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Jacek Calik,1 Monika Migdal,1 Tomasz Zawada,2 Torsten Bove2 1Old Town Clinic, Wrocław, Poland; 2TOOsonix A/S, Hoersholm, DenmarkCorrespondence: Torsten BoveTOOsonix A/S, Agern Alle 1, Hoersholm, DK-2970, Denmark, Tel +45- 2059 2999, Email torsten.bove@toosonix.comPurpose: High intensity focused ultrasound operating at 20 MHz has been demonstrated as a safe and efficient treatment modality for a range of dermatological indications. The method is potentially also applicable to removal of seborrheic keratosis.Patients and Methods: A total of 54 seborrheic keratoses in 11 volunteer subjects (8 women and 3 men, average age 51.5 ± 13.2 years) were treated in a single session with a medical 20 MHz high intensity focused ultrasound device developed for dermatological conditions. Handpieces with nominal focal depths of 0.8 mm below the skin surface were used to administer acoustic energy of 0.99– 1.2 J/dose. An integrated dermoscope in the handpiece was used to monitor the treatment in real-time. Treatment efficacy and side-effects were assessed directly after treatment and at follow-up 4– 15 weeks after treatment.Results: The treatment showed positive results in 96.3% of the cases. About 68.5% of the cases were classified as complete response and 27.8% of the cases as partial response. Two cases (3.7%) did not respond to treatment and were classified as stable condition. No subjects experienced worsening of their condition, and no treatment received the classification of progressive condition. Side effects were primarily redness in the treatment area due to superficial telangiectasia, mild scarring, and persisting and slow-healing lichen planus-like keratosis. No adverse events were observed.Conclusion: HIFU is concluded to be a safe and efficient skin treatment for seborrheic keratoses. It has advantages over conventional treatments that can lead to pain during treatment and scarring after healing.Keywords: seborrheic warts, solar lentigo, skin tumor, HIFU, dermoscopy, dermatology

Objectives: We tested a novel technique to treat great saphenous vein (GSV) incompetence in an animal model. Methods: V-block (VVT Medical Ltd, Kfar Saba, Israel), an occlusion device composed of a nitinol frame and anchoring hooks, was percutaneously deployed at the saphenofemoral junction in 12 sheep. Four of the 12 sheep were treated with adjunctive liquid sclerotherapy. Animals underwent duplex ultrasound, venography and histopathological evaluation immediately postimplantation at 30, 60 and 90 days. Results: V-block was successfully deployed in all animals without adverse events. There was no device migration at follow-up. Histopathological analysis demonstrated V-block to be lodged within the GSV and surrounded by fibrous tissue in all samples. Obliteration of the GSV lumen, widespread intimal loss and multifocal medial smooth muscle loss was noted. Conclusions: In this animal study V-block was deployed without complications, remained in stable position and led to GSV occlusion. This device has promise for future use in humans. [ABSTRACT FROM AUTHOR]

Materials and core components for the next generation power reactors technologies require testing that can be performed in existing research reactors. Such experiments employ devices dedicated to reflect the relevant thermal and neutron parameters simulating conditions present in, for example, but not limited to, HTGR reactors. A novel thermostatic irradiation device named ISHTAR (Irradiation System for High-Temperature Reactors) has been designed and constructed in the MARIA research reactor. Its mission is to enable irradiation of samples in controlled, homogeneous temperature field reaching 1000°C and inert gas atmosphere. The high temperature is achieved by a combination of electric and gamma heating, together with carefully designed thermal insulation. Additionally, samples holder made of graphite with high thermal conductivity enables the temperature homogenization in all directions. Device will be placed inside the Beryllium matrix of MARIA core and cooled with forced circulation of water from the reactor pool loop. This paper presents the outcome of experiments conducted with the rig prototype in external hydraulic mock-up of the MARIA reactor irradiation channel. The results have proved that the desired conditions for irradiation of the samples were achieved and their comparison against computational data has shown the adequacy of the design process. Finally, the loss of flow scenario was tested in protected and unprotected conditions (meaning with and without the safety system based on temperature feedback), proving the operational safety of the ISHTAR design. Experimental results will be used in the future to validate the numerical models (two and three dimensional) of the irradiation rig, providing an improved understanding of free convection and radiation phenomena modeling.

The article examines the optimal configuration of a single use, needle free, drug system that has powdered lidocaine into the epidermis for rapid production of local anesthesia in children with venipuncture at the antecubital fossa. Children 3-18 years of age and can identify faces representing the extremes of pain are used for the study. Results showed that giving affected children with lidocaine 2-3 minutes before venipuncture to the epidermis with the use of a rapid, needle free, drug system can safely reduce pain.

OBJECTIVES: The purpose of this study was to determine the optimal configuration of an investigational, single-use, needle-free, drug system (ALGRX 3268) that delivers powdered lidocaine into the epidermis for the rapid production of local anesthesia among pediatric subjects undergoing venipuncture. METHODS: Children 3 to 18 years of age were randomly allocated to receive 1 of 3 treatments, ie, (1) placebo, (2) a system configured to deliver 0.25 mg of lidocaine, or (3) a system configured to deliver 0.5 mg of lidocaine, at the antecubital fossa 2 to 3 minutes before venipuncture. Three age groups were included, ie, 3 to 7 years, 8 to 12 years, and 13 to 18 years. Two sets of pain rating scales were used, the Faces Pain Scale-Revised for the youngest age stratum and a visual analog scale for the oldest age stratum. Children in the middle age stratum used both scales. RESULTS: One-hundred forty-four subjects completed the study. For all ages combined, there was a statistically significant and clinically meaningful reduction in pain scores for subjects who received 0.5 mg of lidocaine, compared with placebo. The reduction in pain after 0.25 mg of lidocaine did not achieve statistical significance. CONCLUSIONS: Both active configurations were safe and well tolerated by pediatric subjects undergoing venipuncture at the antecubital fossa. ALGRX 3268 at 0.5 mg, administered 2 to 3 minutes before venipuncture, produced significantly lower pain scores, compared with placebo. [ABSTRACT FROM AUTHOR]

Most mitochondrial proteins are encoded by nuclear genes, synthetized in the cytosol and targeted into the organelle. To characterize the spatial organization of mitochondrial gene products in zebrafish ( Danio rerio ), we sequenced RNA from different cellular fractions. Our results confirmed the presence of nuclear-encoded mRNAs in the mitochondrial fraction, which in unperturbed conditions, are mainly transcripts encoding large proteins with specific properties, like transmembrane domains. To further explore the principles of mitochondrial protein compartmentalization in zebrafish, we quantified the transcriptomic changes for each subcellular fraction triggered by the chchd4a -/- mutation, causing the disorders in the mitochondrial protein import. Our results indicate that the proteostatic stress further restricts the population of transcripts on the mitochondrial surface, allowing only the largest and the most evolutionary conserved proteins to be synthetized there. We also show that many nuclear-encoded mitochondrial transcripts translated by the cytosolic ribosomes stay resistant to the global translation shutdown. Thus, vertebrates, in contrast to yeast, are not likely to use localized translation to facilitate synthesis of mitochondrial proteins under proteostatic stress conditions., (© 2022 Uszczynska-Ratajczak et al.)

Background: Myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) is a common, long-term condition characterised by post-exertional malaise, often with fatigue that is not significantly relieved by rest. ME/CFS has no confirmed diagnostic test or effective treatment and we lack knowledge of its causes. Identification of genes and cellular processes whose disruption adds to ME/CFS risk is a necessary first step towards development of effective therapy., Methods: Here we describe DecodeME, an ongoing study co-produced by people with lived experience of ME/CFS and scientists. Together we designed the study and obtained funding and are now recruiting up to 25,000 people in the UK with a clinical diagnosis of ME/CFS. Those eligible for the study are at least 16 years old, pass international study criteria, and lack any alternative diagnoses that can result in chronic fatigue. These will include 5,000 people whose ME/CFS diagnosis was a consequence of SARS-CoV-2 infection. Questionnaires are completed online or on paper. Participants' saliva DNA samples are acquired by post, which improves participation by more severely-affected individuals. Digital marketing and social media approaches resulted in 29,000 people with ME/CFS in the UK pre-registering their interest in participating. We will perform a genome-wide association study, comparing participants' genotypes with those from UK Biobank as controls. This should generate hypotheses regarding the genes, mechanisms and cell types contributing to ME/CFS disease aetiology., Discussion: The DecodeME study has been reviewed and given a favourable opinion by the North West - Liverpool Central Research Ethics Committee (21/NW/0169). Relevant documents will be available online ( www.decodeme.org.uk ). Genetic data will be disseminated as associated variants and genomic intervals, and as summary statistics. Results will be reported on the DecodeME website and via open access publications., (© 2022. The Author(s).)

The COrona VIrus Disease 2019 (COVID-19) pandemic is posing an unprecedented challenge to healthcare systems around the globe. Europe has been struggling for 1 year now, and despite some encouraging progress (above all, the beginning of vaccination), the second wave is ongoing. Even though children are less affected than adults, the COVID-19 pandemic-and in particular the measures to counter it-is having a considerable impact on the paediatric healthcare setting. It is, therefore, the duty of paediatric teams in Europe to prepare for the challenges ahead. We wish to contribute to this necessary preparedness in two ways: firstly, by assessing the direct and indirect impact of the pandemic on children and on the paediatric setting; secondly, and more importantly, by identifying the various responsibilities of paediatric healthcare professionals, in light of established ethical principles. Only abiding by these responsibilities will it be possible to ensure that ill children and their families are properly supported even in these difficult times and to grant that decisions about children's healthcare remain morally justified and lawful. What is Known: • The COVID-19 outbreak is posing an unprecedented challenge to healthcare systems around the globe • Despite the children are less affected than adults, the COVID-19 pandemic is having a huge impact also on paediatric setting What is New: • The COVID-19 pandemic lays out specific responsibilities of paediatric professionals towards our pa-tients, society and ourselves • The paediatric teams in Europe should assess the direct and indirect impact of the pandemic on the chil-dren and on the paediatric settings, ensuring consistency between centres and across regions in Europe., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Brain death/death by neurologic criteria (BD/DNC) guidelines are routinely analyzed, compared and updated in the majority of countries and are later implemented as national criteria. At the same time, extensive works have been conducted in order to unify clinical procedures and to validate and implement new technologies into a panel of ancillary tests. Recently evaluated computed tomography angiography and computed tomography perfusion (CTA/CTP) seem to be superior to traditionally used digital subtraction angiography (DSA), transcranial Doppler (TCD) and cerebral perfusion scintigraphy for diagnosis of cerebral circulatory arrest (CCA). In this narrative review, we would like to demonstrate scientific evidence supporting the implementation of CTA/CTP in Polish guidelines for BD/DNC diagnosis. Research and implementation process: In the first of our base studies concerning the potential usefulness of CTA/CTP for the confirmation of CCA during BD/DNC diagnosis procedures, we showed a sensitivity of 96.3% of CTA in a group of 82 patients. CTA was validated against DSA in this report. In the second study, CTA showed a sensitivity of 86% and CTP showed a sensitivity of 100% in a group of 50 patients. In this study, CTA and CTP were validated against clinical diagnosis of BD/DNC supported by TCD. Additionally, we propose our CCA criteria for CTP test, which are based on ascertainment of cerebral blood flow (CBF) < 10 mL/100 g/min and cerebral blood volume < 1 mL/100 g in regions of interest (ROIs) localized in all brain regions. Based on our research results, CTA/CTP methods were implemented in Polish BD/DNC criteria. To our knowledge, CTP was implemented for the first time in national guidelines., Conclusions: CTA and CTP-derived CTA might be in future the tests of choice for CCA diagnosis, proper and/or Doppler pretest might significantly increase sensitivity of CTA in CCA diagnosis procedures. Whole brain CTP might be decisive in some cases of inconclusive CTA. Implementation of CTA/CTP in the Polish BD/DNC diagnosis guidelines does not show any major obstacles. We believe that in next edition of "The World Brain Death Project" CTA and CTP will be recommended as ancillary tests of choice for CCA confirmation during BD/DNC diagnosis procedures.

Human immunogenetic variation in the form of HLA and KIR types has been shown to be strongly associated with a multitude of immune-related phenotypes. However, association studies involving immunogenetic loci most commonly involve simple analyses of classical HLA allelic diversity, resulting in limitations regarding the interpretability and reproducibility of results. We here present MiDAS, a comprehensive R package for immunogenetic data transformation and statistical analysis. MiDAS recodes input data in the form of HLA alleles and KIR types into biologically meaningful variables, allowing HLA amino acid fine mapping, analyses of HLA evolutionary divergence as well as experimentally validated HLA-KIR interactions. Further, MiDAS enables comprehensive statistical association analysis workflows with phenotypes of diverse measurement scales. MiDAS thus closes the gap between the inference of immunogenetic variation and its efficient utilization to make relevant discoveries related to immune and disease biology. It is freely available under a MIT license., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MM, WFF, and CH are employees of Roche / Genentech.

Immunogenetic variation in humans is important in research, clinical diagnosis and increasingly a target for therapeutic intervention. Two highly polymorphic loci play critical roles, namely the human leukocyte antigen (HLA) system, which is the human version of the major histocompatibility complex (MHC), and the Killer-cell immunoglobulin-like receptors (KIR) that are relevant for responses of natural killer (NK) and some subsets of T cells. Their accurate classification has typically required the use of dedicated biological specimens and a combination of in vitro and in silico efforts. Increased availability of next generation sequencing data has led to the development of ancillary computational solutions. Here, we report an evaluation of recently published algorithms to computationally infer complex immunogenetic variation in the form of HLA alleles and KIR haplotypes from whole-genome or whole-exome sequencing data. For both HLA allele and KIR gene typing, we identified tools that yielded >97% overall accuracy for four-digit HLA types, and >99% overall accuracy for KIR gene presence, suggesting the readiness of in silico solutions for use in clinical and high-throughput research settings., (© The Author(s) 2020. Published by Oxford University Press.)

Background: The immunopathology of autoimmune seronegative myasthenia gravis (SN MG) is poorly understood. Our objective was to determine immune profiles associated with a diagnosis of SN MG., Methods: We performed high-dimensional flow cytometry on blood samples from SN MG patients (N = 68), healthy controls (N = 46), and acetylcholine receptor antibody (AChR+) MG patients (N = 27). We compared 12 immune cell subsets in SN MG to controls using logistic modeling via a discovery-replication design. An exploratory analysis fit a multinomial model comparing AChR+ MG and controls to SN MG., Results: An increase in CD19 + CD20 - CD38 hi plasmablast frequencies was associated with lower odds of being a SN MG case in both the discovery and replication analyses (discovery P-value = .0003, replication P-value = .0021). Interleukin (IL) -21 producing helper T cell frequencies were associated with a diagnosis of AChR+ MG (P = .004)., Conclusions: Reduced plasmablast frequencies are strongly associated with a SN MG diagnosis and may be a useful diagnostic biomarker in the future., (© 2020 Wiley Periodicals LLC.)

Background: Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. BODY: This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research., Conclusion: Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.

Organogenesis involves dynamic regulation of gene transcription and complex multipathway interactions. Despite our knowledge of key factors regulating various steps of heart morphogenesis, considerable challenges in understanding its mechanism still exist because little is known about their downstream targets and interactive regulatory network. To better understand transcriptional regulatory mechanism driving heart development and the consequences of its disruption in vivo, we performed time-series analyses of the transcriptome and genome-wide chromatin accessibility in isolated cardiomyocytes (CMs) from wild-type zebrafish embryos at developmental stages corresponding to heart tube morphogenesis, looping, and maturation. We identified genetic regulatory modules driving crucial events of heart development that contained key cardiac TFs and are associated with open chromatin regions enriched for DNA sequence motifs belonging to the family of the corresponding TFs. Loss of function of cardiac TFs Gata5, Tbx5a, and Hand2 affected the cardiac regulatory networks and caused global changes in chromatin accessibility profile, indicating their role in heart development. Among regions with differential chromatin accessibility in mutants were highly conserved noncoding elements that represent putative enhancers driving heart development. The most prominent gene expression changes, which correlated with chromatin accessibility modifications within their proximal promoter regions, occurred between heart tube morphogenesis and looping, and were associated with metabolic shift and hematopoietic/cardiac fate switch during CM maturation. Our results revealed the dynamic regulatory landscape throughout heart development and identified interactive molecular networks driving key events of heart morphogenesis., (© 2019 Pawlak et al.; Published by Cold Spring Harbor Laboratory Press.)

Purpose: To identify the variables associated with severe action decisions (SADs) (unspecified accreditation term, warning status, probation status) by the Liaison Committee on Medical Education (LCME) regarding the accreditation status of established MD-granting medical education programs in the United States and Canada., Method: The authors reviewed all LCME decisions made on full survey reports between October 2004 and June 2012 to test whether SADs were associated with an insufficient response in the data collection instrument/self-study, chronic noncompliance with one or more accreditation standards, noncompliance with specific standards, and noncompliance with a large number of standards., Results: The LCME issued 103 nonsevere action decisions and 40 SADs. SADs were significantly associated with an insufficient response in the data collection instrument/self-study (odds ratio [OR] = 7.30; 95% confidence interval [CI] = 2.38-22.46); chronic noncompliance with one or more standards (OR = 12.18; 95% CI = 1.91-77.55); noncompliance with standards related to the educational program for the MD degree (ED): ED-8 (OR = 6.73; 95% CI = 2.32-19.47) and ED-33 (OR = 5.40; 95% CI = 1.98-14.76); and noncompliance with a large number of standards (rpb = 0.62; P < .001)., Conclusions: These findings provide insight into the LCME's pattern of decision making. Noncompliance with two standards was strongly associated with SADs: lack of evidence of comparability across instructional sites (ED-8) and the absence of strong central management of the curriculum (ED-33). These results can help medical school staff as they prepare for an LCME full survey visit.

Purpose: To determine the frequency of severe action decisions made by the Liaison Committee on Medical Education (LCME) in two time periods and to speculate about contributing factors for any change., Method: Two study periods were reviewed. Study Period 1 (1996-2000) was before a 2002 reformatting of the standards; Study Period 2 (2004-2009) was after that reformatting. The frequency of severe action decisions and patterns of noncompliance leading to those decisions in both periods were analyzed., Results: There were more severe action decisions during Study Period 2 than Study Period 1, with a notable increase in the number of recommendations for probation. Study Period 1 had substantially more noncompliance with standards within the Institutional Setting and Educational Resource categories, whereas Study Period 2 had substantially more noncompliance within the Educational Program and Medical Student categories., Conclusions: The 2002 reformatting of the standards enhanced the clarity of each standard and connected previously existing annotations to their standards. As a result of the reformatting, all documents and communications to schools were directly tied to specific standards. This has allowed the LCME to more easily identify areas of chronic noncompliance and to improve survey team training. The shift in patterns of standards out of compliance in the more recent time period is consistent with the effect of the reformatting. There may be other contributing factors for the increase in severe action decisions, but it is clear that the reformatting of standards has improved the LCME's ability to monitor medical education programs.

Background and Objectives: Non-healing ulcers represent a significant dermatological problem. Recently, conventional therapy-resistant chronic ulcers have been treated with low energy lasers or light-emitting diodes in the visible and near IR region, but only a few placebo-controlled double-blind studies have been performed to support the efficacy of this approach. The aim of the present study was to evaluate the efficacy of a broadband (400-800  nm) visible light device in the treatment of leg or foot ulcers., Methods: A placebo-controlled double-blind study using broadband light source (400-800  nm) was performed on patients with diabetic foot ulcers or patients with chronic leg ulcers. The treatment group was illuminated with 180  mW/cm(2) broadband light twice a day for 4  min/session, while patients in the placebo group received non-healing light fluency (10  mW/cm(2)) projections. The treatment group included 10 patients with a total of 19 ulcers, whereas in the placebo group, 6 patients had 6 ulcers. The follow-up period was 12 weeks., Results: At the end of the follow up, all the wounds were closed in 9 out of 10 patients (90%) from the treatment group, whereas in the placebo group only 2 out of 6 patients exhibited closed wounds (33%). The reduction in wound size in the treatment group versus the placebo group was 89% and 54%, respectively., Conclusions: In this small scale placebo-controlled double-blind study, broadband (400-800  nm) visible light was an effective modality for the treatment of leg or foot ulcers.

Unlabelled: Infants with deficiency of cytochrome c oxidase (COX) due to SCO2 mutations observed so far usually demonstrated early cardiomyopathy, encephalopathy and lactic acidosis. Milder spinal muscular atrophy-like (SMA-like) phenotype was also rarely reported. The aim is to present 18 Polish patients with SCO2 mutations. Molecular study revealed p.E140K mutation in all cases (on 32 alleles); p.Q53X mutation and novel p.M177T change were identified in single patients. In three families no second mutation was found. Thirteen p.E140K homozygotes presented in infancy with floppiness and remarkable stridor. Survival motor neuron (SMN) gene deletion was excluded. Mild to moderate lactic academia was found. Neurological involvement manifested as spasticity and psychomotor retardation. In some patients strabismus, ptosis and episodes of seizures were seen. During second half of the year chronic respiratory failure with artificial respiration dependency appeared in all homozygotes. Heart involvement was never present at the beginning. Rapidly progressive hypertrophic cardiomyopathy developed in several patients at the terminal stage. The stridor was constant and striking feature. Skeletal muscle biopsy was performed in 16 patients including 11 homozygotes. Four pathological patterns were discerned - from neurogenic muscle changes, including spinal muscular atrophy (SMA) to unspecific findings. Histochemical cytochrome c oxidase (COX) deficit was not a constant feature. Significant decrease in respiratory chain complex IV activity was detected in muscle homogenate by spectrophotometric method only in 7 out of 12 examined cases., Conclusions: 1/Mutations of SCO2 gene should be considered as a possible cause of neurogenic skeletal muscle features (including SMA-like) in infants with encephalomyopathy even in the absence of heart involvement and COX deficit; 2/Inspiratory stridor may be symptomatic of SCO2 gene mutation(s)., (Copyright 2009 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)