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Purpose: In this work, the use of joint Total Generalized Variation (TGV) regularization to improve Multipool-Lorentzian fitting of chemical exchange saturation transfer (CEST) Spectra in terms of stability and parameter signal-to-noise ratio (SNR) was investigated., Theory and Methods: The joint TGV term was integrated into the nonlinear parameter fitting problem. To increase convergence and weight the gradients, preconditioning using a voxel-wise singular value decomposition was applied to the problem, which was then solved using the iteratively regularized Gauss-Newton method combined with a Primal-Dual splitting algorithm. The TGV method was evaluated on simulated numerical phantoms, 3T phantom data and 7T in vivo data with respect to systematic errors and robustness. Three reference methods were also implemented: The standard nonlinear fitting, a method using a nonlocal-means filter for denoising and the pyramid scheme, which uses downsampled images to acquire accurate start values., Results: The proposed regularized fitting method showed significantly improved robustness (compared to the reference methods). In testing, over a range of SNR values the TGV fit outperformed the other methods and showed accurate results even for large amounts of added noise. Parameter values found were closer or comparable to the ground truth. For in vivo datasets, the added regularization increased the parameter map SNR and prevented instabilities., Conclusion: The proposed fitting method using TGV regularization leads to improved results over a range of different data-sets and noise levels. Furthermore, it can be applied to all Z-spectrum data, with different amounts of pools, where the improved SNR and stability can increase diagnostic confidence., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Children and adolescents with Pompe disease (PD) face chronic and progressive myopathy requiring time-intensive enzyme replacement therapy (ERT). Little is known about their perspectives on the disease and its treatment. This study explored their perceptions of disease symptoms and functioning status, and more subjective feelings about the impacts on their lives as part of developing a disease-specific questionnaire., Methods: Eleven pediatric patients aged 8-18 years and 26 caregivers from six children's hospitals in Germany, Austria, and Switzerland underwent semi-structured interviews. Data were recorded, transcribed using MAXQDA software, and analyzed using qualitative content analysis. A system of meaningful categories was developed., Results: Sixteen main categories were derived across four major thematic areas: perceptions of symptoms and limitations, experiences to do with the biopsychosocial impact of PD, treatment experiences, and general emotional well-being/burden. Participants demonstrated broad heterogeneity in symptom perceptions such as muscle weakness, breathing difficulties, pain, and fatigue. Emotional appraisals of limitations were not directly proportional to their severity, and even comparatively minor impairments were often experienced as highly frustrating, particularly for social reasons. The main psychosocial topics were social exclusion vs. inclusion and experiences to do with having a disease. The main finding regarding treatment was that switching ERT from hospital to home was widely viewed as a huge relief, reducing the impact on daily life and the burden of infusions. Emotional well-being ranged from not burdened to very happy in most children and adolescents, including the most severely affected., Conclusion: This study provided qualitative insights into the perceptions and experiences of pediatric PD patients. Interestingly, biopsychosocial burden was not directly related to disease severity, and tailored psychosocial support could improve health-related quality of life. The present findings ensure the content validity of a novel questionnaire to be tested as a screening tool to identify patients in need of such support., (© 2024. The Author(s).)

Background: The primary therapeutic approach for severe secondary mitral regurgitation (MR) in combination with atrial fibrillation is often not clear., Objectives/methods: To create a therapeutic guideline for daily clinical practice based on a case report as well as basic literature., Results: If a functional component is suspected, restoration of sinus rhythm may lead to a significant improvement in MR. The extent of the improvement and the time required to achieve this improvement are often difficult to predict., Conclusions: The involvement of an electrophysiologist is recommended in order to assess the likelihood of successful long-term rhythm control aimed at improving MR. In unclear cases, cardioversion combined with short-term administration of antiarrhythmic medication may be useful to demonstrate potential improvement of MR in sinus rhythm., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Group A Streptococcus (GAS) necrotizing fasciitis (NF) is a difficult-to-treat bacterial infection associated with high morbidity and mortality despite extensive surgery and targeted antibiotic treatment. Difficult-to-treat infections are often characterized by the presence of bacteria surviving prolonged antibiotic exposure without displaying genetic resistance, referred to as persisters. In the present study, we investigated the presence of GAS persisters in tissue freshly debrided from patients as well as in an in vivo mouse model of NF and examined the phenomenon of antibiotic tolerance. Time-lapse imaging of GAS plated directly upon isolation from NF debrided tissue and an antibiotic challenge-based persisters assay were used to assess the presence of persisters. We show for the first time that GAS recovered directly from freshly debrided NF tissue is characterized by heterogeneous and overall delayed colony appearance time, suggesting the presence of persisters. Acidic pH or nutrient stress exposure, mimicking the NF-like environment in vitro , led to a similar phenotypic heterogeneity and resulted in enhanced survival upon antibiotic challenge, confirming the presence of GAS persisters. GAS persisters might contribute to NF treatment failure, despite extensive surgery and adequate antibiotic treatment.IMPORTANCEDifficult-to-treat and recurrent infections are a global problem burdening society and the health care system alike. Unraveling the mechanisms by which bacteria can survive antibiotic treatment without developing genetic resistance is of utmost importance to lay the foundation for new, effective therapeutic approaches. For the first time, we describe the phenomenon of antibiotic tolerance in group A Streptococcus (GAS) isolated from necrotizing fasciitis (NF) patients. Dormant, non-replicating cells (persisters) are tolerant to antibiotics and their occurrence in vivo is reported in an increasing number of bacterial species. Tailored treatment options, including the use of persisters-targeting drugs, need to be developed to specifically target dormant bacteria causing difficult-to-treat and recurrent infections., Competing Interests: The authors declare no conflict of interest.

Background: Treatment of recurring atrial flutter can be challenging due to anatomical obstacles preventing complete conduction block of linear ablation lesions. Epicardial or bipolar ablation can be used as an alternative to create deeper ablation lesions but is still limitedly used in patients with atrial flutter., Case Summary: We describe a case of a 54-year-old patient with recurring peri-mitral flutter treated with ablation of an anteroseptal line using bipolar ablation to achieve a complete conduction block., Discussion: As conventional ablation cannot always achieve, complete conduction block in linear ablation lesions alternatives may be used to create deeper lesions. In this, case bipolar ablation was used successfully for an anteroseptal line in a patient with recurring peri-mitral flutter., Competing Interests: Conflict of interest. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Evidence-informed practice is crucial to perform safe and efficient health interventions. In recent years, the evidence base of acupuncture continuously increased leading to the integration of acupuncture into clinical guidelines by various leading medical associations worldwide. At the same time, recent studies showed that licensed acupuncturists are rarely utilizing scientific research to inform their practice., Methods: This descriptive study using an online survey assessed the role of evidence-informed practice of acupuncturists in Austria, Germany, the United States of America, Australia, and New Zealand and aimed to determine critical factors relevant for promoting research literacy including demographical data, data about the clinical practice patterns, and the role and value of different information sources of traditional, complementary and integrative medicine (TCIM) practitioners., Results: In total, 404 acupuncturists completed the online survey that included questions about demographic characteristics, the role and value of research in clinical practice, and details about the amount and type of continuing professional education. Univariate and multivariate analysis was used to determine significant predictors of the outcome variable "importance of research in clinical practice" (numerical rating scale, 0 to 100). The results showed that the majority of acupuncturists use certified courses as primary source of continuing professional education and value experts' opinions as the most reliable source of information. Multivariate analysis showed that the importance of research is dependent on the interest in research, an interdisciplinary learning environment, and positive experiences with research including if an acupuncture study ever changed the clinical practice of practitioners., Conclusion: Future educational programs should therefore focus on an interactive format aiming to promote skills to critically assess the value and practical use of research studies to improve the general practice of acupuncture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Huemer, Graca, Bitsche, Hofmann, Armour and Pichler.)

Genetic disorders pose great challenges for affected individuals and their families, as they must cope with the irreversible nature of the disease and a life-long dependence on medical assistance and treatment. Children and adolescents dealing with Pompe disease (PD) often struggle to keep up with their peers in physical activities. To gain valuable insights into their subjective experiences and better understand their perception and coping related to daily challenges linked to their condition and treatment, the use of standardized questionnaires is crucial. This study introduces the novel PompeQoL 1.0 questionnaire for children and adolescents with PD, designed for comprehensive assessment of both disease-specific FDH and HRQoL through self- and proxy reports. Content validity was ensured through patients' and parents' involvement at the initial stages of development and in subsequent cognitive debriefing process. Participants found the questionnaire easy to understand, answerable, relevant, and comprehensive. Adjustments based on feedback from patients and their parents improved its utility as a patient- and observer-reported outcome measure. After careful item examination, 52 items were selected, demonstrating moderate to excellent test-retest reliability for most scales and initial evidence for satisfactory construct validity. The PompeQoL questionnaire stands as a valuable screening instrument for both clinical and research purposes. Future research should prioritize additional revisions and larger validation studies, focusing on testing the questionnaire in clinical practice and trials. Nevertheless, the PompeQoL 1.0 stands out as the first standardized measure providing insights into disease-specific FDH and HRQoL among children and adolescents with various forms of PD., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Vitamin B12 (B12) deficiency (B12D) can have detrimental effects on early growth and development. The Austrian newborn screening (NBS) program targets inborn errors of cobalamin metabolism and also detects B12D. Of 59 included neonates with B12D suspected by NBS, B12D was not further investigated in 16 (27%) retrospectively identified cases, not confirmed in 28 (48%), and confirmed in 15 (25%) cases. NBS and recall biomarkers were recorded. Age at sampling of the dried blood spots for NBS and the 1st-tier methionine/phenylalanine ratio were the strongest parameters to predict B12D (67.4% correct allocations). No differences between cases with confirmed, unconfirmed, or unknown B12D or differences to norms were observed for growth and psychomotor development (Vineland III scales, phone interviews with parents of children between months 10 and 14 of life). B12 intake was below recommendations in most mothers. NBS can detect reduced intracellular B12 activity. No advantage of NBS detection and treatment regarding infant cognitive development or growth could be proven. Since conspicuous NBS findings cannot be ignored, and to prevent exposing newborns to invasive diagnostics, assessment of maternal B12 status during pregnancy seems advisable.

The development and clinical implementation of catheter ablation of supraventricular tachycardia is one of the outstanding achievements of modern cardiovascular treatment. Over a period of less than 40 years, a curative and safe treatment strategy for almost all forms of atrial arrhythmias has been developed and implemented. German electrophysiologists and engineers have made a significant contribution to this truly outstanding success story in modern medicine. Their contributions should be appropriately acknowledged because without them, the development of ablation technology and its worldwide dissemination would not have been possible. Both the technological contributions and the medical-electrophysiological contributions were at the absolute forefront of worldwide developments and have made a significant contribution to the fact that today more than 500,000 patients with symptomatic and/or threatening cardiac arrhythmias can be successfully treated every year by use of catheter ablation. We would like to thank them all for their achievements., (© 2024. The Author(s).)

Bacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin-resistant Staphylococcus aureus is one of the deadliest pathogens and a high-priority pathogen according to the World Health Organization. Peptidoglycan hydrolases (PGHs) of phage origin have been postulated as a new class of antimicrobials for the treatment of bacterial infections, with a novel mechanism of action and no known resistances. The modular architecture of PGHs permits the creation of chimeric PGH libraries. In this study, the chimeric enzyme MEndoB was selected from a library of staphylococcal PGHs based on its rapid and sustained activity against staphylococci in human serum. The benefit of the presented screening approach was illustrated by the superiority of MEndoB in a head-to-head comparison with other PGHs intended for use against staphylococcal bacteremia. MEndoB displayed synergy with antibiotics and rapid killing in human whole blood with complete inhibition of re-growth over 24 h at low doses. Successful treatment of S. aureus -infected zebrafish larvae with MEndoB provided evidence for its in vivo effectiveness. This was further confirmed in a lethal systemic mouse infection model in which MEndoB significantly reduced S. aureus loads and tumor necrosis factor alpha levels in blood in a dose-dependent manner, which led to increased survival of the animals. Thus, the thorough lead candidate selection of MEndoB resulted in an outstanding second-generation PGH with in vitro , ex vivo, and in vivo results supporting further development.IMPORTANCEOne of the most pressing challenges of our era is the rising occurrence of bacteria that are resistant to antibiotics. Staphylococci are prominent pathogens in humans, which have developed multiple strategies to evade the effects of antibiotics. Infections caused by these bacteria have resulted in a high burden on the health care system and a significant loss of lives. In this study, we have successfully engineered lytic enzymes that exhibit an extraordinary ability to eradicate staphylococci. Our findings substantiate the importance of meticulous lead candidate selection to identify therapeutically promising peptidoglycan hydrolases with unprecedented activity. Hence, they offer a promising new avenue for treating staphylococcal infections., Competing Interests: C.R. is an employee of Micreos Pharmaceuticals AG. M.H., D.L., F.A., N.H., L.S., F.E., and M.S. are employees of Micreos GmbH. Micreos Pharmaceuticals AG and Micreos GmbH are commercial companies developing bacteriophage-based antimicrobials.

Aims: In patients with atrial flutter (AFL), ablation of the cavotricuspid isthmus (CTI) is a highly effective procedure to prevent AFL recurrence, but atrial fibrillation (AF) may occur during follow-up. The presented FLUTFIB study was designed to identify the exact incidence, duration, timely occurrence, and associated symptoms of AF after CTI ablation using continuous cardiac monitoring via implantable loop recorders., Methods and Results: One hundred patients with AFL without prior AF diagnosis were included after CTI ablation (mean age 69.7 ± 9.7 years, 18% female) and received an implantable loop recorder for AF detection. After a median follow-up of 24 months 77 patients (77%) were diagnosed with AF episodes. Median time to first AF occurrence was 180 (43-298) days. Episodes lasted longer than 1 h in most patients (45/77, 58%). Forty patients (52%) had AF-associated symptoms.Patients with and without AF development showed similar baseline characteristics and neither HATCH- nor CHA2DS2-VASc scores were predictive of future AF episodes. Oral anticoagulation (OAC) was stopped during FU in 32 patients (32%) and was re-initiated after AF detection in 15 patients (15%). No strokes or transient ischaemic attack episodes were observed during follow-up., Conclusion: This study represents the largest investigation using implantable loop recorders (ILRs) to detect AF after AFL ablation and shows a high incidence of AF episodes, most of them being asymptomatic and lasting longer than 1 h. In anticipation of trials determining the duration of AF episodes that should trigger OAC initiation, these results will help to guide anticoagulation management after CTI ablation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Many cancer patients seek adjunctive therapies to biomedical cancer treatments at some point of their disease trajectory. While acupuncture is increasingly recommended by leading oncological associations, limited evidence exists concerning the evidence-informed practice and adherence to current guidelines of traditional complementary and integrative medicine (TCIM) practitioners treating cancer patients., Methods: An international online-survey assessed the demographical data, clinical practice, and sources of information used by TCIM practitioners in Austria, Germany, United States of America, Australia, and New Zealand., Results: In total, 404 respondents completed the survey, of which 254 (62.9%) treated cancer patients. Most practitioners were acupuncturists and herbalists (57.1%), had (16.8 ± 9.9) years of clinical experience and see a median of 2 (1, 4) cancer patients per week. Breast cancer (61.8%) is the most common cancer type seen in TCIM clinics. Adjunctive TCIM treatments are frequently concurrent with the patient's cancer specific treatment (39.9%), which is also reflected by the main goal of a TCIM treatment to alleviate side effects (52.4%). However, only 28.0% of the respondents are in contact with the treating oncologist. According to the respondents, pain is most effectively treated using acupuncture, while herbal medicine is best for cancer-related fatigue. TCIM practitioners mostly use certified courses (33.1%) or online databases (28.3%) but often believe that experts are more reliable to inform their practice (37.0%) than research publications (32.7%)., Conclusion: Acupuncturists and herbalists commonly treat cancer patients. Most practitioners use TCIM as an adjunct to biomedicine as supportive care and use it largely in accordance with current oncological guidelines., Please Cite This Article as: Huemer M, Graca S, Bitsche S, Hofmann G, Armour M, Pichler M. Mapping the clinical practice of traditional, complementary and integrative medicine in oncology in Western countries: A multinational cross-sectional survey. J Integr Med. 2024; 22(1): 64-71., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Shanghai Yueyang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine. Published by Elsevier B.V. All rights reserved.)

Objectives: The MetabQoL 1.0 is the first disease-specific health related quality of life (HrQoL) questionnaire for patients with intoxication-type inherited metabolic disorders. Our aim was to assess the validity and reliability of the MetabQoL 1.0, and to investigate neuropsychiatric burden in our patient population., Methods: Data from 29 patients followed at a single center, aged between 8 and 18 years with the diagnosis of methylmalonic acidemia (MMA), propionic acidemia (PA) or isovaleric acidemia (IVA), and their parents were included. The Pediatric Quality of Life Inventory (PedsQoL) was used to evaluate the validity and reliability of MetabQoL 1.0., Results: The MetabQoL 1.0 was shown to be valid and reliable (Cronbach's alpha: 0.64-0.9). Fourteen out of the 22 patients (63.6%) formally evaluated had neurological findings. Of note, 17 out of 20 patients (85%) had a psychiatric disorder when evaluated formally by a child and adolescent psychiatrist. The median mental scores of the MetabQoL 1.0 proxy report were significantly higher than those of the self report (p = 0.023). Patients with neonatal-onset disease had higher MetabQoL 1.0 proxy physical (p = 0.008), mental (p = 0.042), total scores (p = 0.022); and self report social (p = 0.007) and total scores (p = 0.043) than those with later onset disease., Conclusions: This study continues to prove that the MetabQoL 1.0 is an effective tool to measure what matters in intoxication-type inherited metabolic disorders. Our results highlight the importance of clinical assessment complemented by patient reported outcomes which further expands the evaluation toolbox of inherited metabolic diseases., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest regarding the contents of this manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) was approved in Europe in 2006. Nevertheless, data on the long-term outcome of infantile onset Pompe disease (IOPD) patients at school age is still limited., Objective: We analyzed in detail cardiac, respiratory, motor, and cognitive function of 15 German-speaking patients aged 7 and older who started ERT at a median age of 5 months., Results: Starting dose was 20 mg/kg biweekly in 12 patients, 20 mg/kg weekly in 2, and 40 mg/kg weekly in one patient. CRIM-status was positive in 13 patients (86.7%) and negative or unknown in one patient each (6.7%). Three patients (20%) received immunomodulation. Median age at last assessment was 9.1 (7.0-19.5) years. At last follow-up 1 patient (6.7%) had mild cardiac hypertrophy, 6 (42.9%) had cardiac arrhythmias, and 7 (46.7%) required assisted ventilation. Seven patients (46.7%) achieved the ability to walk independently and 5 (33.3%) were still ambulatory at last follow-up. Six patients (40%) were able to sit without support, while the remaining 4 (26.7%) were tetraplegic. Eleven patients underwent cognitive testing (Culture Fair Intelligence Test), while 4 were unable to meet the requirements for cognitive testing. Intelligence quotients (IQs) ranged from normal (IQ 117, 102, 96, 94) in 4 patients (36.4%) to mild developmental delay (IQ 81) in one patient (9.1%) to intellectual disability (IQ 69, 63, 61, 3x <55) in 6 patients (54.5%). White matter abnormalities were present in 10 out of 12 cerebral MRIs from 7 patients., Conclusion: Substantial motor, cardiac, respiratory, and cognitive deficits are frequent in IOPD long-term survivors who started ERT before 2016. The findings of this study can be valuable as comparative data when evaluating the impact of newer treatment strategies including higher enzyme dosage, immunomodulation, modified enzymes, or early start of treatment following newborn screening.