Three-dimensional acetabular reorientation during periacetabular osteotomy: an intraoperative navigation method using an external fixator for periacetabular osteotomy.

INTRODUCTION: Bernese periacetabular osteotomy (PAO) is an effective procedure for treating acetabular dysplasia. However, limited visual control of the acetabular position during surgery may result in under- or overcorrection or changes in acetabular version resulting in residual dysplasia or femoroacetabular impingement. Thus, we wanted to develop a simple and straightforward navigation method that provides information about acetabular correction in all three planes during surgery. METHOD: Intraoperatively, acetabular coordinates are shown in coronal, sagittal, and transverse plane by two perpendicular tubes of an external fixator mounted onto a third tube that is fixed to the mobilized acetabular fragment with two Schanz screws. The application and fixation of the external fixator on the pelvis are demonstrated in this article. We used this analog navigation method on 27 PAOs, where we mainly performed a lateral rotational correction. The pre- and postoperative radiographs of these 27 hips were analyzed regarding the radiological hip parameters, taking into account the pelvic tilt. RESULTS: The mean preoperative lateral center edge angle (LCEA) of the 27 PAOs improved from 16° (+-6) to a mean of 34° (+-6°) and the mean acetabular index (AI) was corrected from 15° (+-4) to 2° (+-4). This implements highly physiologic postoperative values for lateral coverage in this population. In this case series, no postoperative acetabular retroversion was measured in any of the 27 PAOs. CONCLUSION: Three-dimensional control of the acetabular orientation during periacetabular osteotomy is important to avoid over- and undercorrection. Using a fixateur externe as an analog navigation method this three-dimensional control can be implemented intraoperatively for PAOs.

Implantation of CRT pacemaker during pregnancy: estimated fetal radiation dose.

The benefits of a cardiac resynchronization therapy (CRT) implantation are known in severe heart failure and its implantation may also be considered during pregnancy to ensure safe pregnancy and delivery for both the mother and the fetus. This study on a patient case aimed to estimate the absorbed dose (AD) to the fetus during the CRT implantation of 21st week of the pregnant woman. AD measurement was done using anthropomorphic phantom, radiophotoluminescence dosemeters and Monte Carlo simulation utilizing kerma area product (KAP) of the procedures. The measured AD for a phantom's uterus and heart was 0.116 and 14.7 mGy with total KAP of 27.9 Gycm2. The estimated actual AD to the fetus and the mother's heart was 0.004 and 1.2 mGy, with total KAP of 1.5 Gycm2. The dose to the fetus can be minimized with the optimized procedure.

Temperature dependence of the mutation rate towards antibiotic resistance.

Objectives: Environmental conditions can influence mutation rates in bacteria. Fever is a common response to infection that alters the growth conditions of infecting bacteria. Here we examine how a temperature change, such as is associated with fever, affects the mutation rate towards antibiotic resistance. Methods: We used a fluctuation test to assess the mutation rate towards antibiotic resistance in Escherichia coli at two different temperatures: 37°C (normal temperature) and 40°C (fever temperature). We performed this measurement for three different antibiotics with different modes of action: ciprofloxacin, rifampicin and ampicillin. Results: In all cases, the mutation rate towards antibiotic resistance turned out to be temperature dependent, but in different ways. Fever temperatures led to a reduced mutation rate towards ampicillin resistance and an elevated mutation rate towards ciprofloxacin and rifampicin resistance. Conclusions: This study shows that the mutation rate towards antibiotic resistance is impacted by a small change in temperature, such as associated with fever. This opens a new avenue to mitigate the emergence of antibiotic resistance by coordinating the choice of an antibiotic with the decision of whether or not to suppress fever when treating a patient. Hence, optimized combinations of antibiotics and fever suppression strategies may be a new weapon in the battle against antibiotic resistance.

Antibiotic Use in Communities.

Since their discovery and clinical introduction in the 1930s-1940s, penicillin and sulphonamides have had a profound impact on public health [...].

An Implantable Magnetic Drive Mechanism for Non-Invasive Arteriovenous Conduit Blood Flow Control.

OBJECTIVE: Hemodialysis patients usually receive an arteriovenous fistula (AVF) in the arm as vascular access conduit to allow dialysis 2-3 times a week. This AVF introduces the high flow necessary for dialysis, but over time the ever-present supraphysiological flow is the leading cause of complications. This study aims to develop an implantable device able to non-invasively remove the high flow outside dialysis sessions. METHODS: The developed prototype features a magnetic ring allowing external coupling and torque transmission to non-invasively control an AVF valve. Mock-up devices were implanted into arm and sheep cadavers to test sizes and locations. The transmission torque, output force, and valve closure are measured for different representative skin thicknesses. RESULTS: The prototype was placed successfully into arm and sheep cadavers. In the prototype, a maximum output force of 78.9 ± 4.2 N, 46.7 ± 1.9 N, 25.6 ± 0.7 N, 13.5 ± 0.6 N and 6.3 ± 0.4 N could be achieved non-invasively through skin thicknesses of 1-5 mm respectively. The fistula was fully collapsible in every measurement through skin thickness up to the required 4 mm. CONCLUSION: The prototype satisfies the design requirements. It is fully implantable and allows closure and control of an AVF through non-invasive torque transmission. In vivo studies are pivotal in assessing functionality and understanding systemic effects. SIGNIFICANCE: A method is introduced to transfer large amounts of energy to a medical implant for actuation of a mechanical valve trough a closed surface. This system allows non-invasive control of an AVF to reduce complications related to the permanent high flow in conventional AVFs.

Analytical validation and diagnostic performance of the ASCL1/ZNF582 methylation test for detection of high-grade anal intraepithelial neoplasia and anal cancer.

DNA methylation testing on biopsies can detect high-grade anal intraepithelial neoplasia (HGAIN) in need of treatment and anal cancer. This study aimed to analytically validate and determine the diagnostic performance of a newly developed multiplex quantitative methylation-specific PCR, PreCursor-M AnoGYN (RUO), combining ASCL1, ZNF582 and a reference (ACTB) in one assay. Analytical validation was performed on two qPCR devices using predefined quality criteria. Diagnostic performance was determined on a cross-sectional series of 111 anal biopsies covering all stages of anal disease. Differences in methylation levels were assessed using the Kruskal-Wallis test. Area under the curve was determined using logistic regression analysis. Detection rates were calculated at predefined specificities for the cross-sectional and an additional longitudinal series of 23 HGAIN biopsies preceding anal cancer (i.e., progressive HGAIN). For both devices analytical quality criteria were met. ASCL1 and ZNF582 methylation levels increased with increasing severity of disease (p < 6*10-8). Diagnostic performance for AIN3+ was 0.81. All cancers and virtually all progressive HGAIN were detected at 70% and 80% specificity. In conclusion, the ASCL1/ZNF582 methylation test (PreCursor-M AnoGYN (RUO)) was demonstrated to be highly robust and reproducible. Moreover, it had excellent diagnostic accuracy to detect AIN3+ and can potentially be used to guide HGAIN management.

Antibiotics Knowledge, Attitudes and Behaviours among the Population Living in Greece and Turkey.

Antimicrobial resistance is one of the largest threats to public health worldwide. As the inappropriate use of antibiotics is one of the leading causes of antibiotic resistance, it is important to have an understanding of the public's knowledge, attitudes and behaviours towards antibiotics and antimicrobial resistance. The present study investigated the knowledge, attitudes and behaviours towards antibiotics among the public living in Greece and Turkey using an online cross-sectional survey, with social media advertising (e.g., Facebook) and snowball sampling. In total, 709 individuals completed the survey (Greece n = 309, Turkey n = 400), with an average age of 34.2 (SD = 13.1) and 40.5 (SD = 14.7), respectively. In Greece, 49.4% of the participants were female, and in Turkey, this figure was 62.4%. The Greek respondents reported that obtaining antibiotics without a prescription was easier (52.6% reported "easy or very easy") than the Turkish (35.6% reported "easy or very easy") respondents did. This study reveals that Greek citizens were more educated and knowledgeable about antibiotics (58.5% of Greeks and 44.2% of Turks identified antibiotics correctly), their effects (20.9% of Greeks and 26.3% of Turks agreed with wrong statements about antibiotics) and the risks of antibiotic resistance, compared to those from Turkey. On the other hand, the Greek respondents were more prone to use leftover antibiotics or to give them to someone else later (p < 0.001). The findings of this study indicate that Greece and Turkey, both countries with high rates of antibiotic usage, exhibit distinct variations in their knowledge, attitudes, and perceptions concerning antibiotic use and antibiotic resistance. Effective countermeasures such as public campaigns should be targeted according to the population and those areas of knowledge, attitudes and behaviours in which the main shortcomings lie.

Antibiotics Knowledge, Attitudes and Behaviours among the Population Living in Cyprus.

This study investigated the knowledge, attitudes and behaviours towards antibiotics among the general public living in the Republic of Cyprus (RoC) and the Turkish Republic of Northern Cyprus (TRNC) by using an online questionnaire. Differences were examined using independent samples t-tests, chi-square tests, Mann-Whitney U tests and Spearman's rho. In total, 519 individuals completed the survey (RoC = 267, TRNC = 252), with an average age of 32.7, and 52.2% were female. Most citizens correctly identified paracetamol (TRNC = 93.7%, RoC = 53.9%) and ibuprofen (TRNC = 70.2%, RoC = 47.6%) as non-antibiotic medications. A substantial proportion thought antibiotics could treat viral infections, such as a cold (TRNC = 16.3%, RoC = 40.8%) or the flu (TRNC = 21.4%, RoC = 50.4%). Most participants understood that bacteria can become resistant to antibiotics (TRNC = 71.4%, RoC = 64.4%), that unnecessary use can lead to drug ineffectiveness (TRNC = 86.1%, RoC = 72.3%) and that they should always complete the course of antibiotics (TRNC = 85.7%, RoC = 64.0%). Positive attitudes towards antibiotics correlated negatively with knowledge in both samples, indicating that the more people know, the less positive their attitudes towards their use. The RoC appears to have tighter controls of over-the-counter (OTC) sales of antibiotics than TRNC. This study reveals that different communities can have varying levels of knowledge, attitudes and perceptions about antibiotic use. Tighter enforcement of the OTC regulations, educational efforts and media campaigns are needed for enhancing prudent antibiotic use on the island.

Timing and frequency of oropharyngeal squamous cell carcinoma recurrences after treatment with curative intent.

BACKGROUND: The increasing number of patients under surveillance after treatment of human papillomavirus-related oropharyngeal squamous cell carcinoma (OPSCC) places a great burden on healthcare providers. AIMS/OBJECTIVES: The aim of this study was to explore OPSCC recurrences in a long follow-up period: their site, frequency and timepoint after primary treatment, treatment and outcome. The secondary aim was to investigate if the recurrences are diagnosed on routine follow-up visits, and if the p16 status will have an effect on the pattern of recurrences. MATERIAL AND METHODS: We analyzed recurrences within a 10-year follow-up period after completed curatively intended treatment among OPSCC patients in Finland treated between 2000 and 2009. Patient-, tumor-, treatment- and follow-up -related parameters were investigated. RESULTS: Out of 495 patients with no residual tumor during the first six months, 71 (14%) were diagnosed with a recurrence, of which 47 were locoregional and 28 were treated with curative intent. Of the recurrences, 86% were diagnosed during the first 36 months after primary treatment. Only ten recurrences appeared after 36 months. The median OS after recurrence was 10.9 months. CONCLUSIONS AND SIGNIFICANCE: Routine follow-up longer than three years after treatment seems not to be effective in terms of detecting OPSCC recurrences.

Strong temporal variation of consumer δ13C value in an oligotrophic reservoir is related to water level fluctuation.

Using stable carbon and nitrogen isotope analysis (δ13C and δ15N) to assess trophic interactions in freshwater ecosystems is a well established method, providing insight into ecosystem functioning. However, the spatial and temporal variability of isotope values, driven by environmental fluctuation is poorly understood and can complicate interpretations. We investigated how the temporal variation of stable isotopes in consumers (fish, crayfish and macrozoobenthos) of a canyon-shaped oligotrophic reservoir is associated with environmental factors such as water temperature, transparency, flooded area, and water quality measures. Consumers and their putative food sources were sampled and analyzed for carbon and nitrogen stable isotopes annually, and environmental parameters were measured monthly from 2014 to 2016. Results revealed significant differences in δ13C and δ15N values in each consumer among studied years. Over the years, fish and crayfish expressed differences in δ13C between 3 and 5‰, whereas in zoobenthos differences were 12‰. Variability in δ15N was similar across all consumers (2-4‰). Moreover, results suggest that the flooded area of the reservoir was a major driver of δ13C stable isotope values variation in consumers, while variation in δ15N was not linked to any of the studied environmental factors. Bayesian mixing models further showed significant changes in the origin of detritivorous zoobenthos carbon sources (reversal shift from terrestrial detritus to algae origin) between years with low water level to years with the standard water level. Other species showed only slight differences in food source utilization among years. Our study highlights the importance of environmental factors as sources of variation in consumer's stable isotope values which should be considered especially when studied ecosystem strongly fluctuate in some environmental factor.

Leadership's long arm: The positive influence of digital leadership on managing technology-driven change over a strengthened service innovation capacity.

Introduction: In this qualitative study, we examine digital leadership (DL) capabilities and their positive influence on the management of technology-driven change by leveraging service innovations. The context of digital transformation (DT) has triggered a new leadership paradigm, among others referred to as digital leadership (DL). However, despite its practical relevance, leadership research has yet paid little attention to conceptualise DL as an approach to digitally transform organisations. Methods: Drawing on mid- and top-level mangers' experiences with service innovation projects, and based on Grounded Theory, we develop a taxonomy of DL-related capabilities and a conceptual framework which exemplifies their influences on dynamic service innovation capabilities (DSICs). DSICs build on the dynamic capabilities view (DCV) and represent the "organisational muscle" to repeatedly deliver service innovations indicating an effective management of technology-driven change. Results and Discussion: Taxonomy results show that aggregated dimensions in terms of a digital leader's personal, social, and organisational capital serve as underpinnings (DL-related capabilities) to drive strategic change in DT contexts. The conceptual framework further reveals that especially the personal and organisational capital of a digital leader owns several strong and moderate influences on DSICs which demonstrates DL's "long arm" on the management of technology-driven change. Our findings contribute to leadership research by advancing the conceptualisation of DL and by adding a novel micro-foundational perspective towards the DCV discourse. As organisations struggle to realise the full benefits of DT initiatives, our results also provide a valuable contribution for practitioners by supporting them to strategically prepare for the human-related challenges of DT.

Question-based development of high-risk medical devices: A proposal for a structured design and review process.

INTRODUCTION: The recent introduction of the European Medical Device Regulation poses stricter legislation for manufacturers developing medical devices in the EU. Many devices have been placed into a higher risk category, thus requiring more data before market approval, and a much larger focus has been placed on safety. For implantable and Class III devices, the highest risk class, clinical evidence is a necessity. However, the requirements of clinical study design and developmental outcomes are only described in general terms due to the diversity of devices. METHODS: A structured approach to determining the requirements for the clinical development of high-risk medical devices is introduced, utilizing the question-based development framework, which is already used for pharmaceutical drug development. An example of a novel implantable device for haemodialysis demonstrates how to set up a relevant target product profile defining the device requirements and criteria. The framework can be used in the medical device design phase to define specific questions to be answered during the ensuing clinical development, based upon five general questions, specified by the question-based framework. RESULTS: The result is a clear and evaluable overview of requirements and methodologies to verify and track these requirements in the clinical development phase. Development organizations will be guided to the optimal route, also to abandon projects destined for failure early on to minimize development risks. CONCLUSION: The framework could facilitate communication with funding agencies, regulators and clinicians, while highlighting remaining 'known unknowns' that require answering in the post-market phase after sufficient benefit is established relative to the risks.

A computationally efficient method for approximating reliabilities in large-scale single-step genomic prediction.

BACKGROUND: In this study, computationally efficient methods to approximate the reliabilities of genomic estimated breeding values (GEBV) in a single-step genomic prediction model including a residual polygenic (RPG) effect are described. In order to calculate the reliabilities of the genotyped animals, a single nucleotide polymorphism best linear unbiased prediction (SNPBLUP) or a genomic BLUP (GBLUP), was used, where two alternatives to account for the RPG effect were tested. In the direct approach, the genomic model included the RPG effect, while in the blended method, it did not but an index was used to weight the genomic and pedigree-based BLUP (PBLUP) reliabilities. In order to calculate the single-step GBLUP reliabilities for the breeding values for the non-genotyped animals, a simplified weighted-PBLUP model that included a general mean and additive genetic effects with weights accounting for the non-genomic and genomic information was used. We compared five schemes for the weights. Two datasets, i.e., a small (Data 1) one and a large (Data 2) one were used. RESULTS: For the genotyped animals in Data 1, correlations between approximate reliabilities using the blended method and exact reliabilities ranged from 0.993 to 0.996 across three lactations. The slopes observed by regressing the reliabilities of GEBV from the exact method on those from the blended method were 1.0 for all three lactations. For Data 2, the correlations and slopes ranged, respectively, from 0.980 to 0.986 and from 0.91 to 0.96, and for the non-genotyped animals in Data 1, they ranged, respectively, from 0.987 to 0.994 and from 0.987 to 1, which indicate that the approximations were in line with the exact results. The best approach achieved correlations of 0.992 to 0.994 across lactations. CONCLUSIONS: Our results demonstrate that the approximated reliabilities calculated using our proposed approach are in good agreement with the exact reliabilities. The blended method for the genotyped animals is computationally more feasible than the direct method when RPG effects are included, particularly for large-scale datasets. The approach can serve as an effective strategy to estimate the reliabilities of GEBV in large-scale single-step genomic predictions.

Recurrent febrile seizures and serum cytokines: a controlled follow-up study.

BACKGROUND: The role of cytokines in the pathogenesis of febrile seizures (FSs) is unclear, and information regarding cytokine production outside of FS episodes is scarce. METHODS: In our controlled follow-up study of patients with FSs, we compared the levels of 12 serum cytokines after the patients' first FSs, during febrile episodes without FSs, after recurrent FSs, during healthy periods after FSs, and between patients and controls. RESULTS: Two-hundred fifty-one patients with first FS participated in the study, of whom 17 (mean age 1.6 years, SD 0.7) with recurrent FSs completed the protocol as required by the sample size calculations. The mean IL-1RA level was higher after the first FSs (2580 pg/mL, SD 1516) than during febrile episodes without FSs (1336 pg/mL, SD 1364, P = 0.006) and healthy periods after FSs (474 pg/mL, SD 901, P = 0.001). IL-1RA levels were also higher during first (2580 pg/mL) and recurrent FSs (2666 pg/mL, SD 1747) in comparison with febrile controls (746 pg/mL, SD 551) (P < 0.001 and P = 0.001, respectively), but there was no difference in the IL-1RA between febrile episodes without FSs and febrile controls. CONCLUSIONS: Patients with FSs produce stronger inflammatory reactions during febrile episodes with FSs compared with febrile episodes without FSs and febrile controls. IMPACT: In patients with FSs, IL-1RA was higher following first FS than during febrile episodes without FSs and healthy periods after FSs. IL-1RA was higher in patients with FSs following first and recurrent FSs than in febrile controls. There was no significant difference in IL-1RA between febrile episodes of patients without FSs and febrile controls. Using IL-1RA as a surrogate marker of IL-1 axis activity, our results indicate that patients with FSs produced stronger inflammatory reactions during FS episodes but not during other febrile episodes or healthy periods after FSs. Cytokines may play a role in pathogenesis of FSs.

Microbiome Heritability and Its Role in Adaptation of Hosts to Novel Resources.

Microbiomes are involved in most vital processes, such as immune response, detoxification, and digestion and are thereby elementary to organismal functioning and ultimately the host's fitness. In turn, the microbiome may be influenced by the host and by the host's environment. To understand microbiome dynamics during the process of adaptation to new resources, we performed an evolutionary experiment with the two-spotted spider mite, Tetranychus urticae. We generated genetically depleted strains of the two-spotted spider mite and reared them on their ancestral host plant and two novel host plants for approximately 12 generations. The use of genetically depleted strains reduced the magnitude of genetic adaptation of the spider mite host to the new resource and, hence, allowed for better detection of signals of adaptation via the microbiome. During the course of adaptation, we tested spider mite performance (number of eggs laid and longevity) and characterized the bacterial component of its microbiome (16S rRNA gene sequencing) to determine: (1) whether the bacterial communities were shaped by mite ancestry or plant environment and (2) whether the spider mites' performance and microbiome composition were related. We found that spider mite performance on the novel host plants was clearly correlated with microbiome composition. Because our results show that only little of the total variation in the microbiome can be explained by the properties of the host (spider mite) and the environment (plant species) we studied, we argue that the bacterial community within hosts could be valuable for understanding a species' performance on multiple resources.

Apparent anomalous diffusion and non-Gaussian distributions in a simple mobile-immobile transport model with Poissonian switching.

We analyse mobile-immobile transport of particles that switch between the mobile and immobile phases with finite rates. Despite this seemingly simple assumption of Poissonian switching, we unveil a rich transport dynamics including significant transient anomalous diffusion and non-Gaussian displacement distributions. Our discussion is based on experimental parameters for tau proteins in neuronal cells, but the results obtained here are expected to be of relevance for a broad class of processes in complex systems. Specifically, we obtain that, when the mean binding time is significantly longer than the mean mobile time, transient anomalous diffusion is observed at short and intermediate time scales, with a strong dependence on the fraction of initially mobile and immobile particles. We unveil a Laplace distribution of particle displacements at relevant intermediate time scales. For any initial fraction of mobile particles, the respective mean squared displacement (MSD) displays a plateau. Moreover, we demonstrate a short-time cubic time dependence of the MSD for immobile tracers when initially all particles are immobile.

DNA methylation regulates TIGIT expression within the melanoma microenvironment, is prognostic for overall survival, and predicts progression-free survival in patients treated with anti-PD-1 immunotherapy.

BACKGROUND: TIGIT is an immune checkpoint under investigation as therapeutic target. Understanding the regulation of TIGIT on an epigenetic level might support the development of companion biomarkers. METHODS: We correlated TIGIT DNA methylation of single CpG sites with gene expression, signatures of immune infiltrates and interferon-γ, and survival in melanoma. We further analyzed methylation levels in immune cell subsets, melanocyte and melanoma cell lines. TIGIT expression patterns within components of the melanoma microenvironment were analyzed by single cell sequencing. We used quantitative methylation-specific PCR, flow cytometry, and immunohistochemistry for correlations between expression and methylation and to assess the effect of pharmacological demethylation of melanoma cells treated with 5-aza-2-deoxycytidine (decitabine). Finally, we investigated the association of patients' survival with TIGIT mRNA and methylation. RESULTS: Depending on the sequence context of the analyzed CpG site, we found a cell type-specific TIGIT gene locus methylation pattern and significant correlations of TIGIT methylation with mRNA expression, an interferon γ signature, and distinct immune cell infiltrates, including TIGIT+ lymphocytes. We detected a melanoma cell-intrinsic TIGIT protein expression. Pharmacological demethylation of the A375 melanoma cell line led to a constitutive TIGIT expression. Low promoter flank methylation and high mRNA expression was associated with patients' prognosis and predicted progression-free survival in patients treated with anti-PD-1 immunotherapy. A high TIGIT+ lymphocyte score was associated with better progression-free survival under anti-PD-1 immunotherapy. CONCLUSIONS: Our data demonstrate an epigenetic regulation of TIGIT expression via DNA methylation within the melanoma microenvironment. TIGIT DNA methylation and expression may serve as predictive biomarkers in the context of immunotherapies in melanoma.

Erratum: Rate equations, spatial moments, and concentration profiles for mobile-immobile models with power-law and mixed waiting time distributions [Phys. Rev. E 105, 014105 (2022)].

This corrects the article DOI: 10.1103/PhysRevE.105.014105.