across the included studies, with insufficient detail provided to inform judgement in several cases. We were able to perform two meta-analyses focusing on participants with heart failure with a reduced ejection fraction (HFrEF) and long-term ivabradine treatment. There was evidence of no difference between ivabradine and placebo/usual care/no treatment for mortality from cardiovascular causes (RR 0.99, 95% confidence interval (CI) 0.88 to 1.11; 3 studies; 17,676 participants; I2 = 33%; moderate-certainty evidence). Furthermore, we found evidence of no difference in rate of serious adverse events amongst HFrEF participants randomised to receive long-term ivabradine compared with those randomised to placebo, usual care, or no treatment (RR 0.96, 95% CI 0.92 to 1.00; 2 studies; 17,399 participants; I2 = 12%; moderate-certainty evidence). We were not able to perform meta-analysis for all other outcomes, and have low confidence in the findings based on the individual studies. AUTHORS' CONCLUSIONS: We found evidence of no difference in cardiovascular mortality and serious adverse events between long-term treatment with ivabradine and placebo/usual care/no treatment in participants with heart failure with HFrEF. Nevertheless, due to indirectness (male predominance), the certainty of the available evidence is rated as moderate.

Temperature Threshold Values of Bone Necrosis for Thermo-Explantation of Dental Implants-A Systematic Review on Preclinical In Vivo Research.

PURPOSE: Very high or low temperatures will lead to bone damage. The objective of this review was to analyze threshold values for thermal bone necrosis. METHODS: Histological animal studies evaluating thermal effects on bone necrosis were selected via electronic and hand searches in English and German language journals until 1 November 2019. The outcome measures were temperature-exposure intervals and laser settings effecting bone damage. Furthermore, investigated parameters were the bone-to-implant contact ratios (BIC) and infrabony pockets around dental implants after thermal treatment. For quality assessment of studies, the CAMARADES study quality checklist was applied. RESULTS: A total of 455 animals in 25 animal studies were included for data extraction after screening of 45 titles from 957 selected titles of the MEDLINE (PubMed), The Cochrane Library, Embase and Web of Science search. The threshold values for bone necrosis ranged between 47 °C and 55 °C for 1 min. A threshold value for cryoinsult and laser treatment has not yet been defined. However, temperatures in the vicinity of 3.5 °C produce a histologically proven effect on the bone and in the surrounding tissue. At 50 °C for 1 min, BIC values significantly decreased and infrabony pockets increased. Bone quality had an influence on the outcome, as cancellous bone suffered higher bone damage from thermal treatment compared to cortical bone. CONCLUSION: No clear threshold value for bone necrosis is available according to the current literature for warm and cold stimuli. More in-depth and clinical studies are required to provide further insights in assessing the potential of thermal necrosis for implant removal.