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.

Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice. METHODS: Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7-8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta. RESULTS: The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival. CONCLUSIONS: Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.

Determinants of the use of insecticide-treated mosquito nets in pregnant women: a mixed-methods study in Ghana.

BACKGROUND: Malaria in pregnancy remains a significant cause of morbidity and mortality, affecting the highly endemic countries of sub-Saharan Africa (SSA). Insecticide-treated nets (ITNs) are effective for malaria prevention. However, poor adherence in SSA remains a challenge. METHODS: We conducted a standard questionnaire survey among 710 pregnant women from 37 primary care clinics in the Upper West Region of Ghana from January through May 2019. Using a sequential explanatory design, we integrated the survey data from six focus group discussions with pregnant women. RESULTS: While 67% of women had some general knowledge about malaria prevention, only 19% knew the specific risks in pregnancy. Determinants of ITN use included ITN ownership (odds ratio [OR] 2.4 [95% confidence interval {CI} 1.3 to 4.4]), good maternal knowledge of the risks of malaria in pregnancy (OR 2.4 [95% CI 1.3 to 4.3]) and more antenatal care (ANC) contacts (OR 1.3 [95% CI 1.0 to 1.5)]. Focus group discussions showed that non-use of ITNs resulted from inappropriate hanging infrastructure, a preference for other malaria prevention alternatives, allergy and heat. CONCLUSIONS: Specific maternal knowledge of malaria risks in pregnancy was low and influenced the regular use of ITNs. Community and ANC-based malaria interventions should prioritize increasing knowledge of the specific risks of malaria.

[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.

Gene transfer to the vascular system: Novel translational perspectives for vascular diseases.

Although vessels are directly exposed to the bloodstream, vascular gene transfer is rarely used as a tool for preclinical studies for several reasons: (i) viral and non-viral vectors show a low transduction efficiency in the vascular system; (ii) classical vascular gene therapy approaches such as treatment of peripheral or cardiac ischemia are focusing on non-vascular target cells; and (iii) vascular diseases are rarely monogenetic, thus gene replacement approaches are uncommon. Here, we provide an overview of recent approaches in developing novel vectors and modes of application for improved transduction efficiency of large and small vessels. Increased availability of such tools for vascular gene transfer has already facilitated preclinical studies addressing a broad variety of vascular diseases like transplant vasculopathy, atherosclerosis, and hereditary aortic diseases such as Marfan syndrome.

[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.

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.

Marfan syndrome: A therapeutic challenge for long-term care.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the fibrillin-1 gene. Acute aortic dissection is the leading cause of death in patients suffering from MFS and consequence of medial degeneration and aneurysm formation. In addition to its structural function in the formation of elastic fibers, fibrillin has a major role in keeping maintaining transforming growth factor ß (TGF-ß) in an inactive form. Dysfunctional fibrillin increases TGF-ß bioavailability and concentration in the extracellular matrix, leading to activation of proinflammatory transcription factors. In turn, these events cause increased expression of matrix metalloproteinases and cytokines that control the migration and infiltration of inflammatory cells into the aorta. Moreover, TGF-ß causes accumulation of reactive oxygen species leading to further degradation of elastin fibers. All these processes result in medial elastolysis, which increases the risk of vascular complications. Although MFS is a hereditary disease, symptoms and traits are usually not noticeable at birth. During childhood or adolescence affected individuals present with severe tissue weaknesses, especially in the aorta, heart, eyes, and skeleton. Considering this, even young patients should avoid activities that exert additional stress and pressure on the aorta and the cardiovascular system. Thus, if the diagnosis is made and prophylactic treatment is initiated in a timely fashion, MFS and its preliminary pathophysiologic vascular remodeling can be successfully ameliorated reducing the risk of life-threatening complications. This commentary focuses on new research opportunities and molecular findings on MFS, discusses future challenges and possible long-term therapies.

Optical limiting properties of surface functionalized nanodiamonds probed by the Z-scan method.

This work focuses on the optical limiting behavior of surface modified nanodiamonds (DNDs) namely, amino-terminated DNDs (DND-NH2) and hydrogen-terminated DNDs (DND-H). Their relevant nonlinear optical properties for optical limiting are compared to those of unfunctionalized DNDs. The optical limitation is characterized by means of nonlinear transmittance, Z-scan, and scattered intensity assessments when submitted to a nanosecond pulsed Nd:YAG laser operating at a wavelength of 532 nm. It is stated that the largest nonlinear attenuation is attributed to the DND-H system, whereas the exceedingly low threshold values for optical limiting for the DND-H and the DND-NH2 systems is attributed to their negative electron affinity character (NEA). Using Z-scan experiments, it is shown that nonlinear refraction combined with a significant nonlinear absorption predominates in the DND-H suspension, while the pure thermal origin of the nonlinear refractive index change is conjectured in the case of the DNDs. Besides, an amazing valley to peak profile was measured on DND - NH2indicating an unexpected positive sign of the nonlinear refraction coefficient. In addition, a stronger backscattered intensity signal is highlighted for the unfunctionalized DNDs through nonlinear scattering measurements.

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.

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.

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.

Non-specific effects of childhood vaccinations - A case control study nested into a Health and Demographic Surveillance System in rural Burkina Faso.

INTRODUCTION: Previous studies in African countries have been suggestive of non-specific effects (NSE) of vaccination on child survival. Live vaccines (e.g. measles, MV) have been found to reduce child mortality while inactivated vaccines (e.g. diphtheria-tetanus-pertussis, DTP) have been associated with increased mortality; NSE were often found to be sex-specific. METHODS: A case-control study nested into the Health and Demographic Surveillance System (HDSS) cohort of the Centre de Recherche en Santé de Nouna (CRSN) was conducted in northwestern Burkina Faso. A total of 3,010 children born in 2009-11, were included in the study, 375 cases and 2635 age and village matched controls. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. The main outcome measures were the mortality odds ratios for vaccinated versus unvaccinated children by antigen. RESULTS: Most deaths occurred in late infancy, and there were significantly more deaths in males as compared to females (OR 1.29, CI 1.04-1.60). Overall, there was no statistically significant association between vaccine status and mortality. However, among children in the age group 2-8 months, there was a consistent sex-differential pattern for all doses of oral polio vaccine combined with pentavalent vaccine (OPV + Penta), with the vaccines being associated with lower mortality in boys, but not in girls. Routine MV + yellow fever vaccine was associated with reduced mortality, but only before mass vaccination campaigns with meningitis and measles vaccines took place. CONCLUSIONS: The findings of this study provide further support on the existence of NSE of childhood vaccinations in a large population of rural Burkina Faso. More randomized controlled trials are needed to confirm these observations.

Optical properties of functionalized nanodiamonds.

Detonation nanodiamonds exhibit strong nonlinear optical properties depending on their electronic properties. In the present paper, the nanodiamond functional groups are chemically modified to obtain nanodiamonds with primary amines on their surface. The optical properties of such nanodiamonds placed in water suspensions are studied and compared with the one of classical detonation nanodiamonds. Transmission, scattering and Z-scan experiments are performed for two different wavelengths (532 nm and 1064 nm). A lower threshold for optical limiting associated to more pronounce non-linear optical effects is detected at the wavelength of 1064 nm compared to the one at 532 nm. This effect may be due to a stronger nonlinear backscattering behavior at 1064 nm. Moreover, a striking result obtained from the Z-scan experiments reveals a completely different behavior of the functionalized nanodiamonds for both wavelengths. This result is discussed in regard to the electronic properties of the material and possible charge transfer.

Missed opportunities for earlier diagnosis of rifampicin-resistant tuberculosis despite access to Xpert® MTB/RIF.

OBJECTIVE: To assess the proportion of rifampicin-resistant tuberculosis (RR-TB) patients with potential earlier RR-TB diagnoses in Khayelitsha, South Africa. DESIGN: We conducted a retrospective analysis among RR-TB patients diagnosed from 2012 to 2014. Patients were considered to have missed opportunities for earlier diagnosis if 1) they were incorrectly screened according to the Western Cape diagnostic algorithm; 2) the first specimen was not tested using Xpert® MTB/RIF; 3) no specimen was ever tested; or 4) the initial Xpert test showed a negative result, but no subsequent specimen was sent for follow-up testing in human immunodeficiency virus-positive patients. RESULTS: Among 543 patients, 386 (71%) were diagnosed with Xpert and 112 (21%) had had at least one presentation at a health care facility within the 6 months before the presentation at which RR-TB was diagnosed. Overall, 95/543 (18%) patients were screened incorrectly at some point: 48 at diagnostic presentation only, 38 at previous presentation only, and 9 at both previous and diagnostic presentations. CONCLUSIONS: These data show that a significant proportion of RR-TB patients might have been diagnosed earlier, and suggest that case detection could be improved if diagnostic algorithms were followed more closely. Further training and monitoring is required to ensure the greatest benefit from universal Xpert implementation.

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.