What is the best surgical option after failure of graciloplasty in patients with recurrent rectovaginal fistula? A study of 19 consecutive patients.

BACKGROUND: Management of recurrent rectovaginal fistula (rRVF) remains challenging despite the good results of graciloplasty reported in the literature. However, little is known about how to avoid a permanent stoma if graciloplasty fails. The aim of our study was to report the management of rRVF after failure of graciloplasty. METHODS: A retrospective study was performed on consecutive patients with rRVF after failure of graciloplasty treated at our institution in January 2005-December 2021. RESULTS: There were 19 patients, with a median age at graciloplasty of 39 years (range 25-64 years). Etiologies of RVF were Crohn's disease (CD) (n = 10), postoperative (n = 5), post-obstetrical (n = 3), and unknown (n = 1). After failure of graciloplasty, 45 new procedures were performed, all of them with a covering stoma: trans-anal repairs (n = 31), delayed colo-anal anastomosis (DCAA) (n = 4), biological mesh interposition (n = 3), second graciloplasty (n = 3), stoma only (n = 2) and redo ileal pouch-anal anastomosis (IPAA) (n = 2). One patient was not re-operated on and instead treated medically for CD. After a mean follow-up of 63 ± 49 months, success (i.e., absence of stoma or RVF) was obtained in 11 patients (58%): 4/4 DCAA (100%), 5/31 after local repair (16%), 1 after stoma creation alone (50%) and 1 after redo IPAA (50%). Second graciloplasty and biologic mesh interposition all failed. All 8 patients with failed intervention had CD. CONCLUSIONS: In cases of rRVF after failed graciloplasty, reoperation is possible, although the chance of success is relatively low. The best results were obtained with DCAA. CD is a predictor of poor outcome.

[Interdisciplinary neurovascular networks: state of the art]. / Interdisziplinäre neurovaskuläre Netzwerke: eine Standortbestimmung.

BACKGROUND: In order to treat the complete spectrum of neurovascular diseases at a high level of quality, which goes beyond the purely acute treatment of stroke, the German Stroke Society (DSG) together with the German Societies for Neurosurgery and Neuroradiology developed a certification procedure for neurovascular networks (NVN). Structurally, a NVN consists of a coordinating center with at least three neurovascular network partners with a certified stroke unit. From 2018 to 2020 a total of 15 NVN have so far been audited and certified according to this new standard. OBJECTIVE: How efficient are the NVN? Are high standards maintained? MATERIAL AND METHODS: The reports of the audits were analyzed. The data were taken from the period 2017-2019. RESULTS: The 15 NVN treated a total of 86,510 stroke patients in the years examined and were networked with a total of 107 partner clinics, which were situated an average of 25 km from the coordinating center and transferred a total of 2726 patients. The coordinating centers performed 2463 thrombectomies and treated 2383 patients with nontraumatic intracerebral bleeding. In 712 patients with acute aneurysmatic subarachnoid hemorrhages endovascular treatment was carried out and clipping in 401. The audit was successful in the majority of the NVN. CONCLUSION: The certification process of NVN has been successfully established and the audits proved to be a useful instrument for quality control and improvement. The 15 NVN are highly efficient and treat more than one quarter of stroke patients in German stroke units.

[Treatment recommendations in cardio-oncology: where are we?] / Therapieempfehlungen in der Kardioonkologie ­ wo stehen wir?

This article provides an overview of current prevention and treatment options for typical cardiovascular side effects of oncological therapies as well as cardiovascular complications of malignant disease. Focus is put on the prevention and treatment of heart failure under potentially cardiotoxic cancer therapies. In addition, current options for the treatment of common venous thromboembolism in cancer patients will be discussed.

AAV-mediated cardiac gene transfer of wild-type desmin in mouse models for recessive desminopathies.

Mutations in the human desmin gene cause autosomal-dominant and recessive cardiomyopathies and myopathies with marked phenotypic variability. Here, we investigated the effects of adeno-associated virus (AAV)-mediated cardiac wild-type desmin expression in homozygous desmin knockout (DKO) and homozygous R349P desmin knockin (DKI) mice. These mice serve as disease models for two subforms of autosomal-recessive desminopathies, the former for the one with a complete lack of desmin protein and the latter for the one with solely mutant desmin protein expression in conjunction with protein aggregation pathology in striated muscle. Two-month-old mice were injected with either a single dose of 5 × 1012 AAV9-hTNT2-mDes (AAV-Des) vector genomes or NaCl as control. One week after injection, mice were subjected to a forced swimming exercise protocol for 4 weeks. Cardiac function was monitored over a period of 15 month after injection and before the mice were sacrificed for biochemical and morphological analysis. AAV-mediated cardiac expression of wild-type desmin in both the homozygous DKO and DKI backgrounds reached levels seen in wild-type mice. Notably, AAV-Des treated DKO mice showed a regular subcellular distribution of desmin as well as a normalization of functional and morphological cardiac parameters. Treated DKI mice, however, showed an aberrant subcellular localization of desmin, unchanged functional cardiac parameters, and a trend toward an increased cardiac fibrosis. In conclusion, the effect of a high-dose AAV9-based desmin gene therapy is highly beneficial for the heart in DKO animals, but not in DKI mice.

Case report - coronary vasospasm in transplanted heart: a puzzling phenomenon.

BACKGROUND: Coronary artery spasm (CAS) is an underdiagnosed disease especially in heart transplant patients, and in those patients the etiology and pathophysiology remain largely unknown, although it has been associated with cardiac allograft vasculopathy or graft rejection. CASE PRESENTATION: We report the case of a heart-transplant patient whose cardiac graft experienced two coronary vasospasms: the first before transplantation, and the other at one-month of a postoperative course complicated by primary graft failure. CONCLUSION: Our case illustrates that a transplanted heart predisposed with coronary vasospasm may suffer from early relapse in the recipient despite of complete post-surgical autonomic denervation. Exacerbated endothelial dysfunction of the donor heart after transplant, with the addition of systemic factors in the recipient may be involved in the genesis of this puzzling phenomenon.

AAV-9 mediated phosphatase-1 inhibitor-1 overexpression improves cardiac contractility in unchallenged mice but is deleterious in pressure-overload.

The downregulation of ß-adrenergic receptors (ß-AR) and decreased cAMP-dependent protein kinase activity in failing hearts results in decreased phosphorylation and inactivation of phosphatase-inhibitor-1 (I-1), a distal amplifier element of ß-adrenergic signaling, leading to increased protein phosphatase 1 activity and dephosphorylation of key phosphoproteins, including phospholamban. Downregulated and hypophosphorylated I-1 likely contributes to ß-AR desensitization; therefore its modulation is a promising approach in heart failure treatment. Aim of our study was to assess the effects of adeno-associated virus serotype 9 (AAV9) - mediated cardiac-specific expression of constitutively active inhibitor-1 (I-1c) and to investigate whether I-1c is able to attenuate the development of heart failure in mice subjected to transverse aortic constriction (TAC). 6-8 week old C57BL/6 N wild-type mice were subjected to banding of the transverse aorta (TAC). Two days later 2.8 × 1012 AAV-9 vector particles harbouring I-1c cDNA under transcriptional control of a human troponin T-promoter (AAV9/I-1c) were intravenously injected into the tail vein of these mice (n=12). AAV9 containing a Renilla luciferase reporter (AAV9/hRluc) was used as a control vector (n=12). Echocardiographic analyses were performed weekly to evaluate cardiac morphology and function. 4 weeks after TAC pressure- volume measurements were performed and animals were sacrificed for histological and molecular analyses. Both groups exhibited progressive contractile dysfunction and myocardial remodeling. Surprisingly, echocardiographic assessment and histological analyses showed significantly increased left ventricular hypertrophy in AAV9/I-1c treated mice compared to AAV9/hRluc treated controls as well as reduced contractility. Pressure-volume loops revealed significantly impaired contractility after AAV9/I-1c treatment. At the molecular level, hearts of AAV9/I-1c treated TAC mice showed a hyperphosphorylation of the SR Ca2+-ATPase inhibitor phospholamban. In contrast, expression of AAV9/I-1c in unchallenged animals resulted in selective enhancement of phospholamban phosphorylation and augmented cardiac contractility. Our data suggest that AAV9-mediated cardiac-specific overexpression of I-1c, previously associated with enhanced calcium cycling, improves cardiac contractile function in unchallenged animals but failed to protect against cardiac remodeling induced by hemodynamic stress questioning the use of I-1c as a potential strategy to treat heart failure in conditions with increased afterload.

Efficacy and safety of methylene blue in the treatment of malaria: a systematic review.

BACKGROUND: Methylene blue (MB) was the first synthetic antimalarial to be discovered and was used during the late 19th and early 20th centuries against all types of malaria. MB has been shown to be effective in inhibiting Plasmodium falciparum in culture, in the mouse model and in rhesus monkeys. MB was also shown to have a potent ex vivo activity against drug-resistant isolates of P. falciparum and P. vivax. In preclinical studies, MB acted synergistically with artemisinin derivates and demonstrated a strong effect on gametocyte reduction in P. falciparum. MB has, thus, been considered a potentially useful partner drug for artemisinin-based combination therapy (ACT), particularly when elimination is the final goal. The aim of this study was to review the scientific literature published until early 2017 to summarise existing knowledge on the efficacy and safety of MB in the treatment of malaria. METHODS: This systematic review followed PRISMA guidelines. Studies reporting on the efficacy and safety of MB were systematically searched for in relevant electronic databases according to a pre-designed search strategy. The search (without language restrictions) was limited to studies of humans published until February 2017. RESULTS: Out of 474 studies retrieved, a total of 22 articles reporting on 21 studies were eligible for analysis. The 21 included studies that reported data on 1504 malaria patients (2/3 were children). Older studies were case series and reports on MB monotherapy while recent studies were mainly controlled trials of combination regimens. MB was consistently shown to be highly effective in all endemic areas and demonstrated a strong effect on P. falciparum gametocyte reduction and synergy with ACT. MB treatment was associated with mild urogenital and gastrointestinal symptoms as well as blue coloration of urine. In G6PD-deficient African individuals, MB caused a slight but clinically non-significant haemoglobin reduction. CONCLUSIONS: More studies are needed to define the effects of MB in P. falciparum malaria in areas outside Africa and against P. vivax malaria. Adding MB to ACT could be a valuable approach for the prevention of resistance development and for transmission reduction in control and elimination programs. SYSTEMATIC REVIEW REGISTRATION: This study is registered at PROSPERO (registration number CRD42017062349 ).

Community perception regarding childhood vaccinations and its implications for effectiveness: a qualitative study in rural Burkina Faso.

BACKGROUND: Vaccination has contributed to major reductions in global morbidity and mortality, but there remain significant coverage gaps. Better knowledge on the interplay between population and health systems regarding provision of vaccination information and regarding health staff organization during the immunization sessions appears to be important for improvements of vaccination effectiveness. METHODS: The study was conducted in the Nouna Health and Demographic Surveillance System (HDSS) area, rural Burkina Faso, from March to April 2014. We employed a combination of in-depth interviews (n = 29) and focus group discussions (n = 4) including children's mothers, health workers, godmothers, community health workers and traditional healers. A thematic analysis was performed. All material was transcribed, translated and analyzed using the software ATLAS.ti4.2. RESULTS: There was better social mobilization in the rural areas as compared to the urban area. Most mothers know the Expanded Program of Immunization (EPI) target diseases, and the importance to immunize their children. However, the great majority of informants reported that mothers don't know the vaccination schedule. There is awareness that some children are incompletely vaccinated. Mentioned reasons for that were migration, mothers being busy with their work, the practice of not opening vaccine vials unless a critical number of children are present, poor interaction between women and health workers during immunization sessions, potential adverse events associated with vaccination, geographic inaccessibility during rainy season, and lack of information. CONCLUSIONS: Well organized vaccination programs are a key factor to improve child health and there is a clear need to consider community perceptions on program performance. In Burkina Faso, a number of factors have been identified which need attention by the EPI managers for further improvement of program effectiveness.

Identification of circular RNAs with host gene-independent expression in human model systems for cardiac differentiation and disease.

AIMS: Cardiovascular disease, one of the most common causes of death in western populations, is characterized by changes in RNA splicing and expression. Circular RNAs (circRNA) originate from back-splicing events, which link a downstream 5' splice site to an upstream 3' splice site. Several back-splicing junctions (BSJ) have been described in heart biopsies from human, rat and mouse hearts (Werfel et al., 2016; Jakobi et al., 2016 ). Here, we use human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) to identify circRNA and host gene dynamics in cardiac development and disease. In parallel, we explore candidate interactions of selected homologs in mouse and rat via RIP-seq experiments. METHODS AND RESULTS: Deep RNA sequencing of cardiomyocyte development and ß-adrenergic stimulation uncovered 4518 circRNAs. The set of circular RNA host genes is enriched for chromatin modifiers and GTPase activity regulators. RNA-seq and qRT-PCR data showed that circular RNA expression is highly dynamic in the hiPSC-CM model with 320 circRNAs showing significant expression changes. Intriguingly, 82 circRNAs are independently regulated to their host genes. We validated the same circRNA dynamics for circRNAs from ATXN10, CHD7, DNAJC6 and SLC8A1 in biopsy material from human dilated cardiomyopathy (DCM) and control patients. Finally, we could show that rodent homologs of circMYOD, circSLC8A1, circATXN7 and circPHF21A interact with either the ribosome or Argonaute2 protein complexes. CONCLUSION: CircRNAs are dynamically expressed in a hiPSC-CM model of cardiac development and stress response. Some circRNAs show similar, host-gene independent expression dynamics in patient samples and may interact with the ribosome and RISC complex. In summary, the hiPSC-CM model uncovered a new signature of potentially disease relevant circRNAs which may serve as novel therapeutic targets.

[Choosing wisely recommendations in angiology]. / Klug-entscheiden-Empfehlungen in der Angiologie.

BACKGROUND: The Choosing wisely initiative addresses measures of high medical impact which are frequently not appropriately performed according to expert opinion. OBJECTIVE: To increase the quality of indications by providing supportive information on diagnostic and therapeutic measures in the field of angiology. MATERIALS AND METHODS: As part of the Choosing wisely initiative, the German Society of Angiology has constructed five positive recommendations on underused measures and five negative recommendations concerning those possibly overused. The recommendations were validated by the twelve professional societies of the German Society of Internal Medicine in a consensus conference. RESULTS AND DISCUSSION: The recommendations cover a broad spectrum of diagnostic and therapeutic modalities, such as the role of ultrasound examinations in vascular diseases, screening for abdominal aortic aneurysms, diagnosis and therapy of peripheral artery disease (PAD), investigation of chronic ulcers, therapy of varicosis, and finally, the problems associated with using anticoagulants in PAD or thrombosis. By discussing the evidence, we aim to demonstrate that not all medically possible measures are actually appropriate in every situation.

AAV9-mediated gene transfer of desmin ameliorates cardiomyopathy in desmin-deficient mice.

Mutations of the human desmin (DES) gene cause autosomal dominant and recessive myopathies affecting skeletal and cardiac muscle tissue. Desmin knockout mice (DES-KO), which develop progressive myopathy and cardiomyopathy, mirror rare human recessive desminopathies in which mutations on both DES alleles lead to a complete ablation of desmin protein expression. Here, we investigated whether an adeno-associated virus-mediated gene transfer of wild-type desmin cDNA (AAV-DES) attenuates cardiomyopathy in these mice. Our approach leads to a partial reconstitution of desmin protein expression and the de novo formation of the extrasarcomeric desmin-syncoilin network in cardiomyocytes of treated animals. This finding was accompanied by reduced fibrosis and heart weights and improved systolic left-ventricular function when compared with control vector-treated DES-KO mice. Since the re-expression of desmin protein in cardiomyocytes of DES-KO mice restores the extrasarcomeric desmin-syncoilin cytoskeleton, attenuates the degree of cardiac hypertrophy and fibrosis, and improves contractile function, AAV-mediated desmin gene transfer may be a novel and promising therapeutic approach for patients with cardiomyopathy due to the complete lack of desmin protein expression.

The CHESS score: a simple tool for early prediction of shunt dependency after aneurysmal subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Acute hydrocephalus is an early and common complication of aneurysmal subarachnoid hemorrhage (SAH). However, considerably fewer patients develop chronic hydrocephalus requiring shunt placement. Our aim was to develop a risk score for early identification of patients with shunt dependency after SAH. METHODS: Two hundred and forty-two SAH individuals who were treated in our institution between January 2008 and December 2013 and survived the initial impact were retrospectively analyzed. Clinical parameters within 72 h after the ictus were correlated with shunt dependency. Independent predictors were summarized into a new risk score which was validated in a subsequent SAH cohort treated between January and December 2014. RESULTS: Seventy-five patients (31%) underwent shunt placement. Of 23 evaluated variables, only the following five showed independent associations with shunt dependency and were subsequently used to establish the Chronic Hydrocephalus Ensuing from SAH Score (CHESS, 0-8 points): Hunt and Hess grade ≥IV (1 point), location of the ruptured aneurysm in the posterior circulation (1 point), acute hydrocephalus (4 points), the presence of intraventricular hemorrhage (1 point) and early cerebral infarction on follow-up computed tomography scan (1 point). The CHESS showed strong correlation with shunt dependency (P = 0.0007) and could be successfully validated in both internal SAH cohorts tested. Patients scoring ≥6 CHESS points had significantly higher risk of shunt dependency (P < 0.0001) than other patients. CONCLUSION: The CHESS may become a valuable diagnostic tool for early estimation of shunt dependency after SAH. Further evaluation and external validation will be required in prospective studies.

[Poliomyelitis--Challenges for the Last Mile of the Eradication Programme]. / Poliomyelitis--Herausforderungen in der Endphase des globalen Eradikationsprogramms.

The World Health Organisation initiated the Global Polio Eradication Initiative in the year 1988. With the large-scale application of routine and mass vaccinations in children under the age of 5 years, polio disease has become restricted to only 3 endemic countries (Afghanistan, Pakistan and Nigeria) by today. However, since the beginning of the 21st century, increasing numbers of secondary polio epidemics have been observed which were triggered through migration, political turmoil and weak health systems. In addition, there emerged serious technical (e. g., back-mutations of oral vaccine virus to wild virus) and socio-political (refusal of vaccinations in Muslim populations of Nigeria and Pakistan) problems with the vaccination in the remaining endemic countries. It thus appears questionable if the current eradiation initiative will reach its goal in the foreseeable future.

Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno-associated viral vectors.

Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off-target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors.

Sun-induced fluorescence - a new probe of photosynthesis: First maps from the imaging spectrometer HyPlant.

Variations in photosynthesis still cause substantial uncertainties in predicting photosynthetic CO2 uptake rates and monitoring plant stress. Changes in actual photosynthesis that are not related to greenness of vegetation are difficult to measure by reflectance based optical remote sensing techniques. Several activities are underway to evaluate the sun-induced fluorescence signal on the ground and on a coarse spatial scale using space-borne imaging spectrometers. Intermediate-scale observations using airborne-based imaging spectroscopy, which are critical to bridge the existing gap between small-scale field studies and global observations, are still insufficient. Here we present the first validated maps of sun-induced fluorescence in that critical, intermediate spatial resolution, employing the novel airborne imaging spectrometer HyPlant. HyPlant has an unprecedented spectral resolution, which allows for the first time quantifying sun-induced fluorescence fluxes in physical units according to the Fraunhofer Line Depth Principle that exploits solar and atmospheric absorption bands. Maps of sun-induced fluorescence show a large spatial variability between different vegetation types, which complement classical remote sensing approaches. Different crop types largely differ in emitting fluorescence that additionally changes within the seasonal cycle and thus may be related to the seasonal activation and deactivation of the photosynthetic machinery. We argue that sun-induced fluorescence emission is related to two processes: (i) the total absorbed radiation by photosynthetically active chlorophyll; and (ii) the functional status of actual photosynthesis and vegetation stress.

[Diagnosis and treatment of diving accidents. New German guidelines for diving accidents 2014-2017]. / Diagnostik und Behandlung von Tauchunfällen: Neue "Leitlinie Tauchun2014-2017".

In 2015 the German Society for Diving and Hyperbaric Medicine (GTÜM) and the Swiss Underwater and Hyperbaric Medical Society (SUHMS) published the updated guidelines on diving accidents 2014-2017. These multidisciplinary guidelines were developed within a structured consensus process by members of the German Interdisciplinary Association for Intensive Care and Emergency Medicine (DIVI), the Sports Divers Association (VDST), the Naval Medical Institute (SchiffMedInst), the Social Accident Insurance Institution for the Building Trade (BG BAU), the Association of Hyperbaric Treatment Centers (VDD) and the Society of Occupational and Environmental Medicine (DGAUM). This consensus-based guidelines project (development grade S2k) with a representative group of developers was conducted by the Association of Scientific Medical Societies in Germany. It provides information and instructions according to up to date evidence to all divers and other lay persons for first aid recommendations to physician first responders and emergency physicians as well as paramedics and all physicians at therapeutic hyperbaric chambers for the diagnostics and treatment of diving accidents. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose and the following key action statements: on-site 100% oxygen first aid treatment, still patient positioning and fluid administration are recommended. Hyperbaric oxygen (HBO) recompression remains unchanged the established treatment in severe cases with no therapeutic alternatives. The basic treatment scheme recommended for diving accidents is hyperbaric oxygenation at 280 kPa. For quality management purposes there is a need in the future for a nationwide register of hyperbaric therapy.

[Listening effort with cochlear implants: Unilateral versus bilateral use]. / Höranstrengung bei Cochlea-Implantaten: Einseitige versus beidseitige Versorgung.

AIM: The influence of bilateral cochlear implants (CI) and unilateral CI on the self-reported listening effort in standardized situations is being assessed. SAMPLE AND METHODS: The sample consisted of 34 bilateral and 38 unilateral adult CI users. Unilateral CI users had at least severe hearing loss in the non-implanted ear and had been fitted with a hearing aid. The listening effort has been defined as a subjectively perceived effort in understanding a speaker. Patients were administered a customized questionnaire containing nine examples of listening situations with different demands. The listening effort expended in each situation had to be rated on a six-step scale. Answers were analyzed using repeated measures ANOVA, including the factors "level of background noise," "listening duration," and the covariates "patient age" and "time since CI implantation." RESULTS: Only the factors "level of background noise" and "listening duration" were significant (p = 0.024 and p = 0.001 respectively). Unilateral versus bilateral CI was not significant (p = 0.17). Nevertheless, bilateral CI users reported a lower degree of listening effort than unilateral users in all of the nine situations asked about in the questionnaire (binomial test: p = 0.002). DISCUSSION: We conclude that bilateral CI use has some effect on reducing listening effort, but compared with unilateral use the effect is possibly not very great.